Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer

MedicalResearch.com Interview with:
Matthew B Yurgelun, M.D

Instructor in Medicine, Harvard Medical School
Dana-Farber Cancer Institute

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: It has long been known that hereditary factors play a key role in colorectal cancer risk. It is currently well-established that approximately 3% of all colorectal cancers arise in the setting of Lynch syndrome, a relatively common inherited syndrome that markedly increases one’s lifetime risk of colorectal cancer, as well as cancers of the uterus, ovaries, stomach, small intestine, urinary tract, pancreas, and other malignancies. Current standard-of-care in the field is to test all colorectal cancer specimens for mismatch repair deficiency, which is a very reliable means of screening for Lynch syndrome. The prevalence of other hereditary syndromes among patients with colorectal cancer has not been known, though other such factors have been presumed to be quite rare.

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: We evaluated a cohort of 1058 patients seen at the Dana-Farber Cancer Institute for a diagnosis of colorectal cancer and performed genetic testing using a 25-gene hereditary cancer panel. This panel included the five genes linked to Lynch syndrome as well as an additional 20 cancer susceptibility genes, including genes linked to colorectal cancer risk (e.g., APC and MUTYH) and genes not traditionally thought of as being linked to colorectal cancer (e.g., BRCA1, BRCA2, PALB2, among others). We found that, overall, nearly 10% of colorectal cancer patients in this cohort carried inherited mutations in cancer susceptibility genes, including 3% with Lynch syndrome and 7% with non-Lynch syndrome mutations.

MedicalResearch.com: What should readers take away from your report?

Response: It is currently well-established that approximately 3% of all colorectal cancers arise in the setting of Lynch syndrome, a relatively common inherited syndrome that markedly increases one’s lifetime risk of colorectal cancer, as well as cancers of the uterus, ovaries, stomach, small intestine, urinary tract, pancreas, and other malignancies. Current standard-of-care in the field is to test all colorectal cancer specimens for mismatch repair deficiency, which is a very reliable means of screening for Lynch syndrome. Our study demonstrates, however, that hereditary factors that underlie colorectal cancer risk extend well beyond Lynch syndrome with an additional 7% of colorectal cancer patients having an inherited mutation in a cancer susceptibility gene. Thus, for healthcare providers who manage patients with colorectal cancer, it is important that we think beyond just Lynch syndrome when considering whether or not a patient has an inherited risk to cancer. Importantly, many features that we typically think of as indicating a high likelihood for underlying hereditary risk (e.g., young age at colorectal cancer diagnosis; family history of colorectal cancer) did not seem to be effective at identifying which colorectal cancer patients had mutations in these non-Lynch syndrome genes in this study, indicating that these individuals may be very difficult to identify with current paradigms of genetic testing.

MedicalResearch.com: What recommendations do you have for future research as a result of this study?

Response: These findings raise the provocative question as to whether or not all patients with colorectal cancer should undergo genetic testing with a multi-gene cancer panel. Our study does not definitively answer this question, since the clinical significance of some of the “unexpected” genetic mutations (e.g., germline BRCA1 or BRCA2 mutations in colorectal cancer patients; mutations in genes associated with only modestly increased risks of cancer) seen in this study is admittedly unclear. Exploring whether such mutations are truly causative of colorectal cancer and also what sorts of preventive measures are effective at reducing cancer risk for these mutation carriers are key questions that will need to be answered to understand how best to perform hereditary cancer risk assessment for our colorectal cancer patients going forward.

MedicalResearch.com: Is there anything else you would like to add?

Response: Disclosure: I have previously received research funding from Myriad Genetic Laboratories, Inc., who partially supported this study.

MedicalResearch.com: Thank you for your contribution to the MedicalResearch.com community.

Citation:

Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer
Matthew B. Yurgelun, Matthew H. Kulke, Charles S. Fuchs, Brian A. Allen, Hajime Uno, Jason L. Hornick, Chinedu I. Ukaegbu, Lauren K. Brais, Philip G. McNamara, Robert J. Mayer, Deborah Schrag, Jeffrey A. Meyerhardt, Kimmie Ng, John Kidd, Nanda Singh, Anne-Renee Hartman, Richard J. Wenstrup, and Sapna Syngal
Published at ascopubs.org/journal/jco on January 30, 2017.

Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.

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