Association of Loss-of-Function Variants With Colorectal Cancer Risk in a Cohort of Over 950,000 Individuals.

PURPOSE

is a proposed colorectal cancer (CRC) predisposition gene, with only four families with putative loss-of-function (pLoF) variants published. The prevalence, phenotypic spectrum, and clinical management recommendations for heterozygotes remain unknown.

METHODS

Retrospective review of approximately 950,000 individuals undergoing multigene panel testing (MGPT) for cancer predisposition identified 36 individuals with pLoF variants in . Clinical features, tumor prevalence, and age at onset were compared with Lynch syndrome (LS) and wild-type (WT) cohorts.

RESULTS

Thirty-six individuals (0.004%) had 28 unique pLoF variants in and a total of 42 primary tumors, 78.6% of which were CRC with a median age of diagnosis of 50 years. A total of 16.7% of individuals had multiple CRC primaries, and a majority (71.4%) were mismatch repair-proficient (pMMR). Signet ring cell (SRC) pathology was significantly enriched compared with WT ( = <.0001). The odds ratio for CRC was significantly higher than that for the -related LS cohort (odds ratio [OR], 45.3 [95% CI, 21.3 to 101] and OR, 16.9 [95% CI, 14.9 to 19.2], respectively).

CONCLUSION

is associated with early-onset, pMMR CRC enriched for SRC pathology. Comparison of prevalence showed a statistically significant two-fold increase in the odds of developing CRC compared with an LS cohort. These data confirm the gene-disease relationship between and CRC and support clinical management guidelines similar to -related LS.