||3R01CA246620-03S2 Interpret this number
||Sloan-Kettering Inst Can Research
||Collecting Whole Genome Sequence Data to Enhance the Value of the First Multi-Center Study of Colorectal Cancer Risk Factors and Biology in Nigeria
ABSTRACT: This application is being submitted in response to the Notice of Special Interest (NOSI) identified
as NOT-CA-22-056. We request germline whole genome sequencing in 250 well-phenotyped colorectal cancer
(CRC) cases and 250 matched cancer-free controls in Nigeria. These germline data will enhance the value of
our NCI-funded project, the first multi-center study of risk factors and tumor genetics for CRC in Nigeria. Our
parent study is motivated by the rapidly rising incidence and mortality of CRC in this region; CRC is now the 4th
most common cancer in the World Health Organization-Africa region. This rising burden is mirrored in Nigeria,
where >50% of patients die within 1 year of diagnosis. This highlights the need for cost-effective, evidence-based
prevention, screening, and treatment interventions in this limited-resource region. However, the severe dearth
of data in African populations hinders our ability to develop such efforts. The African Research Group for
Oncology (ARGO) has established infrastructure and local scientific partnerships for cancer studies in Nigeria.
We have banked specimens and successfully sequenced ARGO samples. Sequencing of 505 cancer genes in
tumors/matched blood from 64 Nigerian CRC patients identified compelling somatic and germline differences vs.
US patients. Nigerian patients had ~3-fold higher prevalence of high microsatellite instability in their tumors and
~3-fold higher prevalence of hereditary Lynch syndrome, among other differences. Data in only 505 genes
suggest CRC in Nigeria possesses unique biology—reinforcing the need for expanded genomic data in African
populations to confirm these findings and identify possible population-specific CRC genes. Large NCI-supported
consortia have been remarkably successful, uncovering ~100 CRC signals and pointing to novel disease
pathways. However, heavy European bias limits their generalizability, and greater inclusion of African ancestry
individuals in discovery efforts is essential. The expanded 1000 Genomes Project has sequenced the entire
genomes of 893 African ancestry individuals (including 327 Nigerians); however, these data were not designed
to examine cancer outcomes, epidemiologic factors, or somatic alterations in concert with germline alterations.
We will use our ongoing parent project to augment these efforts by creating a comprehensive resource in
~250 CRC cases and ~250 matched cancer-free controls in Nigeria. We will maximize the value of our
understudied population by combining whole genome sequence data with individual-level data in our parent
project, including outcomes, somatic and germline alterations in 505 cancer genes, clinical factors, and
epidemiologic factors. These data will serve as a powerful resource when combined with other NIH-backed
initiatives and can help bolster diversity in gene discovery studies, serve as a source of African ancestry controls,
or act as an additional genomic reference for West Africans. We will also evaluate the utility of a polygenic
risk score constructed from known risk alleles with CRC risk in Nigeria to inform if loci uncovered at great
NIH expense can be applied in West Africans while large-scale gene discovery efforts remain to be conducted.
None. See parent grant details.