Background: The oncogenic pathways, including WNT, TP53, RAS, PI3K and TGFβ, were associated with tumor progression in colorectal adenocarcinomas (CRC). However, a majority of CRC patients have mutations from multiple pathways simultaneously, which makes it difficult to identify the key pathway influencing prognosis of CRC. Herein, we aimed to evaluate the novel dominant pathway-typing method in predicting the prognosis of Stage-III CRC.

Methods: Clinicopathologic and molecular variation data of Stage-III CRC patients (n=152) were obtained from The Cancer Genome Atlas database (TCGA). Immune cell infiltration level of the tumor was calculated by xCell ( Oncogenic pathway genes were classified according to a TCGA study (PMID: 29625050). In each patient, the dominant pathway-typing were based on which pathway the genes with the highest variant-allele-frequency (VAF) belongs to.

Results: In all, 124/152 (82%) patients had mutation on at least one of the oncogenic pathway genes and 120/124 (97%) patients harbored mutations from two or more pathways simultaneously. According to their dominant pathway-typing method, the patients were classified into five groups: WNT (n=45), RAS (n=26), TP53 (n=36), PI3K (n=8) and TGFβ (n=9) groups. There was no significant difference in OS among the five groups. However, the two-year survival rate of RAS group was significantly lower than that of WNT (p=0.042) and TP53 (p=0.035) groups. Further, we found that the infiltration of CD8+ T cell was significantly lower in RAS group compared to WNT group (with median infiltration score: 0.005 vs 0.013, p=0.024). Importantly, we found that among the RAS group without CD8+ T-cell infiltration, 63% (5/8) patients were died within two years after diagnosis. While the two-year death rate of WNT and TP53 groups without CD8+ T cell infiltration were zero (0/6) and 14% (1/7). And the two-year death rate of RAS, WNT and TP53 groups with CD8+ T cell infiltration were 17% (1/6), 11% (3/27) and 8% (1/13), respectively.

Conclusion: RAS pathway mutation may be associated with low CD8+ T cell infiltration and promote the two-year death rate of stage-III CRC patients using dominant pathway-typing method. And further larger cohorts are needed to validate these findings and the underlying mechanisms.

Citation Format: Zhipeng Jiang, Feilong Zhao, Hui Chen, Xiaochen Zhao, Yuezong Bai. Association of RAS pathway mutations with lower CD8+ T cell infiltration and 2-year survival rate in Stage-III colorectal adenocarcinoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1189.