Comprehensive genetic characterization of rectal cancer in a large cohort of Japanese patients: differences according to tumor location

Background In clinical practice, rectal cancer (RC) is classified according to tumor location. However, RC’s genetic characteristics according to tumor location remain unclear. Therefore, we aimed to compare RC’s genetic characteristics according to tumor location. Methods In 611 patients with surgically resected RC, we performed genetic analyses and compared the results between low and other RCs. Low RC was defined according to the European Society for Medical Oncology (ESMO) guidelines and Japanese Classification of Colorectal, Appendiceal, and Anal Carcinoma (JCCRC). Results KRAS mutation accumulation was significantly higher in low RC under the ESMO classification. Gene expression levels significantly differed between the groups for CTNNB1 , KRAS , and ERBB2 , under the ESMO classification and for TP53 , KRAS , and ERBB2 under the JCCRC. Under the JCCRC, low RC had a significantly higher prevalence of fusion genes, such as EIF3E-RSPO2 , PTPRK-RSPO3 , and VTI1A-TCF7L2 . Consensus molecular subtype (CMS) distribution was significantly different between the groups under both classifications. In particular, low RC had lower and higher frequencies of CMS2 and CMS4, respectively. CMS2 and CMS4 frequencies in low RC were 14.8% and 41.5% under the ESMO classification and 14.5% and 41.6% under the JCCRC, respectively. Multivariate Cox regression analysis demonstrated that pT3-4, pN1-2, and CMS4 were associated with poor relapse-free survival. Conclusions Low RC exhibited distinct genetic characteristics from other RCs. In particular, CMS4 was more frequent in low RC and was a risk factor for poor prognosis. These findings potentially avail further information regarding tumor biology and could lead to improvements in RC treatment.