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.
