Differential gain of chromosomal regions 20q or 13q with loss of 8p and 18q differentiates disease-free survival in colorectal cancer.

Abstract

126 Background: In microsatellite stable (MSS) colorectal cancer (CRC) cases, frequent amplifications in 13q and 20q regions have been reported with limited understanding of their potential role for prognosis and treatment. Based on an internal research molecular tumor board case analysis of a KRAS WT, MSS left-sided (LS), metastatic CRC patient, we noted 50% of the 11 listed variants of unknown significance were on 20q. This study aims to investigate the potential prognostic role for gain of 20q chromosomal regions relative to other chromosomal imbalances using a retrospective cohort. Methods: We performed a genome-wide CN cluster analysis using the TCGA data with resulting patient clusters compared based on Kaplan-Meier estimated disease-free interval (DFI) in months (mos) using a log-rank. We examined associations between CN-derived clusters and CRC phenotypes. Results: Using TCGA data, we identified four CN-derived patient clusters of which two had significantly different DFI’s. One longer DFI cluster (n = 83; median DFI = 28mos) was defined by a signature of copy neutral genes along Chr8p and 18q regions. The shorter DFI cluster (n = 46; median DFI = 20mos) was defined by a signature of Chr8p and 18q regions of loss. The two clusters significantly differed in terms of site (85% right-sided in the shorter vs. 85% LS in the longer DFI cluster) and MS status (81% MSS in the shorter vs. 72% MSI in the longer DFI cluster) with no significant differences in age (mean of 70 years at diagnosis) and KRAS status (around 50% WT) between clusters. The shorter DFI was able to be further differentiated based on gain of chromosomal regions 20q (n = 26; median DFI = 24mos) and 13q (n = 20; median DFI = 18mos). No significant differences in mean age, tumor stage, site, and MS status between the shorter DFI subgroups were noted. Enriched pathways in the Chr20q gain sub-cluster include cell differentiation (Hippo, Rap1, VEGF), whereas metabolic signaling pathways via AGE-RAGE and AMPK, as well as cell growth and malignant transformation via RAS are enriched in the Chr13q gain sub-cluster. Conclusions: Clinical sequencing is able to identify regions of gain in Chr20q and Chr13q as part of VUS’s. Gain of Chr20q has been reported with better survival in mCRC patients. Gain of chromosomal region 20q and loss of 18q has been reported to discriminate between Lynch Syndrome and familial colorectal cancer. Herein, we show that gain of the 20q region with 18q and 8p regions of loss is associated with shorter DFI and gain of 13q region with loss of 8p even worse prognosis.