Multiple Hereditary Cancer Syndromes May Underlie Early-Onset CRC

More than 15% of patients with early-onset colorectal cancer (CRC) may harbor mutations to cancer susceptibility genes, according to a new study. The mutations were found in a wide spectrum of genes, suggesting that genetic counseling and a multigene panel might be useful in patients with early-onset CRC.

“With the advent of next-generation sequencing, genetic testing for hereditary CRC has shifted from phenotype-specific single gene assessment to broad panels providing simultaneous assessment of multiple genes implicated in various hereditary cancer syndromes,” wrote Heather Hampel, MS, CGC, of the Ohio State University Comprehensive Cancer Center in Columbus, and colleagues. Previous studies have shown that multigene testing is feasible, but its utility in early-onset CRC was not previously known.

This study included 450 patients with CRC diagnosed before the age of 50; they were unselected for family history or mismatch repair (MMR) status. The results were published in JAMA Oncology.

Lynch syndrome, the most common known genetic cause of hereditary CRC related to mutations in MMR genes, was found in 37 patients. In total, 48 patients (10.7%) had MMR-deficient tumors; three of those had MLH1 methylation.

In total, the study found 75 gene mutations considered pathogenic or likely pathogenic, in 72 patients (16%). Thirty-four patients had a hereditary cancer syndrome other than Lynch syndrome; 61 patients (13.6%) had mutations in “high- or moderate-penetrance genes,” and 11 (2.4%) had mutations in low-penetrance genes.

Thirty-two patients with MMR-proficient tumors had at least one gene mutation. Of these, 9 had mutations in high-penetrance CRC genes including APC (5 patients), APC/PMS2, and others; 13 had mutations in high- or moderate-penetrance genes that have not traditionally been associated with CRC, including ATM, ATM/CHEK2, BRCA1/2, and others.

“Importantly, 24 of 72 patients (33.3%) with pathogenic mutations did not meet National Comprehensive Cancer Network guidelines for at least 1 of the gene(s) in which they were found to have a mutation,” the authors wrote, meaning they may not have been tested for these mutations. They also noted that the 16% prevalence of hereditary cancer syndromes found in this study is likely an underestimate, as there are likely other CRC susceptibility genes which have yet to be discovered and thus were not screened, and some variants of uncertain significance may eventually be found to be pathogenic.

“While it is important to continue MMR tumor screening for all patients with CRC for treatment purposes…genetic counseling and testing with a broad multigene panel should be considered for all patients with early-onset CRC due to their high prevalence of hereditary cancer syndromes,” the authors concluded.

In an accompanying editorial, Eduardo Vilar, MD, PhD, and Elena M. Stoffel, MD, MPH, of the University of Texas MD Anderson Cancer Center in Houston and the University of Michigan in Ann Arbor, respectively, noted that there are still some downsides to such multigene panel testing. “Variants of uncertain significance are common, identified in nearly 1 in 3 younger patients with CRC, and leave patients and healthcare professionals with ‘uncertain’ results,” they wrote.