LAUSR

Colorectal cancer (CRC) is one of the most life-threatening gastrointestinal cancers with around 1.9 million new cases and 935,000 deaths in the year 2020 worldwide. With limited access to health care, Hispanics tend to present with later-stage CRC when compared to NHWs, which likely accounts for their inferior survival after CRC diagnosis. Given the rising incidence of CRC among 20-39-year-old Hispanic individuals and the rapid growth in this segment of the population, this is a significant problem to study. As tumorigenesis is contingent upon oxidative stress, reactive oxygen species (ROS) may be one of the important progenitors in carcinogenesis. Here, we have hypothesized that ethnicity-based variations in the stress survival response axis and other related pathways may influence the capacity to suppress ROS, repair DNA damage, and regulate cell death signaling pathways in Hispanic CRC patients. To decipher the role of stress-survival pathway genes in Hispanic CRC disparities, we performed a meta-analysis of microarray and RNA-seq datasets obtained from the GEO, Oncomine, and TCGA and identified 28 stress-survival pathway-associated genes in the CRC datasets. These genes were screened for transcript-level expression by qRT-PCR in one normal colon and six CRC cell lines. cDNA arrays containing normal, and Stage I-IV human CRC samples were used to determine the transcript level expressions of the target genes in different stages of CRC from human tissues. Protein level expressions were evaluated by immunohistochemistry in CRC tissue microarrays containing different stages of tumor and normal human CRC tissues. These genes were also analyzed for their transcript level expressions in Hispanic (n=10) and NHW (n=10) tissues. Twenty-three out of the 28 genes were found to be differentially expressed in Hispanic CRC tissues when compared to NHW CRC tissues. Genes such as CHEK1 and MCM10 were found to be upregulated, whereas BCL2L12, CCNB1, CDK1, CDK4, FOXM1, and PDCD2L were seen to be down-regulated. Transcriptomic analysis (RNA-seq) revealed that 213 and 363 genes, respectively, were differentially expressed in NHW and Hispanic CRC tissues compared to the normal adjacent tissues. The genes involved in cytochrome P450 and PPAR pathways were found to be enriched in the Hispanic cohort. Cytokine IL17 signaling and chemical carcinogenesis pathways were enriched in Hispanic males, whereas PI3K-Akt pathway and chemokine signaling pathways were enriched in Hispanic females as compared to their NHW counterparts. The PPAR and IL17 signaling were seen to be enriched in early-stage (I/II) Hispanic CRC tissues, however, TGF-b and coagulation cascades were enriched in the later stages (III/IV) of Hispanic CRC tissues as compared to NHWs. The genes identified to be differentially regulated in Hispanic tissues and the pathways in which they are involved in should lead to potential biomarkers or therapeutic targets specific to the Hispanic population. Citation Format: Sourav Roy, Aditi Kulkarni, Urbashi Basnet, Soumya Nair. Genes and pathways related to Hispanic colorectal cancer disparities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1905.