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

<b>Background/Objective:</b> 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 <i>KRAS</i>, <i>NRAS</i>, and <i>BRAF</i> hot-spot mutations and primary CRC sidedness. <b>Methods:</b> We performed a retrospective cohort analysis of 722 patients diagnosed with primary CRC and tested for <i>KRAS</i>, <i>NRAS</i>, and <i>BRAF</i> hot-spot mutations at the University of Texas Medical Branch (UTMB) from January 2016 through July 2023. Multivariable logistic regressions analyses were conducted. <b>Results:</b><i>KRAS</i>, <i>NRAS</i>, and <i>BRAF</i> 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%). <i>KRAS</i> and <i>BRAF</i> hot-spot mutations were significantly different according to tumor sidedness. <i>KRAS</i> p.Gly12Asp, p.Gly12Val, and p.Gly13Asp showed a significantly increased likelihood of right-sided primary CRC compared to <i>KRAS</i> wildtype, 128%, 134%, and 221% higher, respectively. Conversely, <i>KRAS</i> p.Gly12Val and p.Gly13Asp mutations were associated with decreased likelihood of rectal cancer (53% lower) and left-sided tumors (56% lower), respectively. <i>BRAF</i> p.Val600Glu mutation, as opposed to <i>BRAF</i> wildtype, was associated with a 278% higher likelihood of right-sided CRC. No significant associations were observed between <i>NRAS</i> mutations and primary CRC sidedness. <b>Conclusions:</b> In primary CRC, specific mutations in <i>KRAS</i> (p.Gly12Asp, p.Gly12Val, and p.Gly13Asp) and <i>BRAF</i> p.Val600Glu were associated with increased likelihood of right-sided tumors. <i>KRAS</i> 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.