Understanding risks is considered to be crucial for informed decision-making. Inaccurate risk perception is a common finding in women with a family history of breast cancer attending genetic counseling. As yet, it is unclear how risks should best be communicated in clinical practice. This study protocol describes the design and methods of the BRISC (Breast cancer RISk Communication) study evaluating the effect of different formats of risk communication on the counsellee's risk perception, psychological well-being and decision-making regarding preventive options for breast cancer.The BRISC study is designed as a pre-post-test controlled group intervention trial with repeated measurements using questionnaires. The intervention-an additional risk consultation-consists of one of 5 conditions that differ in the way counsellee's breast cancer risk is communicated: 1) lifetime risk in numerical format , 2) lifetime risk in both numerical format and graphical format (population figures), The BRISC study allows for an evaluation of the effects of different formats of communicating breast cancer risks to counsellees. The results can be used to optimize risk communication in order to improve informed decision-making among women with a family history of breast cancer. They may also be useful for risk communication in other health-related services.Current Controlled Trials ISRCTN14566836. BRCA1 and BRCA2 have been identified as most important [BRCA1/2 mutations account for only a small subgroup of women with a family history of breast cancer. A substantial group of women attending genetic counselling because of their family history have a slightly (11–20%) or moderately (20–30%) increased risk of getting breast cancer. Genetic counselling generally takes place at specialised centres and focuses on the communication of personalised risk information. The aim is to have a well-informed counsellee, who understands both risks and consequences, and acts accordingly [Risk communication aims to improve people's understanding of health risks in order to contribute to informed decision-making. Of particular interest and complexity are risks regarding hereditary or familial cancer, such as breast/ovarian or colon cancer . It is cmportant  to a rismportant ,5. Howevordingly .BRCA1/2 mutations, introduces complexity into risk communication regarding hereditary and familial breast cancer. Based on these complex risk contexts, decisions have to be made such as whether and when to start mammography screening, and, assuming eligibility, whether to test for mutations in BRCA1/2, and subsequent decisions in the case of positive or negative genetic test-outcome. Understanding risks is considered to be crucial for informed decision-making [The multiple risks and uncertainty of the risks, e.g. because of the incomplete penetrance of n-making , whereasn-making . Overestn-making . Previoun-making ). In genn-making , and sign-making ,12, but n-making , or for Risk communication in genetic counselling is difficult, not only due to the complexity of the risks involved, but also due to problems that counsellors themselves experience in conveying these risks in an understandable way . In addiRegarding the risk communication process, research has shown that the context and format in which genetic risks are presented affect people's risk perception, and their subsequent decisions ,18. AlthFurthermore, the time horizon in which risks are presented is relevant. Time horizons may raise confusion, especially for long-term cumulative risks such as lifetime breast cancer risks . Short-tSeveral dimensions or outcomes in evaluating the effectiveness of the risk communication process have been distinguished ,32,33. ACurrently, protocols in genetic counselling for breast cancer contain no guidelines for the optimal format of risk communication. Therefore, counsellors present risks in ways that seem right to them despite a lack of evidence to support this . ObservaIn the Netherlands, current information booklets on hereditary breast cancer to support genetic counselling generally present risks, e.g. chance of developing breast cancer, as absolute percentages with a long-term time horizon ('lifetime risk'). In genetic counselling, generally the same formats are used, although one study recently revealed that a time horizon is not often stated in breast cancer counselling . In addiThe main objective of the present study is to evaluate the effects of different formats of risk communication on the counsellee's understanding and perception of the risk (cognitive outcomes), psychological well-being, and decision-making. In particular, we aim to investigate numerical versus graphical risk formats and lifetime breast cancer risks versus age-related risks. The research questions are:1) What is the effect of the addition of a graphical format to standard risk information on cognitive outcomes, psychological well-being, and decision-making?2) What is the effect of the addition of an age-related format to standard risk information on cognitive outcomes, psychological well-being, and decision-making?3) What is the effect of the combination of both the addition of a graphical format and the addition of an age-related format on outcomes compared to research questions 1 and 2 (i.e. effect modification/interaction)?4) How do the counsellee's personal experiences and characteristics mediate the effect on the communication of risk?This article describes and discusses both the design and the content of the intervention of the BRISC (Breast cancer RISk Communication) study, a multicentre controlled clinical trial, to optimise the communication of breast cancer risks in genetic counselling among women with a family history of breast cancer.The BRISC study is designed as a pre-post-test controlled group intervention trial with repeated measures using questionnaires. The trial is carried out in three of the nine familial cancer clinics in the Netherlands. The Medical Ethics Committees of the VU University Medical Center Amsterdam, the University Medical Center Groningen, and the Leiden University Medical Center approved the protocol in 2005.The intervention consists of one additional consultation by a trained "risk counsellor" immediately after a standard genetic counselling session with a clinical geneticist, a clinical geneticist in training, or non-medical genetic counsellor, henceforth defined as a "genetic counsellor" Figure . Since gDuring the additional consultation, risks are communicated in one of five ways (conditions), namely:1) lifetime breast cancer risk in numerical format ,2) lifetime breast cancer risk in both numerical format and graphical format (i.e. population figures in 10 rows of 10),3) lifetime breast cancer risk and age-related breast cancer risk in numerical format,4) lifetime breast cancer risk and age-related breast cancer risk in both numerical format and graphical format, and5) lifetime breast cancer risk in percentages.Since the information given during the intervention not only differs from usual care regarding the format of the risks but also to the extent to which the information is structured, two control conditions are included. Condition 5, in which the risk is communicated in percentages as in the standard genetic counselling session , controls for the effect of giving risk information also in a structured way, enabling us to compare the effects of different risk formats. Condition 6, in which no intervention is given  is used to control for the effect of repetition of the risk information (as compared to condition 5), and will control for Hawthorne effects .BRCA1/2 mutation (carriers), and risk for women with the same family history as the counsellee. An example of risk information given in condition 1 is: "On average, 10 out of every 100 women in the Netherlands will develop breast cancer during their lifetime". In conditions 3 and 4, not only the structure of a cumulative risk is explained, but also age-related risks are presented  by presenting the woman's breast cancer risk as one of three risk groups, and using percentages for presenting risks. A "counselling checklist" is designed to be used as a guideline during the counselling session. The standard counselling procedures will be discussed with all counsellors involved.Women with a family history of breast cancer who are first-time attendees applying for breast cancer counselling are invited to participate in the study. A family history of breast cancer is defined as having or having had at least one first-degree- and/or paternal second-degree family member with breast cancer. Women are considered ineligible if they are under 18 years of age, have evident psychiatric illness or terminal disease, and are unable to read and write Dutch. Women with a personal history of breast or ovarian cancer are also excluded, because of the complexities in risk counselling of women with a previous history of cancer. Participants are allocated into an intervention or control group . Stratification to first-degree family members is applied to ensure that all family members receive the same condition.The study will be powered on the main outcome measure, namely (change in) risk perception. In order to be able to detect a clinically relevant difference of 10–20% difference between the intervention group and the control group, a sample of 60 women per condition is needed . These calculations are based on a power of 0.80 (1-β) and a significance level of 0.05 . With an expected drop-out rate of 20%, the sample size for the study is therefore determined at 450. Recruitment and data collection (including follow-up) is anticipated to continue for 31 months.Randomisation takes place at 'condition round' level. The inclusion period is divided into condition rounds using a Latin Square design. Every round takes 5 months and switches when a total of n = 75 is reached. The ranking order of conditions (1–5) is varied to correct for learning effect by the risk counsellors. Each condition is given according to the design shown in Table Women applying for genetic breast cancer counselling are invited to participate by means of an information letter send to their home address. All participants provide written informed consent. In the intervention group, participants receive a self-administered questionnaire at four points in time T0, T1, T2, T3), the control group receives this at three points in time  : The women will receive the first questionnaire at home before their first appointment with the genetic counsellor.- T1 (after standard counselling session): A second questionnaire will be given after the standard genetic counselling session with the genetic counsellor and prior to the intervention .- T2/T1C (2 weeks follow-up): A third questionnaire will be sent to the woman's home address at 2 weeks after the intervention, or a comparable point in time (control group).- T3/T2C (6 months follow-up): The final questionnaire will be sent to the woman's home address.A maximum of two reminders is sent to participants not returning their questionnaires. The three risk counsellors  who provide the intervention, have been specifically trained for this study. The intervention lasts for approximately 30 minutes. The risk counsellor is informed about the content of the previous standard counselling session by means of a "checklist after standard counselling", which the genetic counsellor fills in immediately after each session. This checklist includes information about the participant's risks e.g. individual estimated risk of getting breast cancer, also describing the risks formats that were used during counselling. When risks are not yet known, because, for instance, medical records need to be checked, intervention takes place after a second visit. Thus, enforcement of an intervention implies that in the genetic counselling session with the genetic counsellor at least the woman's breast cancer risk group  was communicated.After the intervention, all participants receive a BRISC brochure in which risks are presented corresponding to the format of the intervention given.Outcome measures are classified in four dimensions: 1) cognitive outcomes; 2) psychological well-being; 3) decision-making; 4) evaluation of the intervention . Table Risk perception (primary outcome measure). Table Recall is assessed by asking women to what breast cancer risk group they belong: 1 (not increased risk group) to 5 (very strongly increased risk group). Two additional answering categories are "this has not been discussed" and "don't know (anymore)".Knowledge of familial breast cancer is measured by using a 10-item questionnaire based on questionnaires designed by Lerman et al. [n et al.  and Blumn et al. ; adaptedBreast cancer-related worries about the risk of developing cancer and the impact of worry on daily functioning is measured by an 8-item adapted Lerman Cancer Worry Scale (CWS) [le (CWS) .Breast cancer-related distress and anxiety is measured by a Dutch version of the 15-item Impact of Events Scale (IES) [le (IES) .Affect, which can be subdivided into positive affect and negative affect (distress), is measured by the 20-item PANAS Scale (Positive and Negative Affect Schedule) [chedule) . ParticiState anxiety is measured by a Dutch version of the 6-item version of the State scale of the Spielberger State-Trait Anxiety Inventory (STAI) [y (STAI) .Anxiety and depression is measured by a Dutch translation of the 14-item Hospital Anxiety and Depression Scale (HADS), using the timeframe of "last week" [st week" .Intention is measured using 7 self-developed items regarding: breast self-examination; adherence to population mammography screening (above 50 years of age); breast screening by a physician every 6 months; mammography screening every year (own initiative); DNA testing; having a preventive breast operation (mastectomy); informing close relatives. Each item has a 7-point scale: 1 (definitely not) to 7 (definitely), and an additional category "not applicable".Behaviour is measured by 6 items using a timeframe of "the last 6 months", regarding: breast self-examination; adherence to population screening; breast screening by a physician; mammography screening (own initiative); consulting a specialist about a preventive breast operation; preventive breast operation.Informed choice with regard to genetic testing, which is based on knowledge, attitudes, genetic test uptake and value consistency, is assessed using a multi-dimensional measure of informed choice (MMIC) developed by Marteau [ Marteau  and exte Marteau . Attitud Marteau .Difficulties in decision-making or decisional conflict are measured by the Dutch version of the Decisional Conflict Scale (DCS) of O'Conner [O'Conner .The extent to which the additional risk information (intervention) is regarded as useful for decision-making, threatening, and easy to understand was assessed using a 7-point rating scale. Satisfaction with the information provided is measured by a 7-point response format, ranging from 1 (very dissatisfied) to 7 (very satisfied).Several personal characteristics and experiences are measured which may have mediating effects on the efficacy of risk communication.Sociodemographic characteristics included age, level of education, marital status, parent's country of birth, number of children, religious affiliation.Impact of family history is measured using 4 self-developed items regarding: the number of family members that have or have had breast cancer (including the family relationship); perceived impact of this experience by a 7-point scale ranging from 1 (no strong impact) to 7 (very strong impact); the effect of this experience on perceived anxiety regarding getting breast cancer by a 7-point scale ranging from 1 (no strong effect) to 7 (very strong effect); the extent to which the subject "hereditary breast cancer" plays a part in the family by a 7-point scale ranging from 1  to 7 (very).Severity of breast cancer is measured by 6 items on the Consequences Subscale of the Dutch version for at-risk individuals of the Revised Illness Perception Questionnaire, that is IPQ-RAR [ IPQ-RAR .Perceived Personal Control is measured by a Dutch translation of the Perceived Personal Control questionnaire (PPC) [re (PPC) .Coping is measured by the 19-item Utrecht Coping List (UCL) [st (UCL) .General anxiety is measured by a 20-item version of the Dutch version of the Trait scale (STAI-form Y) of the Spielberger State-Trait Anxiety Inventory (STAI) [y (STAI) .Need for Cognition can be described as an "individual disposition to engage in and enjoy thinking", and is measured by an 18-item Dutch version of the Need for Cognition Scale (NCS) [le (NCS) .Cognitive ability is measured using the 3-item Cognitive Reflection Test (CRT) [st (CRT) .Decision-making style is measured by the 22-item Melbourne Decision Making Questionnaire (Melbourne DMQ) [rne DMQ) .Social support is measured by the 16-item Social Experiences Checklist (SEC) [st (SEC) .Analyses will be performed to estimate the effect of the different interventions (formats) by comparing pre-test- (T0/T1) with post-test- (T2/T1C) outcome measures between the five different intervention groups and the control group, using multivariate analyses. At baseline (T0) and at T1 similar variables will be measured in order to be able to assess the effect of the regular counselling session with the genetic counsellor. Personal variables will be included as covariates. Repeated measures in MANOVA will be used to analyse changes over time and long-term effects (T3/T2C).Understanding risks is considered to be crucial for informed decision-making. However, inaccurate risk perception is a common finding in women attending genetic counselling regarding breast cancer. Although the literature provides recommendations for the use of frequencies, graphical displays and short-term risks such as age-related risks (i.e. risks for the next ten years) in risk communication, these recommendations are based primarily on research using hypothetical scenarios. In addition, the recommended approaches are not generally used in standard care. The BRISC study is designed to fill the gaps with an evaluation of the effects of different formats of communicating risks to counsellees facing real decisions in a clinical setting. Results will be used to improve risk communication in order to stimulate informed decision-making among women with a family history of breast cancer.BRCA1/2.The BRISC study is a field study; in other words, a clinical trial which offers a unique opportunity to evaluate effects of different formats of communicating risks to counsellees facing decisions such as informing relatives who may also be at risk, whether and when to start mammography screening, and, assuming eligibility, whether to test for mutations in Quantitative outcome measures are collected using questionnaires at four points in time. The follow-up questionnaire is sent 6 months after the intervention, thereby enabling medium-term effects to be detected. With this comprehensive collected data, it will be possible to clarify the various effects of different formats on four dimensions evaluating the effectiveness of the risk communication process. It is not inconceivable to expect that some formats have positive effects on one of the dimensions and negative effects on another dimension. Additionally, the outcomes of this project will give a better understanding of who, for example, as a function of cognitive capacity, might or might not benefit from different formats.Two control conditions are introduced in the BRISC study: condition 5 in which the risk information is communicated in percentages as is commonly done in usual care, and a second control condition (condition 6) in which no intervention is given. With these two control conditions, it is possible to distinguish between the effect of repetition and the effect of giving the risks in a structured way on the one hand, and between the effects of giving the risks in a structured way in different formats on the other.Because the genetic counsellor involved has no role in the inclusion of participants, selection bias is restricted, other than from self-selection. Cluster-randomisation is applied as it is too complex to randomise at the level of counsellees because in that case a risk counsellor is asked to give different risk formats of genetic risks to different counselees on the same day. An exception is made for participants who are close family members.The risk counsellors who give the intervention are not involved in usual care. This will overcome concerns of contamination bias. All risk counsellors are women, eliminating bias due to gender differences. The Latin Square design and the control group, which is constructed in addition to all condition rounds, both serve to eliminate bias due to time. To achieve uniform risk communication in the genetic counselling sessions, several precautions have been taken , minimising confounding.Some limitations of the BRISC study need to be addressed. This study aims at improving women's understanding of the risks, and we acknowledge that there are factors other than risk that can influence the decision-making process. In addition, although several precautions have been taken to achieve an optimal standardisation in counselling and procedures, interactive features must be acknowledged. Another limitation of this study is that it is not possible to blind the genetic counsellors completely because of the nature of the intervention. This applies to the intervention allocation and to the age-related formats due to anticipation of questions by the counsellee. Participants are informed that the BRISC study concerned different kinds of risk counselling and are blinded. Furthermore, although we would have preferred to test an integrated intervention in standard counselling sessions, it is not considered feasible, either ethically or practically, to have the intervention done in a structured way by the genetic counsellors themselves. If one of the formats proves to be most effective, this format could be integrated into the standard counselling session. Since members of the research team provided the additional consultations (interventions), implementation of a format in daily practice will need to receive further attention.Finally, results may be extended to women with a personal history of cancer, other cancers, and also other diseases and settings, but further study would be required. Imprudent generalization should be avoided, although the BRISC study may provide an indication for risk communication in healthcare in general and cancer genetic counselling in particular.The authors declare that they have no competing interests.CO is responsible for data collection and drafted the manuscript. CO works under direct supervision of DT  and LH. DT, LH and FM are co-applicants of the grant. All authors enhanced the design, participated in the standardisation of the counselling sessions, and the development of the intervention. CO, DT and LH designed the questionnaires. CA, JO and FM are involved in recruitment of participants as heads of the family cancer clinics in the clinical genetics centres involved. All authors provided comments on the drafts and have read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


DNA repair systems that protect the genome from deleterious endogenous and exogenous damages have been shown to have significantly reduced. In particular, enzymes of the nucleotide excision repair pathway are suspected to be implicated in cancer. In this study, 2 functional polymorphisms in a DNA repair gene ERCC2 were analyzed. The population included 911 breast cancer cases, 51 ovarian cancer cases and 1000 controls. The genotyping of 2 SNP (Single Nucleotide Polymorphism) was carried out on the population with the MGB (Minor Groove Binder) probe technique which consists of the use of the allelic discrimination with the Taqman® method. This study enabled us to show an increase in risk of breast cancer with no oral contraceptive users and with women exhibiting a waist-to-hip ratio (WHR) > 0.85 for Asn homozygous for ERCC2 312.Breast and ovarian cancers increased in the last decades. Except rare cases with a genetic predisposition and high penetrance, these pathologies are viewed as a polygenic disease. In this concept, association studies look for genetic variations such as polymorphisms in low penetrance genes,  ERCC2 (formely XPD) is one of seven nucleotide excision repair enzymes that cause Xeroderma Pigmentosum when mutated in germ line . . ERCC2 aERCC2 312.This study enabled us to show an increase in risk of breast cancer with no oral contraceptive users and with women exhibiting a waist-to-hip ratio superior to 0.85 for Asn homozygous for BRCA mutation and no more than one first degree relative breast cancer.911 breast cancer cases and 51 ovarian cancer cases (aged 26–89 years), from the Auvergne region in France were included. They are belonging to the COSA program (Breast and Ovarian Cancer in the Auvergne region) that consisted of the recruitment of identified women from different clinics and hospitals in the Auvergne region in France from November 1996 through November 1999. Eligible subjects were women who had been diagnosed with breast or ovarian cancer with no 1,000 healthy control women (aged 24–85 years) were recruited in a mammographic screening center from July 2005 to April 2006. Eligible controls were women with no previous history of cancer and resident in the Auvergne region. All study subjects received counseling and provided written consent for the study.Participants completed a questionnaire about their medical and reproductive histories in particular. Breast and ovarian cases filled in the questionnaire at the time of clinic appointment whereas controls were interviewed at the medical center at the time of enrollment. Data regarding reproductive history , use of oral contraceptives (OC) ("Ever use" of OC was defined as at least 3 months of use), age at first OC use and duration of OC, anthropometric characteristics , smoking status ("ever smoker" was defined as at least 1 year of smoking) were collected.ERCC2 were selected (Table ®) was chosen for genotyping on the ABI PRISM 7700 Sequence Detection Systems  and consisted of the use of allele-specific fluorogenic probes , BMI at 20 years old, waist-to-hip ratio [WHR] and smoking) were evaluated by adjusting for unconditional logistic regression and calculation of ORs. As no changes in ORs were noted, results were reported without adjustment for these factors.Allelic frequencies and the distribution of genotype were compared within the two populations using The authors declare that they have no competing interests.DBG, LD was responsible for genotyping polymorphisms, statistical analyses and interpretation, and drafting of the manuscript; RB, NC, SS, NR contributed with the coordination of the study and helped in statistical analyses; FK provided expertise in data analyses; YJB, DBG, LF, AC contributed to the study design and manuscript preparation. All authors participated in the preparation of the manuscript and approved the final version.


A recent publication from California in this journal has suggested that both prolonged oral contraceptive use and abortion before first term pregnancy increases the risk of breast cancer in young women. Data are presented on 1176 women aged 16-50 years with breast cancer, interviewed in London or in Oxford, together with a like number of matches control subjects. The results are entirely reassuring, being, in fact, more compatible with protective effects than the reverse. Possible reasons for the differences between the 2 sets of data are discussed.


Diabetics have been found to have a greater risk of colorectal cancer than non-diabetics.We examined whether this relationship differed by ethnic group, cancer site or tumour stage in a population-based prospective cohort, including 3549 incident colorectal cancer cases identified over a 13-year period (1993–2006) among 199 143 European American, African American, Native Hawaiian, Japanese American and Latino men and women in the Multiethnic Cohort.P-value (P)<0.001). Positive associations were observed for colon cancer, cancers of both the right and left colon, and cancers diagnosed at a localised and regional/distant stage. The association with colorectal cancer risk was significantly modified by smoking status (PInteraction=0.0044), with the RR being higher in never smokers  than past  and current smokers .Diabetics overall had a significantly greater risk of colorectal cancer than did non-diabetics (relative risk (RR)=1.19, 95% confidence interval (CI)=1.09–1.29, These findings provide strong support for the hypothesis that diabetes is a risk factor for colorectal cancer. The participants are primarily individuals of Native Hawaiian, Japanese, White, African American and Latino race/ethnicity, who entered the cohort between 1993 and 1996 by completing a detailed, self-administered questionnaire that obtained information on basic demographic variables, as well as several lifestyle factors (e.g. diet) and medical conditions (e.g. diabetes). Potential cohort members were identified primarily through the Department of Motor Vehicles drivers’ license files and additionally for African Americans, Health Care Financing Administration (Medicare) data files. Participants were between the ages of 45 and 75 years at the time of recruitment. In the cohort, incident colorectal cancer cases are identified through cohort linkage to population-based cancer Surveillance, Epidemiology and End Results registries, which cover Hawaii and Los Angeles County, as well as the rest of the state of California. For this analysis, linkage with these registries was complete through 31 December 2004, in Hawaii and 31 December 2006 in California. Over this period, 1921 male and 1628 female cases of colorectal cancer were identified. Deaths within the cohort are determined from linkages to the death certificate files in Hawaii and California, supplemented with linkages to the National Death Index. Diabetes status is defined based on self-report to a question on the baseline questionnaire asking whether a doctor had ever told the respondent that he/she had diabetes (high blood sugar). The question did not differentiate between type 1 and type 2 diabetes mellitus and thus we expect a small fraction (<10%) of the self-reported diabetes cases to have type 1 diabetes and be potentially misclassified. Year of diabetes diagnosis  was defined using a second questionnaire in 2001, and 90.3% (79 178 men and 100 663 women) of the subjects who returned the first questionnaire also returned the second questionnaire.In the analysis, we excluded one male subject missing information for diabetes status on the baseline questionnaire. The prospective analysis of the association between diabetes status and colorectal cancer incidence in this study includes 89 478 men and 109 664 women in the Multiethnic Cohort from the five main ethnic groups.The study protocol was approved by the institutional review boards at the University of Southern California and the University of Hawaii.−2 and missing), smoking status , educational level , alcohol intake , non-steroidal anti-inflammatory drugs (NSAIDs) use , saturated fat intake , non-saturated fat intake , dietary fibre intake , total calories , vigorous activity , family history of colorectal cancer (yes and no), menopausal status and hormone replacement therapy (HRT) use  among women only. For each covariate, an indicator variable was used for those missing data.Cox regression was used to estimate hazard ratios (reported as relative risks (RRs)) for the effect of diabetes on colorectal cancer incidence. Models were stratified by age at entry of the cohort, and were minimally adjusted for ethnicity and sex, or further adjusted for the following risk factors as potential confounders: body mass index (BMI)  and by stage . We also examined whether the association may be modified by known risk factors (at baseline): age , BMI , smoking status  and NSAIDs use .RRs were estimated separately for colon and rectal cancer, by location in the colon  at baseline of the cohort was 60.2 years , which ranged from 57.2 years for Native Hawaiians to 62.5 years for African Americans. The prevalence of diabetes varied widely across populations, from 9.5% in European Americans to 21.6% in Latinos. Diabetic men were slightly older than non-diabetic men for each racial/ethnic group, ranging from 62.7 years (vs 59.2 in non-diabetics) in European Americans to 61.9 years (vs 60.3 in non-diabetics) in Latinos. Among men, the age-standardised incidence rate of colorectal cancer was higher in diabetics than non-diabetics among European Americans, African Americans, Japanese Americans and Latinos, but lower in Native Hawaiians. In each population, diabetic men were more likely to be overweight and less physically active than men without diabetes (The mean age of the men (diabetes .n=109 664) was 59.7 years , with Native Hawaiians being the youngest  and Japanese and African Americans being the oldest  than in men . A positive association between diabetes and colorectal cancer risk was noted in all ethnic groups except among Native Hawaiians, with the RR estimates ranging from 1.16 in European Americans  and African Americans  to 1.27 in Japanese Americans . Risk was non-significantly lower in Native Hawaiians ; however, a test of heterogeneity suggested no significant difference in the risk estimates across ethnic groups (PInteraction=0.43)  .vs rectum) (P<0.0001) as was rectal cancer risk . Test of heterogeneity by ethnicity was not significant for colon cancer (PInteraction=0.30) or for rectal cancer (PInteraction=0.18). However, for rectal cancer, a particularly strong association between cancer risk and diabetes was observed only in Latinos  (P=0.050) and women  (P=0.002) and in the left colon . For both locations, tests of heterogeneity suggested no difference across ethnic groups  , risk ofP=0.007) , with thP=0.067) . The risc groups .P=0.005 for localised cancer; RR=1.14, 95% CI=1.01–1.30, P=0.036 for regional/distant cancer). No significant heterogeneity across ethnic groups was observed by stage. For regional/distant colorectal cancer, the RR was similar in men  and women ; whereas for localised cancer, there was no significant increase in risk observed in diabetic men , but the risk was significantly increased in diabetic women   .−2: RR=1.21, 95% CI=1.09–1.34; <25 kg m−2: RR=1.23, 95% CI=1.05–1.45, PInteraction=0.14; PInteraction=0.0044). The association was strongest in never smokers, with a RR of 1.32 ; in past smokers, the RR was 1.19 ; no positive association was observed in current smokers . This pattern was generally consistent in both sexes and in all colorectal cancer subgroups .We also investigated the relationship between time since diagnosis with diabetes and colorectal cancer risk. Compared with diabetics diagnosed in 1994 or later, those with an earlier diagnosis were at non-significantly lower risk of colorectal cancer risk (RRPInteraction=0.071), and the positive association was observed in all populations except Native Hawaiians, which was the smallest group.In the prospective analysis of five racial/ethnic populations in the Multiethnic Cohort, we found a highly statistically significant association between diabetes status and colorectal cancer incidence, with diabetics having 19% greater risk of developing colorectal cancer than non-diabetics after adjusting for known risk factors. The risk associated with diabetes was slightly greater in women (RR=1.28) than in men (RR=1.12) , which is consistent with earlier reports in Koreans and Singapore Chinese , but not in any of the other ethnic groups. In analyses by stage, significant increases in risks were noted for both regional/distant and localised disease. Risks within tumour subgroups were generally consistent across ethnic groups. The relationship between diabetes status and colorectal cancer was significantly modified by smoking status. In contrast to an earlier report of greater colorectal cancer risk in current and former smokers than never smokers among diabetics . These findings support the results from earlier studies (In this large, multiethnic prospective study, we observed consistent positive associations between diabetes and colorectal cancer risk in African Americans, Latinos, Japanese and European Americans. The lack of positive association between diabetes and colorectal cancer risk in Native Hawaiians is consistent with the relatively low rate of colorectal cancer in this group despite a high rate of diabetes (


BsmI, an intronic 3′ gene variant, was significantly associated with increased breast cancer risk: odds ratio bb vs BB genotype = 2.32 . The BsmI polymorphism was in linkage disequilibrium with a candidate translational control site, the variable length poly (A) sequence in the 3′ untranslated region. Thus, the ‘L’ poly (A) variant was also associated with a similar breast cancer risk. A 5′ VDR gene variant, FokI, was not associated with breast cancer risk. Further investigations into the mechanisms of interactions of the VDR with other environmental and/or genetic influences to alter breast cancer risk may lead to a new understanding of the role of vitamin D in the control of cellular and developmental pathways. © 2001 Cancer Research Campaign http://www.bjcancer.comThere is increasing evidence that vitamin D can protect against breast cancer. The actions of vitamin D are mediated via the vitamin D receptor (VDR). We have investigated whether polymorphisms in the VDR gene are associated with altered breast cancer risk in a UK Caucasian population. We recruited 241 women following a negative screening mammogram and 181 women with known breast cancer. The VDR polymorphism


We used multivariate logistic regression to evaluate factors in relation to risk of ovarian cancer and the major tumour histologic subtypes. Ovarian cancer risk was reduced among parous women, relative to nulliparous women . Among parous women, higher parity (P= 0.0006), increased age at first (P= 0.03) or last (P= 0.05) birth, and time since last birth (P= 0.04) were associated with reduced risk. Early pregnancy losses, abortions, and stillbirths were unrelated to risk, but preterm, term, and twin births were protective. Risk was lower among women who had breast-fed, relative to those who had not , but the average duration of breast-feeding per child was unrelated to risk (P for trend = 0.21). Age at menarche and age at menopause were unrelated to risk overall, although increasing menarcheal age was protective among premenopausal women (P= 0.02). Menstrual cycle characteristics and symptoms were generally unrelated to risk, although cycle-related insomnia was associated with decreased risk . We found no association between the type of sanitary product used during menstruation and ovarian cancer risk. In analyses by histologic subtype, reproductive and menstrual factors had most effect on risk of endometrioid/clear cell tumours, and least influential with regard to risk of mucinous tumours. Overall, our findings offer some support to current hypotheses of ovarian pathogenesis, and show aetiologic differences among the tumour subtypes. © 2001 Cancer Research Campaign http://www.bjcancer.comWe assessed menstrual and reproductive factors in relation to ovarian cancer risk in a large, population-based, case–control study. 563 cases in Massachusetts and New Hampshire were ascertained from hospitals and statewide tumour registries; control women (


During 1968-1980, 1176 women aged 16-50 years with newly diagnosed breast cancer and a like number of matched controls were interviewed at 9 teaching hospitals in London and Oxford and asked about their use of oral contraceptives. The results were reassuring. A few statistically significant differences in oral contraceptive use were found between the breast cancer and control groups, but the data were subdivided in many ways so that some "significant" differences would have been expected through the play of chance alone. Certainly no patterns of risk emerged which would suggest that any of the associations were causal. It must be stressed, however, that the data are still sparse in some important subcategories--for example, only small numbers of both cases and controls had prolonged oral contraceptive use before their first term pregnancy. For this reason, it is important that information on the possible relationship between pill use and breast cancer should continue to be collected. Women who had never used oral contraceptives presented with appreciably more advanced tumours than those who had been using oral contraceptives during the year before detection of cancer, while past users were in an intermediate position. These differences in staging were reflected in the pattern of survival. Possible explanations for these observations include "surveillance bias" among oral contraceptive users leading to earlier diagnosis and a beneficial biological effect of oral contraceptives on tumour growth and spread. Women with breast cancer reported never having used any method of contraception and heavy cigarette smoking  significantly less often than controls. We could find no obvious explanation for the former observation, but suspect that the latter reflects the unrepresentative smoking habits of our hospital controls rather than a protective effect of smoking against breast cancer.


Estrogens are crucial tumorigenic hormones, which impact the cell growth and proliferation during breast cancer development. Estrogens are metabolized by a series of enzymes including COMT, which converts catechol estrogens into biologically non-hazardous methoxyestrogens. Several studies have also shown the relationship between estrogen and cell cycle progression through activation of CCND1 transcription.In this study, we have investigated the independent and the combined effects of commonly occurring CCND1  and COMT  polymorphisms to breast cancer risk in two independent Caucasian populations from Ontario (1228 breast cancer cases and 719 population controls) and Finland (728 breast cancer cases and 687 population controls). Both COMT and CCND1 polymorphisms have been previously shown to impact on the enzymatic activity of the coded proteins.High (AA) was associated with increased breast cancer risk in both the Ontario  and the Finland sample . The heterozygous COMTMedium  and the high enzymatic activity of COMTHigh  genotype was also associated with breast cancer risk in Ontario cases,  and , respectively. However, there was neither a statistically significant association nor increased trend of breast cancer risk with COMTHigh  genotypes in the Finland cases . In the combined analysis, the higher activity alleles of the COMT and CCND1 is associated with increased breast cancer risk in both Ontario  and Finland  populations studied. The trend test was statistically significant in both the Ontario and Finland populations across the genotypes associated with increasing enzymatic activity.Here, we have shown that the high enzymatic activity genotype of CCND1Using two independent Caucasian populations, we have shown a stronger combined effect of the two commonly occurring CCND1 and COMT genotypes in the context of breast cancer predisposition. It has been suggested that COMTLow (Met) may have 3 to 4-fold less enzymatic activity compared to COMTHigh   and the Finland sample   and the high enzymatic activity of COMTHigh  genotype was also associated with breast cancer risk in Ontario cases, with an OR of 1.3, 95%CI (1.07–1.68) and 1.4, 95%CI (1.07–1.81), respectively. However, there was no statistically significant association or increased trend of breast cancer risk with COMTHigh  genotypes in the Finland cases .We observed that the potentially high enzymatic activity CCND1heterogeneity = 0.06; I2 = 41%] .Low/COMTLow) were taken as a reference compared to the medium (heterozygote combinations) and high activity (CCND1High/COMTMedium and CCND1High/COMTHigh) combinations. In Ontario, the heterozygote (medium activity)  and high activity  combinations of CCND1 and COMT genotypes showed statistically significant association with increased breast cancer risk. In Finland, the high activity genotype combinations (CCND1High/COMTHigh and CCND1High/COMTMedium) were also significantly associated with increased breast cancer risk . The medium activity combinations in Finland sample followed a trend of increased breast cancer risk , but did not reach statistical significance. The trend test was statistically significant in both the Ontario  and Finland  populations across the genotypes associated with increasing enzymatic activity. We have also investigated the COMT and CCND1 genotype interactions by age, familial status and ER subgroups; however we did not observe any differences from the overall analysis (data not shown).The association of the combined CCND1 and COMT genotypes was also tested and the results are presented after grouping the genotypes according to their level of enzymatic activity Table . The lowThe study in Ontario was designed to reach 80% power to detect an odds-ratio (OR) of about 2.1 for the interaction assuming a recessive model for CCND1 and a dominant model for COMT using a two-sided test. Although the study in Finland enrolled less cases and controls than in Ontario, this study achieved almost the same power assuming we know the direction of the effect and we can use a one-sided test. This can be justified in a replication study.High  allele has been suggested to be 3 to 4-fold more active compared to the COMTHigh  allele. Also, the protein encoded by the CCND1High (A) allele has also been hypothesized to produce a more stable protein compared to the CCND1Low (G) allele. Both COMT and CCND1 polymorphisms occur frequently in the population controls studied. The frequency of CCND1High (AA) genotype was 21.7% and 21.3%, whereas the COMTHigh  genotype was 22.4% and 20.8 % in Ontario and Finland control populations, respectively.In this study, we have investigated the contribution of independent and the combined effects of CCND1 Pro241Pro and COMT Met108/158Val polymorphisms to breast cancer risk in two independent Caucasian populations from Ontario and Finland. Both CCND1 and COMT polymorphisms have been previously shown to have an impact on the function of the protein products, altering their overall enzymatic activity in the cell. The protein product encoded by the COMTAnalysis of the independent contribution of the CCND1 polymorphism to breast cancer risk has shown a statistically significant association with increased breast cancer risk in both Ontario and Finland. To date a total of three studies with relatively small sample sizes (with a range of ~200–500 cases) have examined the contribution of the CCND1 polymorphism to breast cancer risk; however none of them has shown statistically significant association with breast cancer risk -46. ThusHigh  genotypes and increased breast cancer risk in Ontario but not in Finland sample. As summarized in Figure High  genotype with breast cancer risk [High  enzymatic activity which includes the conversion of the catechol estrogens into their proper methoxyestrogens. This activity reduces the chance of DNA damage caused by reactive oxygen species that are created by oxidation of estrogen. However, a recent study reported a non-competitive negative feedback inhibition of CYP1A1 and CYP1B1 enzymes by methoxyestrogens [Analysis of the independent contribution of COMT polymorphism has also shown a statistically significant association between the COMTcer risk ,34-43. Tstrogens . Accordistrogens , the samstrogens , suggestHigh (A) variant also encodes a more stable form of the protein, thus the cells containing this combination will be under pressure for increased cell cycle progression and proliferation. However this needs to be experimentally validated. Genetically, our findings suggests that the individuals inheriting the combinations of high activity COMT and CCND1 alleles have relatively higher breast cancer risk probably due to simultaneous reduction in estrogen metabolism, and increase in cell proliferation.Due to the complementary functional roles of COMT and CCND1, we have also investigated the combined effect of their genotypes in association with altered breast cancer risk. Our results suggest a genetic cross-talk between the medium and higher enzymatic activity allele combinations of CCND1 and COMT in breast cancer development. The biological relevance of this combined effect between CCND1 and COMT polymorphisms can be explained in regard to their common relationship with estrogen. Here, we suggest that the reduced estrogen metabolization by the negative feedback of high COMT activity may result in increased levels of estrogen, which in turn may lead to enhanced expression of CCND1. Given that CCND1The magnitude of the increased combined risk effect was higher in Ontario compared to Finland; however a test for trend supported the association of increased breast cancer risk with increasing activity of both CCND1 and COMT genotypes in both populations. Although the ORs associated with the "at-risk" genotype combinations were slightly lower in Finland compared to Ontario, the confidence intervals of the estimates overlap and therefore there is no clear evidence of a difference between the two populations.In this study, we have shown a combined effect between the two commonly occurring polymorphisms associated with higher enzymatic activity of CCND1 and COMT in the context of breast cancer predisposition. The results of this study also supports our initial findings where SNP-SNP interactions between these polymorphisms was observed in the subset of the Ontario sample . About 9The author(s) declare that they have no competing interests.UVO participated in study design, assisted in the production and organization of Ontario samples genotyping data, and participated in manuscript preparation.KA, OK and HN provided the genetic and clinical data for Finland samples, and critically revised the manuscript.LB and JAK provided statistical assistance and critically revised the manuscript.CB provided specimens for Finland data, and participated in the critical revision of the manuscript.NP provided statistical assistance and participated in critical revision of the manuscript.ILA provided specimens for Ontario data, and participated in the critical revision of the manuscript.HO participated in study and manuscript preparation.All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


N=1640) were compared with age-matched community controls (N=1492). Women who recently used oral contraceptives containing more than 35 μg of ethinyl oestradiol per pill were at higher risk of breast cancer than users of lower dose preparations when compared to never users . This relationship was more marked among women <35 years of age, where risks associated with high- and low-dose ethinyl oestradiol use were 3.62 and 1.91 (Ptrend<0.01), respectively. We also found significant trends of increasing breast cancer risk for pills with higher progestin and oestrogen potencies (Ptrend<0.05), which were most pronounced among women aged <35 years of age (Ptrend<0.01). Risk was similar across recently used progestin types. Our findings suggest that newer low-potency/low oestrogen dose oral contraceptives may impart a lower risk of breast cancer than that associated with earlier high-potency/high-dose preparations.Recent use of oral contraceptive pills is associated with a modest risk of breast cancer among very young women. In this US population-based case–control study, we evaluated whether the excess risk associated with recent oral contraceptive use is ubiquitous for all pill types or attributable to specific oral contraceptive preparations. Hormonal content and potency of combination oral contraceptives used for the longest duration within 5 years of interview for breast cancer cases aged 20–44 years ( A small study of women with early-onset breast cancer published in 1983 initially sparked the debate about combination oral contraceptives and breast cancer by suggesting that a woman's risk of breast cancer increased if she used oral contraceptives early in life, particularly pills with high progestin potency . Whetherμg)  ; Brintonμg) .Since Food and Drug Administration (FDA) approval in 1960, the oral contraceptive pill has been formulated using two oestrogens and nine different progestins, varying in both dose and potency . Oral coin situ or invasive breast cancer in 1990–1992 while living in either the metropolitan areas of Atlanta, Georgia or Seattle/Puget Sound, Washington, or five counties of central New Jersey. Regional and governmental institutional review boards approved the study protocol. Hospital records of eligible patients were abstracted to document details on the clinical and pathologic characteristics of the breast cancers. Control subjects in the three geographic areas were ascertained through random-digit dialling, with a 90.5% screening response rate.Following written informed consent, participants were interviewed in person about oral contraceptive pill use from menarche until the date of interview. Pregnancies and other life events were first marked on a month-by-month family planning calendar to serve as a frame of reference and to aid recalling dates of changes in contraceptive use over time. Months of oral contraceptive use were subsequently shaded on the calendar. On a complementary worksheet, interviewers recorded the start and stop dates for each episode of pill usage, the brand name, reason for use, and reason for discontinuing use. Colour photographs of oral contraceptives and listings of the year they were first marketed in the United States were shown to help participants identify the brand name of each oral contraceptive used.In addition, in-person interviews included questions about demographic factors, reproductive and menstrual history, use of exogenous hormones, medical and screening history, anthropometry and physical activity, adolescent diet, alcohol consumption, smoking, occupation, family history of cancer, and certain lifestyle factors. Interviews were obtained from 2002 eligible patients (86%) and 2009 eligible control subjects (78%). A comparison of respondents to nonrespondents who were willing to complete an abbreviated questionnaire reported no important differences for the distributions of variables assessed in this study (N=3132), the age group for which oral contraceptive use is a risk factor for breast cancer (n=28) or that they had a previous diagnosis of breast cancer (n=19). We also excluded 16 of the young women who used solely progestin-only pills. After the exclusions, 1640 cases and 1429 controls remained in this investigation.This investigation included only women younger than 45 years of age  and progestin content .Oral contraceptive use was defined as use of combination oral contraceptive pills for a total of 6 or more months. Women who never used oral contraceptives or who used them for less than 6 months were classified as nonusers. For each oral contraceptive preparation used, we obtained information on oestrogen and progestin content and dose from the Physician's Desk Reference available during the time that the preparation was marketed in the United States  and breast cancer risk is reported overall and for two age strata: <35 and 35–44 years of age. Risk associated with hormonal content and potency was also assessed within these age strata after restricting the population to nonusers and those who used oral contraceptives (1) within 5 and (2) within 10 years of diagnosis (cases)/interview (controls). We also evaluated whether risk estimates for recently used pill formulations varied by duration of oral contraceptive use by repeating the above-described analyses separately for women who used pills for less than 5 years or for 5 or more years in total.vs never; recency of use) or by specific hormonal preparations, stratifying by age group and controlling for potential confounders. We used unadjusted and adjusted logistic regression models to obtain maximum likelihood estimates of the odds ratio, which were used to approximate RR . All tests were two-sided, and P values less than 0.05 were considered to be statistically significant.Relative risks (RRs) and their 95% confidence intervals (CIs) were used to assess whether breast cancer risk was elevated by oral contraceptive use , younger women were more likely to have used combination oral contraceptives within 5 years prior to interview .As shown in The use of combination oral contraceptive formulations by control subjects in this population paralleled the introduction of new preparations into the US market . Women wPinteraction<0.05), subsequent analyses are presented within age strata defined by <35 and 35–44 years.Risk of breast cancer associated with combination oral contraceptive use diminished with increasing age (from <35 to 35–44 years) and with time since last use . Since risk was most elevated among recent oral contraceptive users in this and other populations , we focuTable 4Among combination oral contraceptive users in this study, younger women were more likely to recall pill brand names: 93% of women younger than 35 years and 81% of those aged 35–44 provided at least one brand of pill that they used. Since breast cancer risk was slightly higher among women who could not recall pill brand names (as shown in Ptrend<0.01) and within each age group (Ptrend<0.01 for women aged 20–34 years and 0.13 for those aged 35–44 years). Women aged 20–44 years who used pills containing more than 35 μg of ethinyl oestradiol were at an approximately 50% higher risk of breast cancer than recent users of lower-dose preparations when compared to nonusers (respective RRs of 1.99 and 1.27). This relationship was most pronounced in the youngest age group, where risk associated with high- and low-dose ethinyl oestradiol use was 3.62 and 1.91, respectively. Breast cancer risk associated with mestranol was almost entirely explained by doses higher than 50 μg per pill among women younger than 35 years; however, risk was slightly lower among high- compared to low-dose mestranol users in the older age group. With the exception of ethynodiol diacetate (RR=12.0 among women aged 20–34 years based on 12 cases and three controls), risk was similar across all progestin types recently used by women in this study.Hormonal content and potency of the pill preparation used for the longest duration in the 5 years prior to interview and breast cancer risk is summarised in Ptrend<0.01). Combination progestin/oestrogen potency similarly showed a significant trend of increasing breast cancer risk with increasing potency (Ptrend<0.01); recent use of low progestin/low oestrogen potency pills was associated with a RR of 1.79, low progestin/high oestrogen potency with a RR of 2.53, and high progestin/low oestrogen potency with a RR of 8.07. No woman aged younger than 35 years recently used high progestin/high oestrogen potency pills. High progestin/high oestrogen potency pills were used only by women aged 35–44 years (n=7), with a RR of 1.54, only slightly higher than the risk associated with low progestin/low oestrogen pills (RR=1.27) in this age group. Similar trends were seen with hormonal potency among women aged 20–44 years (Ptrend<0.05), although not as strong as in the youngest age group. The association of breast cancer risk with hormonal content and potency of oral contraceptive preparations was similar to the findings presented in In addition to hormonal content, we also examined the relationship between oestrogen and progestin potency and breast cancer risk . High prIn this population-based study of women younger than 45 years of age, we found that breast cancer risk increased with either higher oestrogen dose or higher progestin or oestrogen potency pills used within 5 years of interview, and that these findings were more marked among women younger than 35 years of age. Our findings and those from other studies have shown that recent oral contraceptive use imparts a modest excess in breast cancer risk among women younger than 45 years of age and that this relationship is strongest among very young women . PreviouProgestins contained in oral contraceptives differ in both dose and potency . For exaIn addition to progestational activity, many progestins demonstrate varying degrees of androgenic metabolic effects, being derived from 19 nortestosterone . LevonorOne of the weaknesses of this study was that pill brand name was based on subject recall. Validation studies have shown that recall of oral contraceptive use and timeframe of use is accurate, but that recall of specific brand names is less accurate . By emplSince their inception, oral contraceptive pills have undergone substantial changes in formulation. For example, the FDA reported that in 1964, 94% of the oral contraceptives dispensed by retail pharmacies were high oestrogen potency pills, and by 1984, 85% of oral contraceptives dispensed were low oestrogen potency pills ; the oesin vivo (Although it is possible that the modest increase in breast cancer risk associated with recent use of higher oestrogen dose or high- potency pills is explainable by a detection bias, several plausible biologic mechanisms exist. The steroid hormones of oral contraceptives, oestrogen and 19-nortestosterone-derived progestogens, have long been shown to stimulate breast cell mitotic activity by acting directly, alone or synergistically, on breast cells in vivo . In addiAlthough our findings suggest that newer low oestrogen dose/low-potency oral contraceptives may impart a lower risk of breast cancer than that associated with earlier high-dose/high-potency preparations, we only had small numbers of women within strata of specific pill preparations. Thus, reanalysis of earlier studies (μg per pill (Our analysis examines formulations of oral contraceptive pills used prior to 1993. Since that time new major developments in pill preparations include widespread use of third-generation progestins with low androgenic activity, and further reduction in the dosage of ethinyl oestradiol from 35 to 20 per pill . Since oper pill , even mo


BRCA mutation carriers. The absence of the IGF1 19-repeat allele has been associated with high insulin-like growth factor-1 (IGF-1) levels during OC use. High IGF-1 levels are linked to early-onset breast cancer and larger breast volumes in the general population. The goal of this study was to elucidate the relationships between IGF1 genotype, early-onset breast cancer, breast volume, circulating IGF-1 levels and OC use in a prospective cohort of 258 healthy women ⩽40 years old from high-risk breast cancer families. All women completed a questionnaire including information on reproductive factors and OC use. We measured the height, weight, breast volumes and plasma IGF-1 levels. IGF-1 levels were similar among parous and nulliparous women not using OCs. In all, 13% had no IGF1 19-repeat allele. There was an interaction between IGF1 genotype and OC use on IGF-1 levels (P=0.026) in nulliparous women and another interaction between IGF1 genotype and parity on breast volume (P=0.01). Absence of the 19-repeat allele was associated with high IGF-1 levels in nulliparous OC users and with larger breast volumes in parous women and OC users. Incident breast cancers were also more common in women without the 19-repeat allele (log rank P=0.002). Our results suggest that lack of the IGF1 19-repeat allele modifies IGF-1 levels, breast volume and possibly early-onset breast cancer risk after hormone exposure in young high-risk women.BRCA1/2 mutations predispose to early-onset breast cancer, especially after oral contraceptive (OC) use and pregnancy. However, the majority of breast cancers might be due to more prevalent low-penetrance genes, which may also modify the risk in  BRCA1 and BRCA2. Carriers of the BRCA1 and BRCA2 mutations face a lifetime risk of breast cancer of over 80%  is essential for the normal development of the female breast both during puberty and pregnancy, along with various hormones, including oestrogen, progesterone and prolactin . The IGFThe levels of circulating IGF-1 have also been linked to breast volume. High IGF-1 levels are associated with larger breast volumes in nulliparous women who are not using OCs . It has IGF1 gene contains a CA-repeat sequence, which ranges from 12 to 23 repeats  in the context of an absent 19-repeat allele, may play an important role in the pathogenesis of early-onset breast cancer and lead to an increase in breast volume . AccordiBRCA1 or BRCA2 mutation carrier or a first- or second-degree relative of a breast cancer case or known male or female BRCA1 or BRCA2 mutation carrier with or without breast cancer. We considered a family to be at high risk for breast cancer if three women had been diagnosed with breast cancer and at least one of these was below age 50 years at diagnosis, or two women and at least one was below age 40 years at diagnosis or one woman was diagnosed with breast cancer prior to age 30 years. Participants had to be 40 years of age or younger and menstruating. Exclusion criteria were a previous prophylactic mastectomy or a bilateral oophorectomy or any type of cancer diagnosis at the time of enrolment between 1996 and 2002. In all, 258 young women from breast cancer high-risk families volunteered to participate in this study. Potential participants were identified from charts and pedigrees from the Lund Oncogenetic Clinic. Individuals who themselves had been to the clinic were contacted, first by a letter including brief information on the study, then by phone. In cases where the index individuals were not eligible, they were asked whether they were willing to inform relatives of the study and then inform us as to whether we might contact their relatives directly. The ethical committee at the Lund University approved the study.To be eligible for participation, the women had to belong to high-risk breast cancer families and be either a known A letter including an extensive epidemiologic questionnaire and a written consent form was mailed to women who verbally agreed to participate. The questionnaire included questions on reproductive factors, such as age at menarche, menstrual cycle length, age at full-term pregnancies, duration of breast-feeding for each child, the use of OCs and other medications, smoking habits, diet, coffee consumption, physical exercise, etc. Other questions included the number of older siblings, the age of the mother and the age of the father of the woman when she was born. A trained research nurse collected blood samples and body measurements during menstrual cycle days 5–10 and again 5–10 days before the predicted onset of the following menstrual period. All women were asked to call back with the date of the first day of their next menstrual period. Body measurements included height, weight, waist and hip circumferences, and breast volume. Breast volumes were measured while the woman was on her hands and knees with the breasts hanging down. The volume was approximated to a pyramid (base area × height/3). Total breast volume, that is, the sum of the right and left breast volumes, was calculated for each visit. Initially, we only measured one of the breasts and for the first woman total breast volume is missing for both visits and for the next three women total breast volume is missing for one visit. The plasma and blood cells were separated and frozen at minus 70°C at our laboratory at the Department of Oncology, Lund.BRCA1 and BRCA2 genes was not performed as part of this study. BRCA1 and BRCA2 mutation testing is offered at the Oncogenetic clinic at the Department of Oncology in Lund if an individual has at least three first-degree relatives with breast cancer and one diagnosed before age 50; two first-degree relatives with breast cancer and one diagnosed before age 40; or one first-degree relative with breast cancer diagnosed before age 30. Women are usually not offered testing before age 25 years. BRCA gene mutation carriers included only those with confirmed deleterious alterations, that is, nonsense or frameshift indel mutations that cause protein truncation, or known disease-associated missense mutations.Mutation testing of the BRCA1 mutation carriers (n=20);BRCA1 mutation carriers from a family with a known BRCA1 mutation (n=47);non-BRCA1 mutation (n=17);untested women from a family with a known BRCA2 mutation carriers (n=7);BRCA2 mutation carriers from a family with a known BRCA2 mutation (n=6);non-BRCA2 mutation (n=2);untested women from a family with a known BRCA1 or BRCA2 mutations could be detected, that is, members of a ‘non-BRCA1/2 family’ (n=113);women belonging to a family where no n=46). These families were untested for various reasons, for example, all breast and ovarian cancer cases were deceased or refused testing.women from untested high-risk families .Genomic DNA was extracted from 300 μl reactions using 25 ng DNA, 0.4 μM of each primer, 0.1 mM of each deoxynucleotide , 5% DMSO , 2.5 mM MgCl2 , 1 × PCR Gold buffer (Applied Biosystems) and 1 U AmpliTaq Gold (Applied Biosystems).PCR was performed in 15-The PCR product was analysed in an ABI3100 Genetic Analyzer (Applied Biosystems) and the results were evaluated using Genescan software. The number of repeats was determined by sequencing samples of varying sizes  and using them as standards in fragment size analysis.μg l−1.Insulin-like growth factor-1 was analysed in EDTA plasma using the radio-immuno assay (RIA) method at the Endocrinological laboratory at the Karolinska Hospital, Stockholm, Sweden, as previously described by U-test was used to compare the body weight between parous and nulliparous women. Chi-square was used to compare the frequency of the absence of IGF1 19-repeat allele between known BRCA1 mutation carriers and other women. Multivariate linear regression was used to compare circulating IGF-1 levels in relation to genotype, parity and use of hormonal contraceptives. A log-rank test was used to analyse the risk of breast cancer in relation to IGF1 genotype. Cox regression was used to analyse the hazard of developing breast cancer in relation to IGF1 genotype adjusting for other factors. As the study was based on a priori hypotheses, that is, that the IGF1 genotype was associated with an idiosyncratic response to hormone exposure in young women  than among the women without breast cancer (11.7%). Total breast volume measurements, taken 5–10 days before the predicted onset of the next menstrual period, were available for 240 women who were not currently breast-feeding and who had not undergone previous breast augmentation or reduction surgeries.The characteristics of the 258 women at baseline are described in rs=0.68; P<0.001) and the waist-to-hip ratio , but not with height . Parous women were on average 5.4 kg heavier than nulliparous women (P=0.001). The weight-adjusted breast volumes in nulliparous and parous women depended on the IGF1 genotype and current hormonal contraceptive status. In all, 87% of the women carried at least one IGF1 19-repeat allele. Women who lacked the IGF1 19-repeat allele were nonsignificantly lighter than women with at least one 19-repeat allele , while no effect on height was seen. There was a strong interaction between parity and IGF1 genotype on breast volume (P=0.01). We therefore stratified the women depending on the absence or presence of the 19-repeat allele. Among the 209 women with at least one 19-repeat allele, the weight-adjusted breast volume was significantly smaller in parous women compared with nulliparous women (P=0.02) and nonsignificantly smaller in current oral or hormonal contraceptive users (P=0.06). Conversely, among the 30 women with no 19-repeat allele, the weight-adjusted breast volumes were nonsignificantly larger in parous than in nulliparous (P=0.06), and also nonsignificantly larger in current OC users (P=0.12).Breast volume was strongly correlated with body weight  and during cycle days 18–23 . There were no major differences in age decline in circulating IGF-1 levels in the samples collected during cycle days 5–10 between women with or without the IGF-1 19-repeat allele , while the age decline in the samples obtained during cycle days 18–23 was larger among women with than without the 19-repeat allele .Age was correlated with IGF-1 levels both during cycle days 5–10 . During cycle days 18–23, there was an interaction between parity and current hormonal contraception on IGF-1 levels (P=0.05). The age-adjusted IGF-1 levels during cycle days 18–23 were similar among parous and nulliparous women not using hormonal contraception  among nulliparous women, while no such effect was seen among parous women (P=0.35). Among hormonal contraceptive users, parous women had nonsignificantly higher circulating IGF-1 levels compared with nulliparous hormonal contraceptive users (P=0.11). The results remained essentially the same if women who were using other types of hormonal contraception than combined OCs were excluded.Parity and current hormonal contraception had no significant impact on the age-adjusted IGF-1 levels obtained during cycle days 5–10 , but not hormonal contraceptive users lacking the 19-repeat allele (P=0.81), confirming previous studies of an idiosyncratic response in circulating IGF-1 levels to hormonal contraception among nulliparous women lacking the IGF1 19-repeat allele. The results remained essentially the same for nulliparous women if women who were using hormonal contraception other than combined OCs were excluded. Among parous women, no significant effect on age-adjusted IGF-1 levels from hormonal contraceptive use was seen, independent of IGF1 genotype. The results remained essentially the same if women who were using hormonal contraception other than combined OCs were excluded.The P=0.026, . NullipaIGF1 genotype did not significantly modify the effect of pregnancy on circulating IGF-1 levels among women not using hormonal contraception and who were not currently breast-feeding. No significant difference between parous and nulliparous women was seen irrespective of the absence or presence of the 19-repeat allele.The IGF1 19-repeat allele was associated with breast cancer during follow-up . In the second model, we included only parous women. The age-adjusted hazard ratio for parous women lacking the 19-repeat allele was 6.62  compared with parous women with at least one copy of the 19-repeat allele.To date, six women have been diagnosed with breast cancer, three with bilateral disease. The median follow-up time of the cohort was 1.4 years (range 0.07–6.93 years). Two of the breast cancers were diagnosed at the time of prophylactic mastectomy. In all, 14 other women reported having undergone prophylactic mastectomies after inclusion in this study, but no cancers were detected at the time of surgery. Four cases were known BRCA1 mutation carriers and two cases belonged to untested families and have chosen to not undergo testing themselves after their cancer diagnoses. The median age at diagnosis was 38.5 years (range 28–44 years). All cases had started OC use during their teenage years and only one had never given birth. Absence of the BRCA1 and BRCA2 mutations, mostly because of their young age or because no affected family member could be tested. Absence of the 19-repeat allele of the IGF1 gene was more often found in known BRCA1 mutation carriers than in other women  and the two variables could therefore not be examined in the same model. Our data suggest that BRCA1 mutation carriers who also lack the IGF1 19-repeat allele may be at a higher risk for early-onset breast cancer than BRCA1 mutation carriers with presence of the 19-repeat allele. Among the 20 women with known BRCA1 mutations, six were lacking the 19-repeat allele. Of these six women, two have undergone prophylactic mastectomy, three have been diagnosed with breast cancer and one is still healthy. Among the 14 women with at least one copy of the 19-repeat allele, six have undergone prophylactic mastectomy, one has been diagnosed with breast cancer and seven are still healthy.A large proportion of the women are still untested for IGF1 genotyping on 86 women with available DNA from the South Swedish BRCA1 mutation families who did not carry the mutation in their respective families and who did not have breast cancer at the time of testing. These women were between 20 and 91 years old at the time of testing. Three of the 32 women (9.4%) who were 40 years or younger at the time of testing lacked the 19-repeat allele, and two of the 54 women (3.7%) who were 41 years or older at the time of BRCA1 mutation testing lacked the 19-repeat allele. When this additional control group and the 45 BRCA1 negative women in the present study were considered together, the frequency of the absence of the 19-repeat allele was 8.4% among all BRCA1-negative women in the South Swedish region with available DNA. For women aged 40 years or younger at testing, the frequency was 11.7%.As an additional control group, we also performed IGF1 19-repeat allele was associated with larger breast volumes in parous women and in hormonal contraceptive users, after adjustment for body weight, and secondly that parity was not associated with a decrease in circulating IGF-1 levels contrary to the report based on women in the general population  compared with other women (11.5%) in the present study. Conversely, all women who belonged to families with BRCA2 mutations carried at least one copy of the 19-repeat allele in the present study. BRCA1, and reported that the transcription of the IGF-1 receptor gene in breast cancer-derived cell lines is under the inhibitory control of BRCA1. Others have reported that the IGF1 genotype is linked to a low birth weight . Using brassiere cup size as a measurement of breast volume is a less satisfactory method, since different brands of brassieres differ in size. Furthermore, an increase in rib cage circumference results in a decrease in cup size. Thus, for two women with the same breast volume but different rib cage circumferences, the woman with the narrower rib cage would wear a larger cup size than the one with the wider rib cage. A more exact procedure may have been to use water displacement, which we actually tried, but it ended up being very messy and was actually less reproducible than the approximated pyramid. We only have breast measurements taken either before or after pregnancy, and serial measurements in each woman to confirm an actual increase or decrease in breast volume depending on IGF1 genotype would have been preferable. Mammography or ultrasound would have allowed us to validate the amount of breast epithelium of each woman. However, because many women in our study were very young, not all of them have undergone mammography or ultrasound.There is no standard way of measuring breast volume. In this study, breast volume was measured and approximated to a pyramid for practical reasons. We have previously published data on breast volume measured by the same technique as in the present study in relation to exogenous and endogenous hormone exposure among 19–25-year-old healthy nulliparous women . The corIGF1 19-repeat allele was associated with larger breast volumes in parous women and hormonal contraceptive users and an idiosyncratic response to hormonal contraceptives among nulliparous women. An early analysis of new breast cancers in the cohort also supported our hypothesis that absence of the 19-repeat allele in combination with hormonal contraceptives may be associated with an increased risk of early-onset breast cancer. The absence of the IGF1 19-repeat allele may be a new biomarker of increased OC- and pregnancy-associated breast cancer, especially among BRCA mutation carriers where early-onset breast cancer is common. To our knowledge, this is the first time the effect of the IGF1 genotype in combination with teenage OC use on early-onset breast cancer incidence has been explored. Our data are strong enough to tolerate up to four additional cases that all carry the common IGF1 19-repeat allele instead of the high-risk genotype, that is, absence of the 19-repeat allele, and still remain significant. However, this is an early report and whether the absence of the IGF1 19-repeat allele could be used as an additional marker to improve risk estimates for early-onset breast cancer during genetic counselling warrants confirmation in a larger cohort.The main findings of this prospective study were that the absence of the


Caloric restriction sufficient to reduce adult height may reduce breast cancer risk. During World War II (WWII) there was a marked reduction in average caloric intake in Norway that resulted in greater nutritional diversity. We hypothesized that a positive association between height and risk of breast cancer would be stronger among women who were born during this period than among women born before or after the war. A total of 25 204 Norwegian women were followed up for approximately 11 years, and 215 incident cases of breast cancer were registered. We found the strongest positive association between height and breast cancer among women born during WWII: women in the tallest tertile (>167 cm) had a relative risk of 2.5  compared with the shortest (≤ 162 cm). Among women born before or after the war we found no clear association with height. The association with height in the WWII cohort may imply a role for early nutrition in breast cancer aetiology. © 2001 Cancer Research Campaign


The association between breast and endometrial cancer was investigated in a cohort consisting of 60,065 subjects . Complete follow-up until 1981 revealed a total of 260 endometrial cancers, as against an expected number of 151.1 (relative risk (RR) = 1.72; 95% confidence limits (CL) 1.46; 1.87). RR increased steadily from close to unity in women younger than 50 at breast cancer diagnosis to 2.40  in those 70 years of age and older. The excess number of endometrial cancers occurred primarily during the first five years of follow-up . A common causal agency for breast and endometrial cancer is more likely to lie in environmental than in genetic factors and other observations in the same population do not support that such factors are related to characteristics of the women's reproductive histories.


In a previous study in France, we reported that the relative risk of breast cancer associated with a family history of breast cancer was higher in those subjects with a history of abortions. The present study was undertaken to check the existence of this interaction in other studies and to investigate whether the interaction is modified by the time at which abortions occur. Data were obtained from six case-control studies in France, Australia and Russia, with information on family history of breast cancer and abortion for 2693 breast cancer cases and 3493 controls. The interaction effect was estimated in each study separately, then combined using a multivariate weighted average. The relative risk conferred by a family history of breast cancer increased with the number of abortions . There was a significant interaction between total number of abortions and family history (P = 0.04), but this was no longer significant when adjusted for other risk factors. The familial risk was highest for those who had had an abortion before first childbirth . The adjusted risk associated with family history was significantly higher in those with an abortion before first childbirth (P = 0.04). Our findings suggest a synergism between familial factors and abortion. The interaction was not substantially modified by the type of abortion (spontaneous or induced) but was modified by the time at which it occurred in relation to first childbirth. This suggests an effect of abortion itself rather than predisposition to abortion. Further studies of breast cancer cases, particularly among BRCA1 gene carriers and their families, could improve our understanding of this effect.


Chlamydia trachomatis antibodies as a surrogate marker of chlamydial pelvic inflammatory disease. Women with ovarian cancer (n = 521) and population-based controls (n = 766) were tested. IgG antibodies to serovar D of chlamydia elementary bodies (EBs) were detected using an ELISA assay. The odds of having ovarian cancer among women with the highest titers (≥0.40 OD units) were 0.6 (95% CI 0.4–0.9). These data do not support our earlier finding of elevated titers for antibodies to C. trachomatis among women with ovarian cancer.Pelvic inflammation has been implicated in the genesis of ovarian cancer. We conducted serologic measurements of  Ovarian canceris an often fatal disease with an uncertain etiology. We suggested that pelvicinflammation may play a role in the development of ovarian cancer . PID hasNeisseria gonorrhoeae or Chlamydiatrachomatis ascending into the upper genital tract to inflame theendometrium, tubes, and ovarian epithelium [C.trachomatis is the most common in American women [One quarter tothree quarters of proven cases of PID are caused by ithelium . Of the an women .C. trachomatis [ Chlamydia serology is a relatively specific marker of past chlamydial PID,particularly of more severe infections . Its senchomatis  and amonchomatis .We previouslyreported pilot results from a population-based case-control study (117 cases and 170 controls)of ovarian cancer showing that ovarian cancer was significantly associated withhigh IgG antibody titers to chlamydia . The purSubjects for this serologic analysis were part of a population-based case-control studyconducted in a contiguous region comprising Western Pennsylvania, Eastern Ohio,and Southwestern New York State. Cases were residents of this geographicregion with histologically confirmed, primary, epithelial ovarian, fallopiantube, or peritoneal cancer diagnosed between February 2003 and July 2006. Both invasive and borderline tumors wereincluded. Women were referred fromhospital tumor registries, clinical practices, or pathology databases andcontacted with the permission of their gynecologists. Eligiblewomen were at least 25 years of age and within 9 months of initial diagnosis.Controls consisted of women at least age 25 who lived intelephone exchanges wherein cases resided. Random digit dialing was used to identify age-eligible women, and thesewere further screened by the study team to ensure that they had not had aprevious oophorectomy or diagnosis of ovarian cancer. Eligible women were then invited toparticipate. Potential controls were frequency matched by 5-yearage group and telephone exchange to cases in an approximately 2:1 ratio.Women were interviewed in their homes by trained interviewers. The questionnaire included a reproductive andgynecological history, a contraceptive history, a medical history, a familyhistory, and information on lifestyle practices.We were able to draw blood on 92.5% of the interviewed cases and 84.4% of the interviewedcontrols. Blood samples were processedwithin 2 hours of collection by a laboratory technician. For this analysis, we selected the first 521cases and 766 controls with complete questionnaires, tumor registry  information, and adequate serum samples.C. trachomatis elementary bodies (EBs), the extracellular form of the chlamydiabacteria, was conducted in the reference laboratory of one of the authors (RB)using an ELISA technique. Final readings are based on a mean ofduplicate runs. All assays wereconducted by personnel masked to case/control status. The intra-assay coefficient of variation forchlamydia antibodies was 0.06, representing excellent intra-assayreplication. Among masked replicates admixedinto the test set, Pearson correlation coefficients were 0.90 for chlamydia, againrepresenting excellent interassay variability.Serologic testing for IgG antibodies to serovar D of Each of the antibody levels tested was measured in optical density (OD) units (range 0.0–0.4+). We log transformed all OD units to reduceskewing when considering these as continuous measures and categorized OD unitsinto neat whole number categories when considering these as discretemeasures. These cut points correspondedto those in our published pilot study . Odds raAbout onequarter of women were youngerthan the age of 50 and halfwere age 50 to 65 see . Only abP = .001)  see . We then001) see . After aP = .021).In age-stratified analyses, we continued to find the chlamydia antibodies that reducedovarian cancer risk see . ResultsC.trachomatis serovar D EBs. Our dataare inconsistent with our previously published pilot results [C. trachomatis among ovarian cancer patients.We found that women with ovarian cancer were less likely to have high levels of IgG to  results  which shOur current finding is the reverse of the link between chlamydia and ovarian cancer in our previousanalysis . This isExplanations for a lack of association include the longperiod between exposure to chlamydia (in the reproductive period) and bloodcollection  in our population. If titers fall significantly over time, theymay have become undetectable in some women. Data from a Dutch study suggested that 18% of women had a decline oftwofold in chlamydia titers over four years . HoweverAnother explanation is the lack of sensitivity of antichlamydial antibody serologic testing. Only about 60% of women with PID developdetectable serology, and the test does not detect gonorrhea, another cause ofPID. This lack of sensitivity would haveresulted in erroneously missing some women with prior PID and would haveresulted in an odds ratio biased toward the null. Moreover, it is possible that ovarian cancer itself orits treatment might acutely reduce chlamydia titers, and therefore mask an association.Strengths of this study include the population-based ascertainment of cases and controls, thestandardized collection and storage of bloods, the measurement of chlamydia EB antibodiesat a reference, research laboratory, with laboratory personnel masked tocase-control status, and evidence of an independent effect after adjustment forpotentially confounding factors.In summary, our findings do not support previous evidence of a link between chronic persistentchlamydia infection, the most common cause of PID, and risk for ovarian cancer.