Germline cancer susceptibility gene testing in unselected patients with colorectal adenocarcinoma: A multi-center prospective study.

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Hereditary factors play a role in the development of colorectal cancer (CRC). Identification of germline predisposition can have implications on treatment and cancer prevention. To determine prevalence of pathogenic germline variants (PGV) in CRC patients using an universal testing approach, association with clinical outcomes and the uptake of family variant testing.We undertook a prospective multi-site study of germline sequencing using an >80 gene NGS platform among CRC patients (not selected for age or family history) receiving care at Mayo Clinic Cancer Centers between April 1, 2018 and March 31, 2020.Of 361 patients, the median age was 57 years (SD 12.4), 43.5% were female, 82% were white and 38.2% had stage IV disease. PGV were found in 15.5% (n=56) of patients, including 44 in moderate and high penetrance cancer susceptibility genes. Thirty-four (9.4%) patients had incremental clinically actionable findings that would not have been detected by practice guideline criteria or a CRC specific gene panel. Only younger age at diagnosis was associated with presence of PGV (OR 1.99, 95% CI:1.12-3.56). After a median follow-up of 20.7 months, no differences in overall survival was seen between those with or without a PGV (P=0.2). 11% of patients had modifications in their treatment based on genetic findings. Family cascade testing was low (16%).Universal multi-gene panel testing in CRC was associated with a modest, but significant detection of heritable mutations over guideline-based testing. One in ten patients had changes in their management based on test results. Uptake of cascade family testing was low, a concerning observation which warrants further study.

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Authors: P L S Uson Junior, D Riegert-Johnson, L Boardman, J Kisiel, L Mountjoy, N Patel, B Lizaola-Mayo, M J Borad, D Ahn, M B Sonbol, J Jones, J A Leighton, S Gurudu, H Singh, M Klint, K L Kunze, M A Golafshar, E D Esplin, R L Nussbaum, A K Stewart, T Bekaii-Saab, N J Samadder