# Project 2: Translational Significance of a Mutational Signature of African American Colon Cancers

> **NIH NIH P50** · CASE WESTERN RESERVE UNIVERSITY · 2020 · $362,917

## Abstract

PROEJCT SUMMARY/ABSTRACT
African Americans (AAs) continue to have the highest incidence and mortality rates of colorectal cancer among
all racial and ethnicity groups. To what extent differences in tumor biology contribute to the striking racial
disparities remain largely unknown. Our team has recently completed the first genome-wide analysis of the
mutational landscape of colorectal cancers specifically arising in AAs. This landmark study has identified a novel
15-gene mutation signature showing an over 3-fold increased mutation rate in AA colorectal cancers, and shown
that 41% of AA colorectal cancers have somatic mutations in at least one of the 15 genes, which is significantly
different from colorectal cancers derived from Caucasians. Furthermore, 14% of AA colorectal cancers harbor
mutations seen exclusively in AAs, most prominently including the ephrin type A receptor 6 gene [EPHA6]. We
further identified that these mutations convey a poor prognostic outcome in AA colorectal cancer patients.
Building upon these discoveries, the current proposal tests our central hypothesis that inherent biological
differences may in part be responsible for the disparate burden of colorectal cancer in AAs. In particular, we
propose to: (Aim 1) validate and establish a novel mutation subtype of colorectal cancer arising from African
ancestry genome and define the role of these mutations in AA colorectal cancer progression; (Aim 2) elucidate
the clinical and etiological significance of the mutation signature in AA colorectal cancer; and (Aim 3) to define
the functionality of AA colorectal cancer-derived EPHA6 mutations. The highly translational aims 1 and 2 will be
accomplished by re-sequencing the 15-gene mutations in a large independent set of AA colorectal cancer
patients (in comparison with Caucasian patients) who have annotated clinical and epidemiological information.
We will use CRISPR/Cas9 and cutting-edge organoid technologies in aim 3 to define the functional significance
of EPHA6 mutations derived from AA colorectal cancers. Our study will generate novel insight into the biological
basis for racial disparities in colorectal cancer and inform tailored prevention and intervention strategies to reduce
the burden of colorectal cancer in AA population.

## Key facts

- **NIH application ID:** 9987280
- **Project number:** 5P50CA150964-09
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** JOSEPH EDWARD WILLIS
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $362,917
- **Award type:** 5
- **Project period:** 2011-09-14 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9987280

## Citation

> US National Institutes of Health, RePORTER application 9987280, Project 2: Translational Significance of a Mutational Signature of African American Colon Cancers (5P50CA150964-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9987280. Licensed CC0.

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