, , and Hot-Spot Mutations in Relation to Sidedness of Primary Colorectal Cancer: A Retrospective Cohort Study.

Studies have shown an association between colorectal cancer (CRC) sidedness and gene mutations that may affect CRC clinical behavior. This study examined the association between specific , , and hot-spot mutations and primary CRC sidedness. We performed a retrospective cohort analysis of 722 patients diagnosed with primary CRC and tested for , , and hot-spot mutations at the University of Texas Medical Branch (UTMB) from January 2016 through July 2023. Multivariable logistic regressions analyses were conducted. , , and hot-spot mutations rates were 37.8%, 4.6%, and 6.1%, respectively. Right-sided primary CRC had the highest prevalence of mutated tumors (64%). and hot-spot mutations were significantly different according to tumor sidedness. p.Gly12Asp, p.Gly12Val, and p.Gly13Asp showed a significantly increased likelihood of right-sided primary CRC compared to wildtype, 128%, 134%, and 221% higher, respectively. Conversely, p.Gly12Val and p.Gly13Asp mutations were associated with decreased likelihood of rectal cancer (53% lower) and left-sided tumors (56% lower), respectively. p.Val600Glu mutation, as opposed to wildtype, was associated with a 278% higher likelihood of right-sided CRC. No significant associations were observed between mutations and primary CRC sidedness. In primary CRC, specific mutations in (p.Gly12Asp, p.Gly12Val, and p.Gly13Asp) and p.Val600Glu were associated with increased likelihood of right-sided tumors. p.Gly12Val and p.Gly13Asp mutations were associated with decreased likelihood of rectal cancer and left-sided tumors, respectively. These findings suggest that tumorigenesis and mutational processes differ based on tumor sidedness. Further studies are needed to substantiate these findings.