Inherited Mutations Linked to Colorectal Cancer More Frequent than Believed, Study Finds

Inherited Mutations Linked to Colorectal Cancer More Frequent than Believed, Study Finds

The likelihood of having an inherited gene mutation linked to colorectal cancer may be higher than previously believed, according to researchers from the Dana-Farber Cancer Institute. In a study of more than 1,000 patients at risk of colorectal cancer, nearly 10% carried a pathologic mutation.

This finding, Cancer Susceptibility Gene Mutations In Individuals With Colorectal Cancer,” was published in the Journal of Clinical Oncology,

It was known that about 3% of colorectal patients have Lynch syndrome (LS), an inherited condition that increases the risk of many types of cancer. But this estimate may fall short of reality.

“We ultimately found that the prevalence of these hereditary cancer susceptibility mutations within [patients in our study] was about one-tenth, quite a bit higher than the traditional thinking,” Matthew Yurgelun, MD, the study’s first author, said in a press release.

The study enrolled 1,058 people considered to be at risk of colorectal cancer. Researchers collected blood samples to test them for mutations in 25 genes associated with inherited cancer risk. Genes were classified as “high penetrance” or “moderate penetrance” depending on the estimates for inherited risk triggered by mutations in each gene. Samples were not pre-selected according to factors such as family history of cancer or age-risk diagnosis.

Results showed that 105 patients (about 10%) had one or more pathogenic mutations; of those, 33 had mutations causing LS.

Also, 74 patients (7%) had non-LS gene mutations, including 23 with mutations in high-penetrance genes (five cases of mutated APC, three cases of altered MUTYH, 11 cases of mutated BRCA1/2, two cases of mutated PALB2, one case of mutated CDKN2A, and one case of mutated TP53). Among those patients, 15 had no clinical signs predictive of their mutation.

Also, 38 patients (3.6%) had moderate-penetrance risk gene mutations (19 cases of altered MUTYH, 17 cases of APC*I1307K, and two cases of mutated CHEK2). These mutations were not predicted by age at diagnosis, family history of colorectal cancer, or personal history of other cancers.

“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,” said Sapna Syngal, MD, senior author of the study. “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,” Syngal said.

“We’ve known for a long time that inherited factors often play into somebody’s risk of developing colorectal cancer,” said Yurgelun. “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,” he said.

Although there are no approved therapies against colorectal cancer that may target the mutations identified in the study, researchers believe that other cancer drugs, such as those targeting mutations in BRCA genes in breast cancer, may be useful.

Importantly, they call for a higher awareness of the need for genetic testing among patients, as it can improve follow-up care after therapy. “If you have a genetic mutation that puts you at risk not only for colorectal but for pancreas or breast cancer, then you need to be followed for those cancers,” Syngal said.

“If we can find a larger fraction of the population where we can identify a risk ahead of time, for them and even more importantly for their healthy family members, and then intervene to prevent cancer or reduce cancer risk, this testing may easily become cost-effective because the potential payoffs are so high,” Yurgelun said.

Researchers said they plan to continue their work by studying the exact role of the identified mutations in colorectal cancer and disease progression.

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Joana brings more than 8 years of academic research and experience as well as Scientific writing and editing to her role as a Science and Research writer. She also served as a Postdoctoral Researcher at the Center for Neuroscience and Cell Biology in Coimbra, Portugal, where she also received her PhD in Health Science and Technologies, with a specialty in Molecular and Cellular Biology.

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