Germline mutations
Thursday 9 June - 09:00-09:30
photo intervenant Stephen CHANOCK
Director of the Division of Cancer Epidemiology and Genetics at the National Cancer Institute, USA

Dr Stephen Chanock is a leading expert in the discovery and characterization of cancer susceptibility regions in the human genome. He has received numerous awards for his scientific contributions to our understanding of common inherited genetic variants associated with cancer risk and outcomes. Dr Chanock received his MD from Harvard Medical School in 1983 and completed clinical training in pediatrics, pediatric infectious diseases, and pediatric hematology/oncology and research training in molecular genetics at Boston Children's Hospital and the Dana-Farber Cancer Institute, Boston. Since 1995, Dr Chanock has served as the Medical Director for Camp Fantastic Exit Disclaimer, a week-long recreational camp for pediatric cancer patients, which is a joint venture of the NCI and Special Love, Inc. From 2001-2007, he was a tenured investigator in the genomic Variation Section of the Pediatric Oncology Branch in the NCI Center for Cancer Research. He also served as co-Chair of NCI's Genetics, Genomics and Proteomics Faculty for five years. In 2001, he was appointed as Chief of the Cancer genomics Research Laboratory (formerly Core Genotyping Facility), and in 2007 as Chief of the Laboratory of Translational genomics, both within the NCI Division of Cancer Epidemiology and Genetics (DCEG). Dr Chanock co-led the Cancer Genetic Markers of Susceptibility project. From 2012 to 2013, he also served as Acting Co-Director of the NCI Center for Cancer genomics. Dr Chanock was appointed Director of DCEG in August 2013.

Genetic Susceptibility to Cancer

For decades, the study of genetic susceptibility to cancer was conducted in families with multiple affected individuals and to date there are more than 115 known ‘cancer predisposition genes’, all rare in frequency. The emerging catalog of common variants by genome-wide association studies (GWAS) represents a distinct component of the underlying genetic architecture of cancer susceptibility, identifying regions that are specific to known cancer types; so far more than 500 independent regions have been identified and roughly 10% of the regions display pleiotropy across cancer types. Each susceptibility region harbors one or more alleles that alters regulation of redundant genes and pathways; interestingly, few result in protein coding changes and none appear to be ‘drivers’ of somatic alterations. Many are investigating the molecular basis of cancer susceptibility, specifically exploring how germline variants predispose individuals to specific cancers.  We are also poised to investigate gene-environment interactions and further understand how the germline informs the landscape of somatic alterations.  Sets of common variants identified in GWAS can be examined as a polygenic risk score and used to stratify populations in an effort to deliver precision prevention; the latter is based on profiles of genetic risk scores, along with other established risk factors and can be applied to public health measures. The study of germline variants has also revealed that with age, germline DNA can undergo somatic alterations as manifest as detectable genetic mosaicism across the spectrum from large structural alterations to point mutations. The patterns of these events underscore the complex nature of maintaining the stability of genomes, and with age, it appears that the genome begins to be at increased risk for events, some of which could be related to risk for cancer and other complex diseases.