A wide spectrum of gene mutations are highly prevalent in patients with early-onset colorectal cancer, suggesting that genetic counseling and testing with a multigene panel should be considered for all patients with early-onset colorectal cancer, according to a study published in JAMA Oncology.1

Hereditary cancer syndromes are associated with high risks of cancer and require intensive cancer surveillance to improve early detection; however, the prevalence and spectrum of these conditions among unselected patients with early-onset colorectal cancer remains unclear. Therefore, researchers sought to assess the frequency and spectrum of cancer susceptibility gene mutations in this population.

Researchers analyzed data from 450 patients diagnosed with colorectal cancer younger than 50 years who were prospectively enrolled in the Ohio Colorectal Cancer Prevention Initiative from 2013 to mid-2016. Using next-generation sequencing, they tested patients’ germline DNA for mutations in 25 cancer susceptibility genes.

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Results showed that 16% of patients harbored 75 gene mutations. Researchers found that 10.7% of patients had mismatch repair (MMR)-deficient tumors, with 83.3% of those having at least 1 gene mutation.

Among patients with MMR-deficient tumors, 37 patients had Lynch syndrome, which included: 13 with a MLH1 mutation; 16 with a MSH2 mutation; 1 with a MSH2/monoallelic MUTYH mutation; 2 with a MSH6 mutation; and 5 with a PMS2 mutation.

One patient had the APC c.3920T>A, p.I1307K mutation and a PMS2 variant, while 9 patients had double somatic MMR mutations, including 2 with germline biallelic MUTYH mutations). One patient also had somatic MLH1 methylation.

Among the 402 patients with MMR-proficient tumors, 8% had at least 1 gene mutation. Gene mutations in this subpopulation included: 9 with mutations in high-penetrance colorectal cancer genes; 13 patients with mutations in high- or moderate-penetrance genes not traditionally associated with colorectal cancer; and 10 patients with mutations in low-penetrance colorectal cancer genes.

Investigators observed gene mutations most frequently in APC, ATM, BRCA1/2, PALB2, APC c.3920T>A, p.I1307K, and monoalleleic MUTYH.

Of note, one-third of the 72 patients harboring mutations would not have received genetic testing under the established genetic testing criteria, suggesting that clinicians should consider multigene panel testing for all patients with early-onset colorectal cancer.


1. Pearlman R, Frankel WL, Swanson B, et al. Prevalence and spectrum of germline cancer susceptibility gene mutations among patients with early-onset colorectal cancer. JAMA Oncol. 2016 Dec 15. doi: 10.1001/jamaoncol.2016.5194. [Epub ahead of print]