Browsing by Author "Odetunde, A."

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"Characterization of Nigerian breast cancer reveals prevalent homologous recombination deficiency and aggressive molecular features"
(Nature Research, 2018) Pitt, J. J.; Riester, M.; Zheng, Y.; Yoshimatsu, T. F.; Sanni, A.; Oluwasola, O.; Veloso, A.; Labrot, E.; Wang, S.; Odetunde, A.; Ademola, A.; Okedere, B.; Mahan, S.; Leary, R.; Macomber, M.; Ajani, M.; Johnson, R. S.; Fitzgerald, D.; Grundstad, A. J.; Tuteja, J. H.; Khramtsova, G.; Zhang, J.; Sveen, E.; Hwang, B.; Clayton, W.; Nkwodimmah, C.; Famooto, B.; Obasi, E.; Aderoju, V.; Oludara, M.; Omodele, F.; Akinyele, O.; Adeoye, A.||; Ogundiran, T.; Babalola, C.; MacIsaac, K.; Popoola, A.; Morrissey, M. P.; Chen, L. S.; Wang, J.; Olopade, C. O.; Falusi, A. G.; Winckler, W.; Haase, K.; Van Loo, P.; Obafunwa, J.; Papoutsakis, D.; Ojengbede, O.; Weber, B.; Ibrahim, N.; White, K. P.; Huo, D.; Olopade, O. I.; Barretina, J
Racial/ethnic disparities in breast cancer mortality continue to widen but genomic studies rarely interrogate breast cancer in diverse populations. Through genome, exome, and RNA sequencing, we examined the molecular features of breast cancers using 194 patients from Nigeria and 1037 patients from The Cancer Genome Atlas (TCGA). Relative to Black and White cohorts in TCGA, Nigerian HR + /HER2 − tumors are characterized by increased homologous recombination deficiency signature, pervasive TP53 mutations, and greater structural variation—indicating aggressive biology. GATA3 mutations are also more frequent in Nigerians regardless of subtype. Higher proportions of APOBEC-mediated substitutions strongly associate with PIK3CA and CDH1 mutations, which are underrepresented in Nigerians and Blacks. PLK2, KDM6A, and B2M are also identified as previously unreported significantly mutated genes in breast cancer. This dataset provides novel insights into potential molecular mechanisms underlying outcome disparities and lay a foundation for deployment of precision therapeutics in underserved populations.
Germline variants and somatic mutation signatures of breast cancer across populations of African and European ancestry in the US and Nigeria
(John Wiley & Sons Ltd, 2019) Wang, S. F.; Pitt, J. J.; Zheng, Y.; Yoshimatsu, T. F.; Gao, G.; Sanni, A.; Oluwasola, O.; Ajani, M.; Fitzgerald, D.; Odetunde, A.; Khramtsova, G.; Hurley, I.; Popoola, A.; Falusi, A.; Ogundiran, T.; Obafunwa, J.; Ojengbede, O.; Ibrahim, N.; Barretina, J.; White, K. P.; Huo, D.; Olopade, O. I.
Somatic mutation signatures may represent footprints of genetic and environmental exposures that cause different cancer. Few studies have comprehensively examined their association with germline variants, and none in an indigenous African population. SomaticSignatures was employed to extract mutation signatures based on whole-genome or whole-exome sequencing data from female patients with breast cancer (TCGA, training set, n = 1,011; Nigerian samples, validation set, n = 170), and to estimate contributions of signatures in each sample. Association between somatic signatures and common single nucleotide polymorphisms (SNPs) or rare deleterious variants were examined using linear regression. Nine stable signatures were inferred, and four signatures (APOBEC C>T, APOBEC C>G, aging and homologous recombination deficiency) were highly similar to known COSMIC signatures and explained the majority (60–85%) of signature contributions. There were significant heritable components associated with APOBEC C>T signature (h2 = 0.575, p = 0.010) and the combined APOBEC signatures (h2 = 0.432, p = 0.042). In TCGA dataset, seven common SNPs within or near GNB5 were significantly associated with an increased proportion (beta = 0.33, 95% CI = 0.21–0.45) of APOBEC signature contribution at genome-wide significance, while rare germline mutations in MTCL1 was also significantly associated with a higher contribution of this signature (p = 6.1 × 10−6 ). This is the first study to identify associations between germline variants and mutational patterns in breast cancer across diverse populations and geography. The findings provide evidence to substantiate causal links between germline genetic risk variants and carcinogenesis.
Whole-genome analysis of Nigerian patients with breast cancer reveals ethnic-driven somatic evolution and distinct genomic subtypes
(Nature Research, 2021) Ansari-Pour, N.; Zheng, Y.; Yoshimatsu, T. F.; Sanni, A.; Ajani, M.; Reynier, J.-B.; Tapinos, A.; Pitt, J. J.; Dentro, S.; Woodard, A.; Rajagopal, P. S.; Fitzgerald, D.; Gruber, A. J.; Odetunde, A.; Popoola, A.; Falusi, A. G.; Babalola, C. P.; Ogundiran, T.; Ibrahim, N.; Barretina, J.; Van Loo, P.; Chen, M.; White, K. P.; Ojengbede, O.; Obafunwa, J.; Huo, D.; Wedge, D. C.; Olopade, O. I.
Black women across the African diaspora experience more aggressive breast cancer with higher mortality rates than white women of European ancestry. Although inter-ethnic germline variation is known, differential somatic evolution has not been investigated in detail. Analysis of deep whole genomes of 97 breast cancers, with RNA-seq in a subset, from women in Nigeria in comparison with The Cancer Genome Atlas (n = 76) reveal a higher rate of genomic instability and increased intra-tumoral heterogeneity as well as a unique genomic subtype defined by early clonal GATA3 mutations with a 10.5-year younger age at diagnosis. We also find non-coding mutations in bona fide drivers (ZNF217 and SYPL1) and a previously unreported INDEL signature strongly associated with African ancestry proportion, under scoring the need to expand inclusion of diverse populations in biomedical research. Finally, we demonstrate that characterizing tumors for homologous recombination deficiency has significant clinical relevance in stratifying patients for potentially life-saving therapies.