Project Grant K99MD019294

IDENTIFYING UNIQUE BIOLOGICAL FACTORS AS POTENTIAL TARGETS TO MITIGATE COLORECTAL CANCER HEALTH DISPARITIES IN NATIVE HAWAIIANS - PROJECT SUMMARY / ABSTRACT NATIVE HAWAIIANS ARE ONE OF THE FASTEST GROWING ETHNIC MINORITIES IN THE US, AND EXHIBIT INCREASED INCIDENCE AND MORTALITY RATES OF COLORECTAL CANCER. TO ADDRESS THESE DISPARITIES, IT IS CRUCIAL TO IDENTIFY ETHNIC-SPECIFIC GENETIC VARIATIONS AMONG NATIVE HAWAIIANS THAT COULD OFFER VALUABLE INSIGHTS INTO COLORECTAL CANCER SUSCEPTIBILITY AND POTENTIAL TARGETS FOR INTERVENTION. BY GAINING A DEEPER UNDERSTANDING OF THESE GENETIC DIFFERENCES, WE AIM TO IMPROVE HEALTH OUTCOMES AND POSITIVELY IMPACT THE OVERALL WELL-BEING OF NATIVE HAWAIIANS. WE INITIATED AN INVESTIGATION TO DETERMINE IF NATIVE HAWAIIAN COLORECTAL CANCER POSSESSES DISTINCT BIOLOGICAL VARIATIONS BY UTILIZING TRANSCRIPTOME SEQUENCING (RNA-SEQ) ANALYSIS. OUR FINDINGS REVEALED A SET OF DIFFERENTIALLY EXPRESSED GENES AND SOMATIC MUTATIONS THAT WERE SIGNIFICANTLY ASSOCIATED WITH NATIVE HAWAIIAN COLORECTAL CANCER. TO VALIDATE THE TOP MUTATED CANDIDATE GENES PREDICTED BY RNA-SEQ, WE PERFORMED WHOLE GENOME DNA SEQUENCING ANALYSIS, AND UNVEILED SOME PREVIOUSLY UNRECOGNIZED SOMATIC MUTATIONS AND ONCOGENIC SIGNALING PATHWAY. THEREFORE, WE HYPOTHESIZE THAT BIOLOGIC VARIATIONS UNIQUE IN NATIVE HAWAIIAN COLORECTAL CANCER DRIVE AGGRESSIVE TUMOR DEVELOPMENT, AND LEAD TO HIGHER MORTALITY OF COLORECTAL CANCER. TO TEST THIS HYPOTHESIS, WE WILL UTILIZE PRE-EXISTING BIOSPECIMENS AND COMPREHENSIVE EPIDEMIOLOGY DATA AVAILABLE FROM PARTICIPANTS IN THE MULTIETHNIC COHORT (U01CA164973) TO IDENTIFY THE KEY RISK FACTORS CONTRIBUTING TO COLORECTAL CANCER DEVELOPMENT AMONG NATIVE HAWAIIANS. THE PROJECT OUTLINES THREE SPECIFIC AIMS THAT BUILDING ON THE PRELIMINARY STUDIES: AIM 1: UTILIZE WHOLE EXOME DNA SEQUENCING TO VALIDATE PRELIMINARY FINDINGS AND IDENTIFY MORE SPECIFIC GENETIC MUTATIONS PRESENT IN COLORECTAL CANCERS AMONG NATIVE HAWAIIANS; AIM 2: PROFILE AND ESTABLISH UNIQUE METABOLOMIC FEATURES SPECIFIC TO NATIVE HAWAIIANS WITH COLORECTAL CANCER; AIM 3: VALIDATE THE ETHNIC-SPECIFIC GENETIC AND METABOLOMIC FEATURES ASSOCIATED WITH NATIVE HAWAIIAN COLORECTAL CANCER RISK AND CLINICAL OUTCOMES BY INDEPENDENT COHORT VALIDATION, WHILE ALSO COMPARING THE FINDINGS WITH OTHER ETHNIC COHORTS. IN COMPLETING THESE AIMS, A ROBUST POPULATION-SPECIFIC MODEL WILL BE DEVELOPED, INTEGRATING BOTH GENETIC AND NON-GENETIC FACTORS, TO IDENTIFY HIGH-RISK NATIVE HAWAIIANS WHO WOULD BENEFIT FROM SCREENING AND EARLY INTERVENTION MEASURES. BY COMBINING GENETIC, METABOLOMIC, CLINICOPATHOLOGIC, AND EPIDEMIOLOGIC INFORMATION, THIS WILL BE THE FIRST COMPREHENSIVE STUDY TO EXAMINE EXOME-WIDE DNA, TRANSCRIPTOMIC, AND METABOLOMIC PROFILES IN COLORECTAL TUMOR TISSUE FROM NATIVE HAWAIIANS. IN DOING SO, WE WILL ESTABLISH A UNIQUE RESOURCE AND PROVIDE A MORE COMPLETE UNDERSTANDING OF NATIVE HAWAIIAN-COLORECTAL CANCER DISEASE ETIOLOGY AND RISK FACTORS, WHICH HAS THE POTENTIAL TO HELP ELIMINATE NATIVE HAWAIIAN COLORECTAL CANCER HEALTH DISPARITIES.