Abstract 5865: Analysis of RNA sequencing data to advance our understanding of colorectal cancer health disparity in Native Hawaiians
Authors: Fu Yuanyuan , Takahashi Devin , Khadka Vedbar , Nasu Masaki , Jijiwa Mayumi , Borgard Heather , Fei Peiwen , Deng Youping 
Published: June 2022

Background Colorectal cancer (CRC) is the third deadliest cancer among Americans. Native Hawaiians (NH) as a unique ethnic group in the US, exhibit many disproportionate health issues. In particular, they suffer from both elevated CRC incidence and mortality rates. This study aimed to investigate if genetic differences could contribute to disparities observed between NH and White CRC patients by defining the association between unique NH-genetic differences and CRC outcomes.

Methods Paired tumor and adjacent normal biospecimens of NH CRC patients were collected from the Hawaii Tumor Registry (HTR), and gene expression and mutation were examined by RNA sequencing. Genomic data of CRC Whites was extracted from The Cancer Genome Atlas (TCGA) database as a comparative cohort. Differential expressed genes (DEGs) were identified for both NH and TCGA cohorts via DESeq2 with FDR q-value &lt; 0.05 and a cutoff of 2-fold change. MutTecT2 and GATK were used to identify significant somatic mutations. Least Absolute Shrinkage and Selection Operator (LASSO) logistic regression with 10-fold cross validation was performed to predict genetic risk factors for early detection, and Ingenuity Pathway Analysis (IPA) was processed for canonical pathways and network discovery. Univariate Cox proportional regression was performed to identify DEGs related to patient survival; multivariable Cox regression model with stepwise fitting generated a prognostic index (PI), and the prediction value was examined by the Area Under the Receiver Operating Characteristic Curve (AUC). A nomogram was developed by integrating PI and clinicopathologic factors; calibration curves were provided to internally validate the performance, and discriminative ability was appraised by concordance index.

Results In total, 2096 DEGs were identified between NH tumor and normal groups, 1740 transcripts and 78 carrying mutations were unique to NH compared to the TCGA Whites cohort. A set of 23 genes including 10 NH specific DEGs were identified as genetic risk factors for detecting NH with CRC, and the AUC was 99.8%. A 9 gene-signature prognostic model including 5 NH specific DEGs was built with high survival prediction capability (AUC=0.99), and Kaplan-Meier curve showed that the low PI group had a better survival than the high PI group in NH with CRC (Logrank P=3.6E-05). After adjustment by age, gender, and tumor grade, the prognostic 9 gene-signature was still significant (P=0.0059). By integrating the above signatures with prognostic clinicopathologic features, a nomogram was constructed to stratified patients with overall survival rates for 3, 10, and 20 years.

Conclusion This study demonstrated that CRC tumors from NH patients differ from White patients in their gene expression patterns and mutations, particularly those associated with clinical outcomes, which reinforced the necessity of NH race-specific biomedical research.

Citation Format: Yuanyuan Fu, Devin Takahashi, Vedbar Khadka, Masaki Nasu, Mayumi Jijiwa, Heather Borgard, Peiwen Fei, Youping Deng. Analysis of RNA sequencing data to advance our understanding of colorectal cancer health disparity in Native Hawaiians [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 5865.