Kenneth Offit: Overview

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Discovery and Characterization of Novel Cancer Predisposition Alleles

The laboratory serves as the translational research arm of the Clinical Genetics Service in the Department of Medicine, and also collaborates closely with colleagues in the Cancer Biology and Genetics Program of the Sloan Kettering Institute. A historical interest of the laboratory has been the study of genetic isolates and the insights the study of founder mutations provide into the phenotypic spectrum of hereditary disease in all populations. The lab discovered the most common BRCA2 mutation, and was among the first to describe the most common BRCA1 mutation associated with susceptibility to breast and ovarian cancer(1–3), as well as the most common MSH2, APC, and BLM mutations associated with colon cancer in Ashkenazi Jews(4, 6, 8, 10). The lab also played a leading role in discovering the common CHEK2 mutation in this population (16, 20).

The description of these recurring mutations has had broad implications on the management of all populations at hereditary risk for cancer. This work included description of other cancer risks associated with BRCA mutations, including ovary (9) colon (12), and prostate (13) cancer and, under the leadership of clinical lab members Drs. Mark E. Robson and Noah Kauff, studies defining  the clinical behavior and optimal management of women and men carrying BRCA mutations(7, 11, 14, 15, 18, 22, 23, 25, 27). Population genetic studies have also defined the haplotype structure of Ashkenazim(5, 17, 24, 26), leading to one of the first genome-wide association studies (GWAS) of  breast cancer (19) and the discovery of a novel cancer risk allele on chromosome 6 (21). A large international GWAS of modifiers of risk of BRCA2 mutations discovered a novel locus on chromosome 10 (28), and a follow up to this study used the “onco-chip” to scan approximately 10,000 BRCA2 carriers on protocols worldwide. That study discovered the first modifying locus that is not by itself a breast susceptibility locus.

The lab has been focused on utilizing massively parallel sequencing to identify novel cancer predisposing genes in humans. This work involves families with hereditary breast, ovarian, colon, renal, and other solid tumors, as well as lymphoma, myeloma, and acute lymphocytic leukemia. The work is supported by significant grants from the Starr Consortium, the Beene Foundation, and a recent RO1 grant from the National Cancer Institute.

Other translational projects have focused on the integration of genetic testing for both common and rare variants into clinical management(29, 30), as well as on the clinical utility of genome-wide association studies (31). Clinicians in the laboratory, including Drs. Robson and Kauff and Zsofia K. Stadler, are extensively exploring the clinical translation of germline genetics of breast, ovarian, colon and other cancers. Pharmacogenomic studies, led largely by Dr. Robert J. Klein as well as clinical fellows rotating in the laboratory, are also in progress for bladder, prostate, lung, ovarian, pancreatic, and other cancers. All of the genotyping in the laboratory, which incorporates next-generation sequencing, is overseen by Dr. Vijai Joseph, who has worked closely with colleagues at the Cold Spring Harbor Laboratories and the Broad Institute as part of ongoing collaborations. Recent translational studies have included a second cancer GWAS (32), identification of a novel de novo mechanism of germline susceptibility to cancer (33), and the identification of a homeobox gene-associated breast cancer risk (34). A major effort is under way to devise approaches to translate germline whole exome associated risks for cancer and other diseases. This effort will serve as a forerunner to clinical availability of the personalized genome(35, 36).