Familial colorectal cancer: a genetics treasure trove for medical discovery.
CANCERS OF THE COLON AND RECTUM ARE AMONG the leading causes of cancer deaths worldwide, accounting for 1 million new cases in 2002 and representing 9.4% of the world total. In 2006, more than 148 000 new cases were diagnosed in the United States, accounting for 10.4% of all cancers. Despite the increased use of screening strategies to identify early stage, more curable colorectal cancers and the availability of novel therapeutic agents, more than one third of patients with colorectal cancer will eventually die of uncontrolled metastatic spread within a few years of diagnosis. In 2006, 55 000 individuals died of colorectal cancer in the United States, which established colorectal cancer as the second leading cause of cancer deaths for men and the third for women. One of the hallmarks of colorectal cancer is its high degree of inheritability. Studies of twins indicate that approximately 35% of colorectal cancers are inherited. Furthermore, more than 11% of patients with colorectal cancer have at least 2 close relatives affected with the same disease. These studies suggest that a significant fraction of colorectal cancers are caused by cancer susceptibility genes. However, current knowledge of cancer genetics is primarily based on the identification of high penetrance tumor susceptibility genes such as APC, MLH1, MSH2, MSH6, and MYH. Germline mutations in these genes only account for up to 6% of all colorectal cancers. Recent results from genome wide association studies suggest that several different genomic regions may account for a significant proportion of the remainder of the familial risk. Whether a family history of colorectal cancer affects the outcome of patients diagnosed with the disease remains a topic of controversy. A study of 15 369 Japanese patients with a diagnosis of colorectal cancer showed that a family history of the disease was associated with a significantly better outcome. In contrast, in another study of 2236 patients with colorectal cancer from Utah, family history of the disease had no effect on survival. In this issue of JAMA, Chan and colleagues examined prospectively the association between family history of colorectal cancer and survival among patients with stage III disease who were enrolled in a large clinical trial of adjuvant therapy. Between April 1999 and April 2001, a total of 1264 patients were randomly assigned to received either a standard combination of fluorouracil plus leucovorin or an experimental combination of irinotecan, fluorouracil, and leucovorin. Eligible patients had completely resected stage III adenocarcinoma of the colon, no radiographic or surgical evidence of distant metastases, and no prior chemotherapy or radiotherapy. At an average of 5.6 years of follow up, the addition of irinotecan had no effect on either disease free survival or overall survival. Family history of colorectal cancer was surveyed in 1087 patients, 195 of whom (17.9% reported a family history in a firstdegree relative. Baseline characteristics of patients with or without a family history of colorectal cancer were essentially identical except for a higher percentage of clinical bowel obstruction in patients without a family history of colorectal cancer. Chan et al report that cancer recurrence or death from any cause was significantly lower among patients with a family history of colorectal cancer than among patients without such a history. Interestingly, the risk reduction associated with family history of colorectal cancer became stronger with an increasing number of affected first degree relatives. The major strengths of these findings are the detailed information regarding tumor stage, treatment, and length of follow up. Limitations include assessment of family history of colorectal cancer, which was self reported and did not include information on kindred size. Because the study only included patients with colon cancer, it is also unknown whether family history of colorectal cancer similarly affects the outcome of patients with a diagnosis of rectal cancer. Analyses of molecular predictors of survival after adjuvant chemotherapy for colon cancer have shown that loss of chromosome 18 correlates with a poor prognosis. Patients with tumors exhibiting microsatellite instability (MSI) have an overall better prognosis than patients with
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