A new sequencing study published in Gastroenterology reports that analyzing DNA changes within colorectal polyps and cancers may help clarify cases of adenomatous or serrated polyposis when standard inherited (germline) genetic testing does not identify a cause.
Polyposis, marked by the development of numerous colorectal polyps, often raises concern for an underlying hereditary cancer syndrome. However, many patients with multiple adenomatous polyps or serrated polyps remain “genetically unexplained” after routine blood-based testing. The new findings suggest that profiling the mutations present in polyp tissue itself may provide additional diagnostic insight, including the identification of mosaic APC alterations that can be missed in traditional germline workups.
Researchers performed whole-exome sequencing on 299 colorectal tumors from 169 patients. The cohort included 153 patients with polyposis (adenomatous, serrated, or mixed phenotypes) and 16 with early-onset colorectal cancer without known pathogenic germline variants. Most lesions sequenced were premalignant polyps (91 percent), including 161 adenomas and 112 serrated polyps, with 26 carcinomas included for comparison.
Mutation profiles aligned with established pathways of colorectal tumor development. Adenomatous polyps were dominated by WNT-pathway driver events, with APC mutations detected in 73 percent of adenomas and hotspot CTNNB1 mutations in 12 percent. Serrated polyps showed strong enrichment of BRAF p.(Val600Glu), identified in 79 percent of serrated lesions, supporting BRAF mutation as a key early event in serrated tumorigenesis.
A clinically important finding was the frequency of APC mosaicism in adenomatous and mixed polyposis. Among individuals with at least two tumors sequenced, confirmed APC mosaicism was identified in 19 percent, with additional cases considered suspected based on shared APC variants detected across multiple lesions. Because mosaic variants may be present in only a subset of cells, they may not be detected through routine blood-based germline testing, which has implications for hereditary risk evaluation, genetic counseling, and laboratory reporting.
The study also assessed CpG island methylator phenotype (CIMP) in serrated lesions. Only 9 percent of tested serrated polyps were classified as CIMP-high, and most serrated lesions were microsatellite stable. Microsatellite instability and MLH1 promoter methylation were uncommon and mainly observed in a serrated colorectal carcinoma rather than in benign serrated polyps. Across samples, tumor mutational burden was generally low, consistent with early-stage neoplasia.
The authors conclude that somatic testing of colorectal lesions can help distinguish adenomatous versus serrated pathways in polyposis patients and may uncover mosaic APC alterations that provide an explanation for cases remaining unsolved after germline testing.
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