Abstract
Ancestrally diverse and admixed populations, including the Hispanic/Latino/a/x/e community, are underrepresented in cancer genetic and genomic studies. Leveraging the Latino Colorectal Cancer Consortium, we analyzed whole exome sequencing data on tumor/normal pairs from 718 individuals with colorectal cancer (128 Latino, 469 non-Latino) to map somatic mutational features by ethnicity and genetic ancestry.
Global proportions of African, East Asian, European, and Native American ancestries were estimated using ADMIXTURE. Associations between global genetic ancestry and somatic mutational features across genes were examined using logistic regression.
TP53, APC, and KRAS were the most recurrently mutated genes. Compared to non-Latino individuals, tumors from Latino individuals had fewer KRAS (OR=0.64, 95%CI=0.41-0.97, p=0.037) and PIK3CA mutations (OR=0.55, 95%CI=0.31-0.98, p=0.043). Genetic ancestry was associated with presence of somatic mutations in 39 genes (FDR-adjusted LRT p<0.05). Among these genes, a 10% increase in African ancestry was associated with significantly higher odds of mutation in KNCN (OR=1.34, 95%CI=1.09–1.66, p=5.74×10-3) and TMEM184B (OR=1.53, 95%CI=1.10–2.12, p=0.011). Among RMGs, we found evidence of association between genetic ancestry and mutation status in CDC27 (LRT p=0.0084) and between SMAD2 mutation status and AFR ancestry (OR=1.14, 95%CI=1.00-1.30, p=0.046). Ancestry was not associated with tumor mutational burden. Individuals with above-average Native American ancestry had a lower frequency of microsatellite instable (MSI-H) vs microsatellite stable tumors (OR=0.45, 95%CI=0.21-0.99, p=0.048).
Our findings provide new knowledge about the relationship between ancestral haplotypes and somatic mutational profiles that may be useful in developing precision medicine approaches and provide additional insight into genomic contributions to cancer disparities.
Significance Our data in ancestrally diverse populations adds essential information to characterize mutational features in the colorectal cancer genome. These results will help enhance equity in the development of precision medicine strategies.
Competing Interest Statement
S.L. Schmit, J.C. Figueiredo, E.M. Siegel, M.C. Stern, and J.K. Teer received funding from the U.S. National Institutes of Health during the conduct of the study. J. Gong reports consulting/advisory roles for: Eisai, Exelixis, Janssen Biotech, Myovant/Pfizer, EMD Serono, Incyte, AVEO, Bayer, Seagen, Elsevier, Taiho Pharmaceutical. S.I. Felder reports a role on the advisory board of GSK and research funding from Natera. The remaining authors declare no competing interests.
Funding Statement
Research reported in this publication was supported in part by the National Cancer Institute of the National Institutes of Health under award numbers R01CA238087, R01CA155101, U54CA163068, U54CA163071, U54CA233465, U2CCA252971, and P30CA014089. It was further supported by a Moffitt Cancer Center Team Science Award. This research was also made possible through the Total Cancer Care Protocol and by the Tissue, Collaborative Data Service, Molecular Genomics, and Biostatistics and Bioinformatics Shared Resources at the H. Lee Moffitt Cancer Center … Research Institute; an NCI-designated Comprehensive Cancer Center (P30CA076292). Sequencing data was based in part upon data generated by the Oncology Research Information Exchange Network (ORIEN; http://www.oriencancer.org/) and support and coordination by Aster Insights (formerly M2Gen; https://www.asterinsights.com/). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. S.L. Schmit, J.C. Figueiredo, E.M. Siegel, M.C. Stern, and J.K. Teer received funding from the U.S. National Institutes of Health during the conduct of the study.
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I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.
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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
The study protocol was approved by the Institutional Review Boards at Cleveland Clinic (LC3 central coordinating center), Cedars Sinai Medical Center (HCCS), H. Lee Moffitt Cancer Center and Research Institute (TCC; PRBB), and Ponce Research Institute (PRBB).
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Footnotes
↵† Jointly supervised this work
Conflicts of interest: S.L. Schmit, J.C. Figueiredo, E.M. Siegel, M.C. Stern, and J.K. Teer received funding from the U.S. National Institutes of Health during the conduct of the study. J. Gong reports consulting/advisory roles for: Eisai, Exelixis, Janssen Biotech, Myovant/Pfizer, EMD Serono, Incyte, AVEO, Bayer, Seagen, Elsevier, Taiho Pharmaceutical. S.I. Felder reports a role on the advisory board of GSK and research funding from Natera. The remaining authors declare no competing interests.
Funding: Research reported in this publication was supported in part by the National Cancer Institute of the National Institutes of Health under award numbers R01CA238087, R01CA155101, U54CA163068, U54CA163071, U54CA233465, U2CCA252971, and P30CA014089. It was further supported by a Moffitt Cancer Center Team Science Award. This research was also made possible through the Total Cancer Care Protocol and by the Tissue, Collaborative Data Service, Molecular Genomics, and Biostatistics and Bioinformatics Shared Resources at the H. Lee Moffitt Cancer Center & Research Institute; an NCI-designated Comprehensive Cancer Center (P30CA076292). Sequencing data was based in part upon data generated by the Oncology Research Information Exchange Network (ORIEN; http://www.oriencancer.org/) and support and coordination by Aster Insights (formerly M2Gen; https://www.asterinsights.com/). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Data availability
Whole exome sequencing, genetic ancestry proportions and core analysis variables are available through dbGaP (phs003464).
Abbreviations used in text
- CRC
- colorectal cancer
- CI
- confidence interval
- HR
- hazard ratio
- ICD
- International Classification of Diseases
- LC3
- Latino Colorectal Cancer Consortium
- OR
- odds ratio
- SD
- standard deviation
- TCC
- Total Cancer Care
- HCCS
- Hispanic Colorectal Cancer Study
- PRBB
- Puerto Rico Biobank
- AFR
- African
- EAS
- East Asian
- EUR
- European
- NAT
- Native American.