As many as one in six patients with early-onset colorectal cancer (CRC) have a pathogenic genetic mutation, but around one-third of these patients may not have met the criteria for genetic testing for at least one of their mutations under current guidelines, researchers say.
Rachel Pearlman, MS, CGC, of The Ohio State University Comprehensive Cancer Center, and her coauthors reported the results of multigene panel testing of 450 patients aged under 50 years, from 51 institutions, who had been diagnosed with CRC (JAMA Oncol 2016 Dec 15. doi: 10.1001/jamaoncol.2016.5194).
Overall, 16% of patients were found to have a pathogenic or likely pathogenic cancer susceptibility gene mutations, with 83.3% having at least one gene mutation.
Thirty-seven patients had Lynch syndrome; 13 were MLH1, 16 were LSH2, 1 patient was MSH2/monoallelic MUTYH; 2 were MSH6, and 5 were PMS2.
“While the prevalence of Lynch syndrome reported herein (8.4%) is consistent with previous publications, this is the first study to our knowledge to determine the prevalence and spectrum of other hereditary cancer syndromes (8%) found in an unselected series of patients with early-onset CRC,” the authors wrote.
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Forty-eight patients (10.7%) had mismatch repair–deficient tumors, nine of which were in high-penetrance genes linked to CRC risk.
But for 145 patients, their genetic variants were of uncertain significance. Thirteen patients had mutations in high- or moderate-penetrance genes not traditionally associated with CRC, including ATM, ATM/ CHEK2, BRCA1, BRCA2, CDKN2A, and PALB2.
The authors pointed out that the multigene panel testing approach enables identification of hereditary cancer syndromes in patients who might not have otherwise met the criteria for testing.
“Importantly, 24 of 72 patients (33.3%) with pathogenic mutations did not meet NCCN Guidelines for at least 1 of the gene(s) in which they were found to have a mutation,” the researchers noted. These included three patients with MMR-deficient tumors who had additional mutations in genes that would not have been assessed, one patient with an MMR-proficient tumor who was also found to have Lynch syndrome, and six patients with BRCA1/2 mutations.
“Previous studies have reported early-onset CRC in women with BRCA1 mutations and BRCA2 mutations in families with familial colorectal cancer type X,” they noted.
The Ohio Colorectal Cancer Prevention Initiative (OCCPI) is supported by a grant from Pelotonia, and by the National Cancer Institute. Myriad Genetics Inc. donated next-generation sequencing testing. Nine authors disclosed ties with private industry, including Myriad Genetics.