Germline Genetic Features of Young Individuals With Colorectal Cancer

Abstract

Background & aims: The incidence of colorectal cancer (CRC) in individuals younger than 50 years is increasing. We sought to ascertain the proportion of young CRC cases associated with genetic predisposition.

Methods: We performed a retrospective study of individuals diagnosed with CRC at an age younger than 50 years, evaluated by the clinical genetics service at a single tertiary care cancer center from 1998 through 2015. We collected data on patient histories, tumor phenotypes, and results of germline DNA sequencing. For subjects with uninformative clinical evaluations, germline DNA samples were (re)sequenced using a research-based next-generation sequencing multigene panel. The primary outcome was identification of a pathogenic germline mutation associated with cancer predisposition.

Results: Of 430 young CRC cases, 111 (26%) had a first-degree relative with CRC. Forty-one of the subjects with CRC (10%) had tumors with histologic evidence for mismatch repair deficiency. Of 315 subjects who underwent clinical germline sequencing, 79 had mutations associated with a hereditary cancer syndrome and 21 had variants of uncertain significance. Fifty-six subjects had pathogenic variants associated with Lynch syndrome (25 with mutations in MSH2, 24 with mutations in MLH1, 5 with mutations in MSH6, and 2 with mutations in PMS2) and 10 subjects had pathogenic variants associated with familial adenomatous polyposis. Thirteen subjects had mutations in other cancer-associated genes (8 in MUTYH, 2 in SMAD4, 1 in BRCA1, 1 in TP53, and 1 in CHEK2), all identified through multigene panel tests. Among 117 patients with uninformative clinical evaluations, next-generation sequence analysis using a multigene panel detected actionable germline variants in 6 patients (5%). Only 43 of the 85 subjects with germline mutations associated with a hereditary cancer syndrome (51%) reported a CRC diagnosis in a first-degree relative.

Conclusions: 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. Germline testing with multigene cancer panels should be considered for all young patients with CRC.

Keywords: APC; FDR; NGS; Risk.

Figure 1

Genes implicated in High and Moderate Penetrance Hereditary Predisposition to Cancer

Figure 2

Outcomes of genetic evaluation in subjects with CRC age<50

Figure 3

Pedigree of Patient with a germline SMAD4 mutation identified on multigene panel 39F patient diagnosed with CRC at age 36 and report of “multiple” colorectal adenomas. At her initial presentation clinical genetic evaluation demonstrated that the colorectal tumor was microsatellite stable (MSS) and germline DNA sequencing identified no pathogenic mutations in APC or MUTYH. Patient returned 3 years later with anemia and underwent upper endoscopy which revealed numerous large gastric polyps which were described by outside pathology as hyperplastic. Clinical genetic testing with a multigene panel identified a pathogenic germline mutation in SMAD4, confirming diagnosis of Juvenile Polyposis Syndrome (JPS).