Approximately 20% of individuals younger than age 50 who are diagnosed with colorectal cancer (CRC) carry a germline mutation associated with cancer, despite having no clinical or family history of the disease, according to a recent retrospective study.
From 1998 through 2015, Elena M Stoffel, MD, MPH, University of Michigan in Ann Arbor, and colleagues evaluated 430 cases of CRC that had been diagnosed in individuals younger than age 50 years. The study was performed at a single tertiary cancer care center.
Data on patient histories, tumor phenotypes, and results of germline DNA were collected and assessed. Germline DNA samples were sequenced via a research-based next-generation sequencing multigene panel among patients with uninformative clinical evaluations.
The primary outcome was defined as the identification of a pathogenic germline mutation associated with predisposition to cancer.
Results of the study showed that 111 (26%) cases had a first-degree relative with CRC, and 41 (10%) cases had tumors with histologic evidence for mismatch repair deficiency. A total of 79 of 315 patients who had undergone clinical germline sequencing had mutations associated with a hereditary cancer syndrome, while 21 of 315 patients had variants of uncertain significance.
Furthermore, 56 patients had pathogenic variants associated with Lynch syndrome. Of these, 25 patients had mutations in MSH2, 24 in MLH1, 5 in MSH6, and 2 in PMS2. Pathogenic variants associated with familial adenomatous polyposis were observed in 10 patients.
Multigene panel tests revealed mutations in other cancer-associated genes including MUTYH (n = 8), SMAD4 (n = 2), BRCA1 (n = 1), TP53 (n = 1), and CHEK2 (n = 1). Additionally, next-generation sequence analysis via multigene panel indicated that 6 (5%) patients carried actionable germline variants. However, the researchers noted, only 43 (51%) of 85 patients with germline mutations associated with a hereditary cancer syndrome had a first-degree relative with CRC.
“Approximately 1 in 5 individuals diagnosed with CRC at age younger than 50 years carries a germline mutation associated with cancer; nearly half of these do not have clinical histories typically associated with the identified syndrome,” the researchers concluded. “Germline testing with multigene cancer panels should be considered for all young patients with CRC.”—Christina Vogt