Germline variants and somatic mutation signatures of breast cancer across populations of African and European ancestry in the US and Nigeria

Abstract

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

“…Patient cohort, ethics, and pathological assessment. This study was embedded within the Nigerian Breast Cancer Study (NBCS) and approved by the Institutional Review Board of all participating institutions: The University of Chicago, University College Hospital, Ibadan (UCH), and Lagos State University Teaching Hospital (LASUTH) 1,7,9,64 . A grand total of 493 subjects were recruited from UCH (n = 284) and LASUTH (n = 209) between February 2013 and September 2015.…”

“…Studies of breast cancer genomes reveal population-specific differences in germline predisposition mutation frequency, somatic mutation landscapes, and mutational signatures, mirroring population differences in molecular subtypes [7][8][9][10] . Breast cancer patients of African ancestry demonstrate more TP53 alterations and fewer PIK3CA alterations 6,8 , and Nigerian HR+ /HER2− tumors are characterized by increased homologous recombination deficiency (HRD) signature 8 .…”

Barriers to Implementing Clinical Pharmacogenetics Testing in Sub-Saharan Africa. A Critical Review

“…In addition to germline variants, somatic variants have been characterised and catalogued in relation to cancer treatment responses. For instance, somatic mutations on EGFR and BCR-ABL genes are highly predictive of gefitinib and imatinib drug response respectively in non-small cell lung cancer patients of European ancestry [ 63 ]. Furthermore, few studies have demonstrated inter-ethnic variability in the frequency of some sensitising somatic variants.…”

“…Furthermore, few studies have demonstrated inter-ethnic variability in the frequency of some sensitising somatic variants. However, studies on somatic variant profiles in cancer patients in African populations are sparse [ 63 ]. Neoplasms are one of the leading causes of deaths from NCDs in the SSA region [ 12 ].…”

The impact of rare germline variants on human somatic mutation processes

“…In addition, an association between RDGVs in the DNA glycosylase MBD4 with an increase of C>T mutations at CpG sites was reported 9 , which was also found in several independent studies 47,48 . Furthermore, in a breast-cancer-specific study, the association of RDGVs with APOBEC and deficient homologous recombination (dHR) SNV signatures was investigated across ancestries, without detecting hits significant in both ancestries 49 .…”