March 06, 2017
3 min read

Cancer susceptibility mutations common in colorectal cancer

You've successfully added to your alerts. You will receive an email when new content is published.

Click Here to Manage Email Alerts

We were unable to process your request. Please try again later. If you continue to have this issue please contact

Nearly one in 10 patients with colorectal cancer harbored mutations in genes that may increase susceptibility to cancer, according to a study published in Journal of Clinical Oncology.

The research suggests the need for an expanded role of genetic testing in the treatment of the disease and in disease prevention for at-risk family members, according to the researchers.

Sapna Syngal
Matthew B. Yurgelun

“What surprised us, was that the likelihood of finding an inherited gene mutation linked to cancer was much higher than what has been shown before,” Sapna Syngal, MD, MPH, chief of gastrointestinal cancer genetics and prevention at Brigham and Women’s Hospital, said in a press release. “This suggests that every patient with colorectal cancer should raise the idea of genetic testing with their physician, and every physician should raise that idea with their patients, because it has implications not only for patients, but for their family members.”

Previous studies have identified Lynch syndrome in 2% to 4% of patients with colorectal cancer. Because those studies focused solely on high-risk patients, the true prevalence of inherited cancer susceptibility among unselected colorectal cancer populations was unknown.

Syngal and colleagues sought to assess the prevalence of cancer susceptibility gene mutations among patients with colorectal cancer, without preselecting for high-risk features.

The analysis included 1,058 patients (55.5% men; 88.8% white; mean age, 55.7 years) with varying stages at diagnosis (11.6% stage 1; 19.1% stage 2; 38.2% stage 3; 30.3% stage 4).

All patients underwent germline testing for mutations in 25 genes associated with inherited cancer risk. Each gene was categorized as high penetrance or moderate penetrance on the basis of published estimates of the lifetime cancer risks conferred by pathogenic germline mutations in that gene.

A total of 105 patients (9.9%; 95% CI, 8.2-11.9) carried one or more pathogenic mutations, including 3.1% (n = 33) with Lynch syndrome.

Additionally, 28 of 29 available Lynch syndrome colorectal cancers (96.6%) demonstrated abnormal microsatellite instability or mismatch repair results.

Another 74 patients (7%) harbored non–Lynch syndrome gene mutations, including 23 patients (2.2%) with mutations in high-penetrance genes: BRCA1/BRCA2 (n = 11) APC (n = 5), biallelic MUTYH (n = 3), PALB2 (n = 2), CDKN2A (n = 1) and TP53 (n = 1). Of those patients, 15 lacked clinical histories suggestive of underlying mutation.

Another 38 patients (3.6%) had moderate-penetrance colorectal cancer risk gene mutations, including monoallelic MUTYH (n = 19) APC*I1307K (n = 17) and CHEK2 (n = 2).

Researchers found that age at diagnosis, family history of colorectal cancer and personal history of other cancers did not significantly predict the presence of pathogenic mutations in non–Lynch syndrome genes.

“We’ve known for a long time that inherited factors often play into somebody’s risk for developing colorectal cancer,” Matthew B. Yurgelun, MD, assistant professor of medicine at Harvard Medical School, said in the release. “We’ve typically relied on factors like having a strong family history of the disease or being diagnosed with the disease at a young age, to guide who gets genetic testing to look for well-described hereditary syndromes, such as Lynch syndrome.”

To date, no therapies have been approved for colorectal cancer that target cancer susceptibility genes among the test panel. However, researchers speculate that drugs that target these genes for other types of cancers, such as BRCA genes in breast cancer, may prove effective in colorectal cancer.

“If you have a genetic mutation that puts you at risk not only for colorectal cancer, but for pancreatic or breast cancer, then you need to be followed for those cancers,” Syngal said, adding that family members of those with cancer susceptibility gene mutations should also be screened.

“It’s time for colorectal patients to have the same awareness about genetic testing that exists for other cancers, such as breast and ovarian cancer,” Syngal said. “More than a million people in this country have Lynch syndrome, but the vast majority of them are unaware that they carry it.”– by Chuck Gormley

Disclosure: NCI and Myriad Genetics funded this study. Syngal reports a consultant/advisory role with Eisai. Yurgelun reports research funding from Myriad Genetics. Please see the full study for a list of all other researchers’ relevant financial disclosures.

click me