Characterizing the Somatic and Germline Mutational Landscape of Colorectal Cancer

The germline and somatic mutational landscape among patients with colorectal cancer was characterized, identifying the most common somatic driver mutations and pathogenic germline variants.

These data were presented by Preethi Srinivasan, Memorial Sloan Kettering Cancer Center, New York, New York, at the 2023 World Congress on Gastrointestinal Cancers in Barcelona, Spain.

This study included the results from 2303 patients with colorectal cancer who had commercial, personalized, tumor-informed circulating tumor DNA (ctDNA) testing ordered. Proportions of patients with somatic driver mutations and pathogenic germline variants in colorectal cancer-associated genes were calculated for the entire population of patients and across different characteristics, such as age of siease onset, sex, disease stage, and microsatellite stability status.

Overall the most common somatic driver mutations were APC (75.5%), TP53 (65.3%), TTN (48.6%), and KRAS (41.9%). There were 7.6% of patients who had pathogenic germline variants in colorectal cancer-associated genes. Most of the high-penetrance genes were due to Lynch syndrome. The rates of pathogenic germline variants were higher among the younger cohorts of patients (<45 years; 45 to 65 years) and among patients with microsatellite instability, compared to microsatellite stability, but were similar regardless of the patient’s sex or disease stage.

Differences in the genomic landscape of colorectal cancer was seen across the genetic ancestry of the patients. Microsatellite instability rates were highest among patients of East Asian ancestry, followed by European, and African patients. The most common somatic driver mutations were similar across the genetic ancestries to the overall population. While pathogenic germline variant rates were similar across the genetic ancestries, high-penetrance genes were more common in East Asian patients compared with African and European. Patients of East Asian ancestry were more likely to have Lunch syndrome genes than European patients.

Srinivasan et al concluded “These results demonstrated that integrated analysis of germline and somatic findings across various patient characteristics is critical for an optimal approach for all patients and for developing risk stratification strategies pertaining to early cancer detection.

Source:

Weitzel J, Srinivasan P, Gutman B, et al. Somatic and germline heterogeneity across colorectal cancer patients characteristics: Implications for early cancer detection. Presented at the 2023 World Congress on Gastrointestinal Cancers; June 28-July 1, 2023; Barcelona, Spain. Abstract O-8