Abstract 5779: Colorectal cancer and its molecular differences between sexes
Authors: Khalife Roy , Magliocco Genevra , Park So Hyeon , Magliocco Anthony 
Published: June 2022

Abstract
Introduction: Although the risk of colorectal cancer is roughly equal between sexes (slightly higher in males), the molecular profile between the two varies significantly. Many genes identified have a distinctive effect on outcome between these two subgroups, including actionable genes, the most frequently altered genes, and the most significantly altered genes. The molecular basis is important for understanding etiology and treatment options. Uncovering these molecular differences could help optimize screening and treatment and improve outcomes for colorectal cancer for both sexes.
Materials and Methods: This study used molecular data from three TCGA Colorectal Adenocarcinoma studies (Firehose Legacy, Nature 2012, and PanCancer Atlas) on cBioPortal. The two subgroups, males and females, were separated and analyzed for molecular differences. 1496 cases (790 male, 706 female) were analyzed on cBioPortal for molecular characteristics including alterations (mutations, deletions, amplifications), overall survival, and mRNA expression vs. copy number variation (CNV). Significant differences were noted, and OncoPrints and survival curves were generated.
Results: The genes analyzed on cBioPortal showed similar alteration rates between males and females, although differences were depicted between sex and specific genes. Out of the 17 actionable genes, four had a significant effect on one sex, but not the other. ARID1A alterations increased the probability of male survival (p-value = 0.0219), ERRB2 (0.0467) and NRAS (1.118e-3) decreased survival odds for males, and NF1 (0.0107) decreased survival odds for females. CDK12 and ERBB2 co-amplification was identified for both sexes, but more prominent in males.
Multiple altered genes also had a lower probability of survival in only females. Of the most altered genes, RBFOX1 (0.0312), CSDM1 (8.631e-3), TTN (4.374e-4), WWOX (2.226e-4), CCSER1 (5.048e-3), MACROD2 (0.0366), and a 20q co-amplification cluster of CHD6 (7.313e-3), PREX1 (5.422e-3), and ZNF335 (0.0439) were significant in females. Also, among the most significant genes between males and females, TENM1 alteration (found in 11% of females and 4% of males) lowered the probability of survival in females (1.384e-6). Lastly, 75% of females remained disease free after 70 months, compared to 45% of males (8.849e-3).
Conclusion: Molecular differences in colorectal cancer between males and females are significant. TTN is important to note due to its comparison to tumor mutational burden (TMB); TTN, combined with MUC4 and MUC16, can predict TMB and may be used as a convenient biomarker for effective immunotherapy in females. ERBB2 is potentially targetable with anti HER2 therapeutics, thus may improve the worse outcome observed in males with ERBB2 alterations. Colorectal cancer has different targetable genes expressed differentially among males and females. This needs to be considered when developing screening and treatment strategies.
Citation Format: Roy Khalife, Genevra Magliocco, So Hyeon Park, Anthony Magliocco. Colorectal cancer and its molecular differences between sexes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5779.