Genetic testing urged for all patients with early-onset colorectal cancer

Reuters Health Information: Genetic testing urged for all patients with early-onset colorectal cancer

Genetic testing urged for all patients with early-onset colorectal cancer

Last Updated: 2016-12-21

By Marilynn Larkin

NEW YORK (Reuters Health) - Genetic counseling and testing with a multigene panel should be considered for all patients with early-onset colorectal cancer (CRC), who are at risk for a "spectrum" of hereditary cancer syndromes, according to the Ohio Colorectal Cancer Prevention Initiative Study Group.

"Hereditary cancer syndromes infer high cancer risks and require intensive cancer surveillance, yet the prevalence and spectrum of these conditions among unselected patients with early-onset CRC is largely undetermined," Dr. Heather Hampel of The Ohio State University Comprehensive Cancer Center in Columbus and colleagues write in JAMA Oncology, online December 15.

To investigate, they recruited 450 patients diagnosed with CRC before age 50 from 2013 to 2016. Mismatch repair (MMR) - a system within the cell for detecting and correcting errors in DNA - was determined by immunohistochemistry and/or microsatellite instability. Next-generation sequencing was used to test germline DNA for mutations in 25 cancer susceptibility genes.

A total of 75 gene mutations were found in 72 patients (16%). Forty-eight patients (10.7%) had MMR-deficient tumors, and 40 (83.3%) had at least one gene mutation: 37 had Lynch syndrome (with multiple variants); one patient had the APC c.3920T>A, p.I1307K mutation and a PMS2 variant; nine patients (18.8%) had double somatic MMR mutations; and one patient had somatic MLH1 methylation.

A total of 402 patients (89.3%) had MMR-proficient tumors, and 32 (8%) had at least one gene mutation: nine had mutations in high-penetrance CRC genes; 13 had mutations in high- or moderate-penetrance genes not traditionally associated with CRC (three in ATM; one in ATM/CHEK2; two in BRCA1; four in BRCA2; one in CDKN2A; and two in PALB2); and 10 patients had mutations in low-penetrance CRC genes.

"Importantly," the authors write, "24 of 72 patients (33.3%) who were mutation positive did not meet established genetic testing criteria for the gene(s) in which they had a mutation."

Dr. Hampel told Reuters Health, "Our study suggests that one out of every six patients with early-onset CRC has a mutation in a cancer susceptibility gene. This has major implications for their risks for developing additional cancers in the future and for their family members who may have also inherited the mutation and if so, also have increased risks for cancer."

"Several major professional organizations have already suggested screening all newly diagnosed colorectal cancer patients for Lynch syndrome, although this has not been implemented everywhere yet," she said by email. "In this approach, the only patients that get referred for cancer genetic counseling and consideration of genetic testing are those whose tumor screening suggests they are more likely to have Lynch syndrome."

"What we are now suggesting is that every colorectal cancer patient who is diagnosed under age 50 should be referred for genetic counseling and consideration of genetic testing regardless of the results of their tumor screening," she said. "The tumor screening still needs to be performed, however, because this determines whether or not the patient might benefit from immune therapy for their cancer."

Editorial coauthors Dr. Eduardo Vila of the University of Texas MD Anderson Cancer Center in Houston and Dr. Elana Stoffel of the University of Michigan, Ann Arbor, told Reuters Health the study "demonstrates that our current algorithms, which rely on specific family history and tumor characteristics for identifying who should have genetic testing, miss individuals with genetic predisposition to cancer."

"Not only did many young CRC patients with germline mutations fail to exhibit the clinical features typically associated with their genetic diagnosis, many had mutations in genes not usually associated with CRC risk," they said in a joint email. "The finding of a germline mutation associated with cancer predisposition in one in six young CRC patients is a strong argument for offering genetic testing with multigene panels, as making the genetic diagnosis of a hereditary cancer syndrome can help guide management of these patients and their family members."

Dr. Anton Bilchik, chief of medicine and of gastrointestinal research at John Wayne Cancer Institute at Providence Saint John's Health Center in Santa Monica, California, said the findings are important "as new drugs are (being) developed which may target these mutations."

"Furthermore," he told Reuters Health by email, "consideration should be given to screen other family members for colon cancer at a younger age . . . (and) every patient diagnosed with colon cancer under age 50 regardless of whether they have a family history."

Myriad Genetics donated the next-generation sequencing testing for mismatch repair-proficient patients with CRC under age 50. One coauthor is a Myriad Genetics employee and two other coauthors receive fees from the company.


JAMA Oncol 2016.

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