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

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.

Single-cell transcriptomics and Mendelian randomization reveal LUCAT1’s role in right-sided colorectal cancer risk

“…Colorectal cancer, a prevalent malignancy, is categorized into left-sided and right-sided types, each differing significantly in molecular characteristics, clinical manifestations, and prognosis ( Choi and Kim, 2023 ; Sustic et al, 2023 ; Talhouni et al, 2023 ). For instance, left-sided colorectal cancers are commonly associated with KRAS and BRAF mutations, whereas right-sided cancers are more linked to microsatellite instability and CpG island methylation anomalies ( Bond et al, 2023 ; Kajiwara et al, 2023 ). Mendelian randomization analysis, a statistical tool, utilizes these genetic variations as natural experiments to establish causative links between specific genetic markers and cancer risk, providing crucial insights into the molecular mechanisms of colorectal cancer and the development of new therapeutic strategies.…”

“…Conversely, left-sided CRC often exhibits mutations in the KRAS and p53 genes, aligning with the typical adenoma-carcinoma sequence ( Brooks et al, 2001 ). Additionally, right-sided CRC shows higher genomic and epigenetic heterogeneity, while left-sided CRC is characterized by chromosomal instability ( Kajiwara et al, 2023 ). These molecular features not only influence the tumor’s biological behavior but also critically impact the response to various treatment modalities, playing a pivotal role in clinical decision-making.…”