domingo, 26 de noviembre de 2017

Germline Genetic Features of Young Individuals with Colorectal Cancer. - PubMed - NCBI

2017 Nov 12. pii: S0016-5085(17)36350-3. doi: 10.1053/j.gastro.2017.11.004. [Epub ahead of print]

Germline Genetic Features of Young Individuals with Colorectal Cancer.

Stoffel EM1, Koeppe E2, Everett J3, Ulintz P4, Kiel M5, Osborne J3, Williams L6, Hanson K3, Gruber SB7, Rozek LS8.

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Abstract

BACKGROUND & AIMS:

The incidence of colorectal cancer (CRC) in individuals younger than 50 years old 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.