Section of Genetics - Genetic Cancer Susceptibility Group
Current Research Topics:
Genetic susceptibility to Nasopharyngeal carcinoma (NPC)NPC has an extremely heterogeneous geographical and ethnic distribution. Genetic susceptibility is likely play a role in susceptibility to NPC but the identity of the genes involved in susceptibility to NPC remains elusive.
Isolated populations, particularly those with unusually high diseases prevalence, offer rare opportunities to investigate the genetic cause of human disease. The Bidayuh ethnic subgroup of Sarawak Malaysia has unusually high prevalence of NPC. We have identified one exceptionally large Bidayuh multiplex pedigree in which 26 NPC cases can be traced back to a single founding village. We are conducting comprehensive genetic analysis of this pedigree using a combination of high-density genotyping and direct whole exome DNA sequencing. The genes of interest identified in this exceptionally large pedigree will be validated and replicated in additional populations.
Investigation of common and rare genetic variants in breast and melanoma cancer susceptibility genes.Bioinformatics tools can be used to classify variants as functional or non-functional or to quantify the functionality of the variants. We have developed a bioinformatics-driven analysis strategy to characterize rare, likely pathogenic sequence variants identified through a case-control mutation screening approach. The underlying assumption for the analysis of rare missense substitutions is that amino acid positions that are important to the native biological functioning of the protein should be conserved across evolutionary history. Our recent studies on the breast cancer susceptibility genes ATM (Tavtigian et al AJHG 2008) and CHEK2 (Le Calvez et al Breast Cancer Res 2011) demonstrate the efficiency of ranking rare missense substitutions using in silico program before comparing the distribution and frequencies of the different types of variants in cases vs controls. Although loss-of-function mutations in ATM and CHEK2 had been associated with intermediate-risk of breast cancer, our strategy allowed us to demonstrate that a subset of rare missense substitutions make a comparable contribution to disease susceptibility. We are now applying this technique to determine contribution of intermediate risk susceptibility genes in breast and melanoma. We are additionally working towards the scalability of these in silico-driven analytical methods to allow analysis of whole exome sequencing data.
Genome wide association (GWA) study approachesIn collaboration with the GEP group, GCS group staff members have provided genetic and analytical expertise for multiple GWAS studies, notably lung (Hung et al., Nature 2008, McKay et al., Nature Genetics 2008), HNSCC (McKay et al PloS Genetics 2011) and Kidney cancers (Purdue et al. Nature Genetics 2011). The GCS group continues to play an important role in these studies, and we are actively pursuing GWA studies of Hodgkin's lymphoma and cancers of the oral cavity. The GCS group also explores innovative bioinformatics approaches, including the optimization and application of SNP imputation methods (particularly in the context of parallel computing) and additionally Bayesian methods that allow the incorporation of prior knowledge (for example from genomics techniques) in the ranking of GWA study results. The GSP similarly plays an important role in GWA studies, providing the genotyping techniques to quickly replicate important findings, and further providing protocol validation, quality control and logistic support for the coordinated genotyping efforts involved in these studies.
The GCS group additionally collaborates extensively within the GEN section and across IARC. For example with the GEP and MOC groups in whole-genome expression profiling in kidney cancers and in HBV infected liver cancer, respectively. With the EGE group we studying epigenetic signatures within hepatocarcinomas (Hernandez-Vargas H et al., PLoS One 2010) and breast cancer stem cells (Hernandez-Vargas H et al., Epigenetics 2011). Finally, with ENV/RAD, we are conducting a genetic study in young people in the wake of the Chernobyl accident to identify genes that may modify the risk of radiation-related PTC.