Sidedness-Dependent Prognostic Impact of Gene Alterations in Metastatic Colorectal Cancer in the Nationwide Cancer Genome Screening Project in Japan (SCRUM-Japan GI-SCREEN)

SIMPLE SUMMARY: The treatment strategies and prognoses of patients with metastatic colorectal cancer differ according to the sidedness of the primary tumor. The aim of this study was to evaluate the sidedness-dependent prognostic impact of gene alterations in metastatic colorectal cancer. Among patients diagnosed with metastatic colorectal cancer enrolled from April 2017 to March 2019, 531 patients who underwent complete gene sequencing were assessed. TP53 gain-of-function and KRAS variants were poor prognostic factors, while the NOTCH3 sole variant was a favorable prognostic factor for left-sided metastatic colorectal cancer. The TP53 non-gain-of-function variant, BRAF V600E, and MYC amplification were poor prognostic factors for right-sided metastatic colon cancer. Prognostic gene alterations in metastatic colorectal cancer differed according to the sidedness of the primary tumor. ABSTRACT: The treatment strategies and prognoses of patients with metastatic colorectal cancer (CRC) differ according to the sidedness of the primary tumor. TP53 gain-of-function (GOF) and non-GOF variants have been reported to be differentially associated with prognosis by sidedness. We aimed to evaluate the sidedness-dependent prognostic impact of gene alterations in metastatic CRC. Patients enrolled between April 2017 and March 2019 were included in this study. Those excluded were individuals whose tumor tissues were obtained after chemotherapy and those who were enrolled in the study more than six months after starting first-line chemotherapy. Finally, we assessed 531 patients who underwent complete gene sequencing. The study revealed a significant difference in overall survival between individuals with left-sided CRC (n = 355) and right-sided colon cancer (CC) (n = 176) when considering the TP53 non-GOF variant, KRAS wild-type, NOTCH1 wild-type, NOTCH1 covariant, NOTCH3 sole variant, and MYC amplification. Multivariate analysis on each side revealed that the TP53 GOF and KRAS variants were independent poor prognostic factors for left-sided CRC (p = 0.03 and p < 0.01, respectively), and the TP53 non-GOF variant, BRAF V600E, and MYC amplification for right-sided CC (p < 0.05, p < 0.01, and p = 0.02, respectively). The NOTCH3 sole variant was an independent and favorable prognostic factor for left-sided CRC (p < 0.01). The prognostic significance of gene alterations differed between left-sided CRC and right-sided CC.