Genome-wide association studies in women of African ancestry identified 3q26.21 as a novel susceptibility locus for oestrogen receptor negative breast cancer

Multiple breast cancer loci have been identified in previous genome-wide association studies, but they were mainly conducted in populations of European ancestry. Women of African ancestry are more likely to have young-onset and oestrogen receptor (ER) negative breast cancer for reasons that are unknown and understudied. To identify genetic risk factors for breast cancer in women of African descent, we conducted a meta-analysis of two genome-wide association studies of breast cancer; one study consists of 1,657 cases and 2,029 controls genotyped with Illumina's HumanOmni2.5 BeadChip and the other study included 3,016 cases and 2,745 controls genotyped using Illumina Human1M-Duo BeadChip. The top 18,376 single nucleotide polymorphisms (SNP) from the meta-analysis were replicated in the third study that consists of 1,984 African Americans cases and 2,939 controls. We found that SNP rs13074711, 26.5 Kb upstream of TNFSF10 at 3q26.21, was significantly associated with risk of oestrogen receptor (ER)-negative breast cancer (odds ratio [OR]=1.29, 95% CI: 1.18-1.40; P = 1.8 × 10 (-) (8)). Functional annotations suggest that the TNFSF10 gene may be involved in breast cancer aetiology, but further functional experiments are needed. In addition, we confirmed SNP rs10069690 was the best indicator for ER-negative breast cancer at 5p15.33 (OR = 1.30; P = 2.4 × 10 (-) (10)) and identified rs12998806 as the best indicator for ER-positive breast cancer at 2q35 (OR = 1.34; P = 2.2 × 10 (-) (8)) for women of African ancestry. These findings demonstrated additional susceptibility alleles for breast cancer can be revealed in diverse populations and have important public health implications in building race/ethnicity-specific risk prediction model for breast cancer

Characterizing Genetic Susceptibility to Breast Cancer in Women of African Ancestry

Background: Genome-wide association studies have identified approximately 100 common genetic variants associated with breast cancer risk, the majority of which were discovered in women of European ancestry. Because of different patterns of linkage disequilibrium, many of these genetic markers may not represent signals in populations of African ancestry. Methods: We tested 74 breast cancer risk variants and conducted fine-mapping of these susceptibility regions in 6,522 breast cancer cases and 7,643 controls of African ancestry from three genetic consortia (AABC, AMBER, and ROOT). Results: Fifty-four of the 74 variants (73%) were found to have ORs that were directionally consistent with those previously reported, of which 12 were nominally statistically significant ( P < 0.05). Through fine-mapping, in six regions ( 3p24, 12p11, 14q13, 16q12/FTO, 16q23, 19p13 ), we observed seven markers that better represent the underlying risk variant for overall breast cancer or breast cancer subtypes, whereas in another two regions ( 11q13, 16q12/TOX3 ), we identified suggestive evidence of signals that are independent of the reported index variant. Overlapping chromatin features and regulatory elements suggest that many of the risk alleles lie in regions with biological functionality. Conclusions: Through fine-mapping of known susceptibility regions, we have revealed alleles that better characterize breast cancer risk in women of African ancestry. Impact: The risk alleles identified represent genetic markers for modeling and stratifying breast cancer risk in women of African ancestry. Cancer Epidemiol Biomarkers Prev; 26(7); 1-11. ©2017 AACR

Whole-genome analysis of Nigerian patients with breast cancer reveals ethnic-driven somatic evolution and distinct genomic subtypes

From Springer Nature via Jisc Publications RouterHistory: received 2020-12-12, accepted 2021-11-02, registration 2021-11-04, pub-electronic 2021-11-26, online 2021-11-26, collection 2021-12Publication status: PublishedFunder: Postdoctoral Research Fellowship P2BSP3_178591Funder: Francis Crick Institute (Francis Crick Institute Limited); doi: https://doi.org/10.13039/100010438Funder: Cancer Research UK (CRUK); doi: https://doi.org/10.13039/501100000289; Grant(s): FC001202Funder: Wellcome Trust (Wellcome); doi: https://doi.org/10.13039/100004440; Grant(s): FC001202Funder: U.S. Department of Health & Human Services | National Institutes of Health (NIH); doi: https://doi.org/10.13039/100000002; Grant(s): U01 CA161032, U01 CA161032, R01 MD013452, R01 CA228198, U01 CA161032, R01 MD013452, P20-CA233307Funder: U.S. Department of Health & Human Services | National Institutes of Health (NIH)Funder: Breast Cancer Research Foundation (BCRF); doi: https://doi.org/10.13039/100001006; Grant(s): BCRF-20-071, BCRF-19-120Funder: DH | National Institute for Health Research (NIHR); doi: https://doi.org/10.13039/501100000272; Grant(s): 203141/Z/16/ZFunder: Susan G. Komen (Susan G. Komen Breast Cancer Foundation); doi: https://doi.org/10.13039/100009634; Grant(s): SAC110026, SAC210203Funder: American Cancer Society (American Cancer Society, Inc.); doi: https://doi.org/10.13039/100000048Abstract: 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, underscoring 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

Cross-ancestry GWAS meta-analysis identifies six breast cancer loci in African and European ancestry women.

Our study describes breast cancer risk loci using a cross-ancestry GWAS approach. We first identify variants that are associated with breast cancer at P < 0.05 from African ancestry GWAS meta-analysis (9241 cases and 10193 controls), then meta-analyze with European ancestry GWAS data (122977 cases and 105974 controls) from the Breast Cancer Association Consortium. The approach identifies four loci for overall breast cancer risk [1p13.3, 5q31.1, 15q24 (two independent signals), and 15q26.3] and two loci for estrogen receptor-negative disease (1q41 and 7q11.23) at genome-wide significance. Four of the index single nucleotide polymorphisms (SNPs) lie within introns of genes (KCNK2, C5orf56, SCAMP2, and SIN3A) and the other index SNPs are located close to GSTM4, AMPD2, CASTOR2, and RP11-168G16.2. Here we present risk loci with consistent direction of associations in African and European descendants. The study suggests that replication across multiple ancestry populations can help improve the understanding of breast cancer genetics and identify causal variants

Non-specific cell-mediated immunity in Nigerian children with uncomplicated malaria

Non-specific cellular immunity was determined in 59 Nigerian children aged between 1-9 years with uncomplicated malaria and 93 age-matched uninfected controls using percentage migration index (%M.I) and Mantoux tuberculin skin test. The mean %M.I (using malaria Pf 155 antigen) was significantly lower in malaria subjects compared with the controls (

Non-specific cell-mediated immunity in Nigerian children with uncomplicated malaria

Non-specific cellular immunity was determined in 59 Nigerian children aged between 1-9 years with uncomplicated malaria and 93 age-matched uninfected controls using percentage migration index (%M.I) and Mantoux tuberculin skin test. The mean %M.I (using malaria Pf 155 antigen) was significantly lower in malaria subjects compared with the controls (p<0.05) while the mean diameter of tuberculin skin reaction (using Purified Protein Derivative of Mycobacterium butyricum ) was significantly lower in children with uncomplicated malaria compared with the controls (p<0.05). The mean total white blood cell count (TWBC) was also significantly reduced in the malaria subjects when compared with the controls (p<0.05). The results show that leucocytes of children with uncomplicated malaria exhibited effective adaptive immune response. This may help to combat initial contact with malaria parasites

Genome-wide association studies in women of African ancestry identified 3q26.21 as a novel susceptibility locus for oestrogen receptor negative breast cancer

Multiple breast cancer loci have been identified in previous genome-wide association studies, but they were mainly conducted in populations of European ancestry. Women of African ancestry are more likely to have young-onset and oestrogen receptor (ER) negative breast cancer for reasons that are unknown and understudied. To identify genetic risk factors for breast cancer in women of African descent, we conducted a meta-analysis of two genome-wide association studies of breast cancer; one study consists of 1,657 cases and 2,029 controls genotyped with Illumina's HumanOmni2.5 BeadChip and the other study included 3,016 cases and 2,745 controls genotyped using Illumina Human1M-Duo BeadChip. The top 18,376 single nucleotide polymorphisms (SNP) from the meta-analysis were replicated in the third study that consists of 1,984 African Americans cases and 2,939 controls. We found that SNP rs13074711, 26.5Kb upstream of TNFSF10 at 3q26.21, was significantly associated with risk of oestrogen receptor (ER)-negative breast cancer (odds ratio [OR] = 1.29, 95% CI: 1.18-1.40; P = 1.8 x 10(-8)). Functional annotations suggest that the TNFSF10 gene may be involved in breast cancer aetiology, but further functional experiments are needed. In addition, we confirmed SNP rs10069690 was the best indicator for ER-negative breast cancer at 5p15.33 (OR = 1.30; P = 2.4 x 10(-10)) and identified rs12998806 as the best indicator for ER-positive breast cancer at 2q35 (OR = 1.34; P = 2.2 x 10(-8)) for women of African ancestry. These findings demonstrated additional susceptibility alleles for breast cancer can be revealed in diverse populations and have important public health implications in building race/ethnicity-specific risk prediction model for breast cance