Extended Mutational Profiles and Clinical Outcome of Colorectal Carcinoma Patients from Rural Maine

Purpose: To test whether consecutive colorectal carcinomas treated in a rural Maine community practice recover the published driver-mutation spectrum, and whether concurrent APC, KRAS, and TP53 alteration identifies inferior overall survival independent of stage and mismatch-repair status. Methods: We analyzed consecutive colorectal carcinoma cases diagnosed and profiled at our pathology and molecular laboratory during 2017-2018 and subsequently treated at Northern Light Cancer Institute. Molecular abnormalities identified by a 50-gene hotspot next-generation sequencing panel (AmpliSeq Cancer HotSpot Panel v2.0, Thermo Fisher) were correlated with clinical characteristics and overall survival. Additional clinicopathologic variables were abstracted from institutional records. Results: The analytic cohort comprised 180 patients, of whom 172 had complete clinical follow-up (103 men [57%], 77 women [43%]; median age 66 years, range 28-95). Nearly all patients with documented race were White (99%); 42% were smokers; 71% had body-mass index >=25; 48% presented with early-stage (I-II) and 51% with advanced-stage (III-IV) disease. Fifteen percent of tumors were microsatellite-high or mismatch-repair deficient. The most frequently detected mutations were TP53 (61%), APC (41%), KRAS (34%), PIK3CA (21%), BRAF (17%), and SMAD4 (10%). After a median follow-up of 17 months, 77% of the survival-evaluable cohort (n = 172) were alive. Independent of strongly predictive advanced clinical stage (p < 0.001), patients with concurrent APC, KRAS, and TP53 mutations had significantly worse overall survival (log-rank p < 0.001). This association was independent of microsatellite-high status. Conclusion: Next-generation sequencing in a regional community oncology setting identified established prognostic and therapeutic markers and additional molecular features that correlated with outcome. The findings support prognostic stratification based on gene mutations outside current guideline-mandated testing, particularly concurrent APC, KRAS, and TP53 alterations, consistent with the multi-hit model of colorectal tumorigenesis and progression.