The Molecular Landscape of Asian Breast Cancers Reveals Clinically Relevant Population-Specific Differences

Abstract

2Molecular profiles of breast cancer have contributed to an improved understanding of the 3 disease, enabled development of molecular prognostic signatures to guide treatment decisions 4 and unveiled new or more accurate therapeutic options for breast cancer patients. However, 5 the extent to which differences in genetic, environmental and lifestyle factors influence 6 molecular profiles in different populations remains poorly characterised, as relatively few 7 large-scale molecular studies of breast tumours in non-Caucasian populations have hitherto 8 been reported. Here, we present the molecular profiles of 560 Asian breast tumours and a 9 comparative analysis of breast cancers arising in Asian and Caucasian women. Compared to 10 the breast tumours in predominantly Caucasian women reported in TCGA and METABRIC, 11we show an increased prevalence of Her2-enriched molecular subtypes and higher prevalence 12 of TP53 somatic mutations in ER+ Asian breast tumours. Using gene expression and 13 immunohistochemistry, we observed elevated immune scores in Asian breast tumours, 14suggesting potential clinical response to immune checkpoint inhibitors. Whilst Her2-subtype 15 and enriched immune score are associated with improved survival, presence of TP53 somatic 16 mutations is associated with poorer survival in ER+ tumours. Taken together, these 17 population differences unveil new opportunities to improve the understanding of this disease 18 and lay the foundation for precision medicine in different populations. 19 20 receptor (ER) negative and human epidermal growth factor receptor 2 (HER2) receptor 1 positive disease (reviewed in Yap et al. 2019 18 ). A recent genomic analysis of 187 early-onset 2 Asian breast cancers show a higher prevalence of TP53 mutations and enrichment in immune 3 signatures 19 , whereas analysis of 465 triple-negative Asian breast cancers demonstrated broad 4 similarities in tumours of the same subtype arising in Asian and Caucasian women 9 . 5 6 Given the potential impact of tumour subtypes, candidate drivers, mutational signatures and 7 immune profiles on treatment options for breast cancer patients, and the hitherto lack of 8 detailed information in Asian breast cancer patients, we have performed WES, shallow WGS 9 (sWGS), and RNA-sequencing (RNA-seq) of 560 breast tumours from a cohort of Asian 10

Germline APOBEC3B deletion increases somatic hypermutation in Asian breast cancer that is associated with Her2 subtype, PIK3CA mutations and immune activation

“…We found that there were no significant differences in the frequencies of molecular subtypes between A3B germline deletion carriers and noncarriers (Figure 3A), suggesting that germline A3B deletion does not significantly affect molecular subtype. We then examined the mutational profiles of these tumours by examining the nonsynonymous mutations in the 10 most frequently affected genes in the MyBrCa cohort 24 , comparing patients with different germline A3B copy number, but also did not find any significant differences (Figure 3B). We found that germline A3B deletion was marginally associated with a higher number of C‐to‐T or G‐to‐A transitions in PIK3CA (Supplementary Figure 8A), but not in the other nine genes.…”

“…One possibility is that the deletion only indirectly affects the immune microenvironment via APOBEC hypermutation, which is itself only weakly associated with expression of the A3A-B hybrid isoform, leading to a very weak overall association between germline A3B copy number and the immune microenvironment. Another possibility is that the immune profiles of breast cancers in Asian women already have enriched immune profiles compared to cancers in women of European descent, 24,40 thereby reducing the impact of germline A3B polymorphism.…”

“…In brief, shallow whole‐genome sequencing (sWGS), whole‐exome sequencing (WES) and RNA‐sequencing were conducted on 560 sequential female breast cancer patients from a single hospital in Subang Jaya, Malaysia, and analysed together with available clinical and overall survival data. The cohort data and sequencing methods are described in full by Pan et al 24 Only the methods important or unique to our study are described later.…”

“…We then examined the mutational profiles of these tumours by examining the nonsynonymous mutations in the 10 most frequently affected genes in the MyBrCa cohort 24 , comparing patients with different germline A3B copy number, but also did not find any significant differences (Figure 3B). We found that germline A3B deletion was marginally associated with a higher number of C-to-T or G-to-A transitions in PIK3CA (Supplementary Figure 8A), but not in the other nine genes.…”

“…These results raise the possibility that population‐specific differences in genetic, lifestyle and environmental factors may modulate the impact of APOBEC3B deletion polymorphism in different populations. To investigate the biological consequences of germline A3B deletion on APOBEC mutagenesis and immune activation in the Asian population, we examined the effect of germline A3B deletion in a cohort of 527 breast tumours from Malaysia, where whole exome and whole transcriptomic sequencing information is available 24 . The high prevalence of the polymorphism allowed for sufficient power to analyse homozygous and heterozygous carriers separately, and also enabled subtype‐specific analyses.…”