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A 30-kb deletion that eliminates the coding region of APOBEC3B (A3B) is >5 times more common in women of Asian compared to European descent. This polymorphism creates a chimera with the APOBEC3A (A3A) coding region and A3B 3'UTR, and is associated with an increased risk for breast cancer in Asian women. Here, we explored the relationship between the A3B deletion polymorphism with tumour characteristics in Asian women. Using whole exome and whole transcriptome sequencing data of 527 breast tumours, we report that germline A3B deletion polymorphism leads to expression of the A3A-B hybrid isoform and increased APOBEC-associated somatic hypermutation. Hypermutated tumours, regardless of A3B germline status, were associated with the Her2 molecular subtype and PIK3CA mutations. Compared to non-hypermutated tumours, hypermutated tumours also had higher neoantigen burden, tumour heterogeneity and immune activation. Taken together, our results suggest that the germline A3B deletion polymorphism, via the A3A-B hybrid isoform, contributes to APOBEC-mutagenesis in a significant proportion of Asian breast cancers. In addition, APOBEC somatic hypermutation, regardless of A3B background, may be an important clinical biomarker for Asian breast cancers. This article is protected by copyright. All rights reserved.

Molecular profiling of breast cancer has enabled the development of more robust molecular prognostic signatures and therapeutic options for breast cancer patients. However, non-Caucasian populations remain understudied. Here, we present the mutational, transcriptional, and copy number profiles of 560 Malaysian breast tumours and a comparative analysis of breast cancers arising in Asian and Caucasian women. Compared to breast tumours in Caucasian women, we show an increased prevalence of HER2-enriched molecular subtypes and higher prevalence of TP53 somatic mutations in ER+ Asian breast tumours. We also observe elevated immune scores in Asian breast tumours, suggesting potential clinical response to immune checkpoint inhibitors. Whilst HER2-subtype and enriched immune score are associated with improved survival, presence of TP53 somatic mutations is associated with poorer survival in ER+ tumours. Taken together, these population differences unveil opportunities to improve the understanding of this disease and lay the foundation for precision medicine in different populations., Molecular profiling of breast cancer in non-Caucasian populations remains underexplored. Here the authors report a high prevalence of HER2-subtypes and enriched immune score with improved survival and higher rates of TP53 somatic mutations with poorer survival in ER+ tumours in a Malaysian cohort.

A 30-kb deletion that eliminates the coding region of APOBEC3B (A3B) is5 times more common in women of Asian compared to European descent. This polymorphism creates a chimera with the APOBEC3A (A3A) coding region and A3B 3'UTR, and is associated with an increased risk for breast cancer in Asian women. Here, we explored the relationship between the A3B deletion polymorphism with tumour characteristics in Asian women. Using whole exome and whole transcriptome sequencing data of 527 breast tumours, we report that germline A3B deletion polymorphism leads to expression of the A3A-B hybrid isoform and increased APOBEC-associated somatic hypermutation. Hypermutated tumours, regardless of A3B germline status, were associated with the Her2 molecular subtype and PIK3CA mutations. Compared to non-hypermutated tumours, hypermutated tumours also had higher neoantigen burden, tumour heterogeneity and immune activation. Taken together, our results suggest that the germline A3B deletion polymorphism, via the A3A-B hybrid isoform, contributes to APOBEC-mutagenesis in a significant proportion of Asian breast cancers. In addition, APOBEC somatic hypermutation, regardless of A3B background, may be an important clinical biomarker for Asian breast cancers. This article is protected by copyright. All rights reserved.

A 30-kb deletion that eliminates the coding region ofAPOBEC3B(A3B) is >5 times more common in women of Asian compared to European descent. This polymorphism creates a chimera with theAPOBEC3A(A3A) coding region andA3B3’UTR, and is associated with an increased risk for breast cancer in Asian women. Here, we explored the relationship between theA3Bdeletion polymorphism with tumour characteristics in Asian women. Using whole exome and whole transcriptome sequencing data of 527 breast tumours, we report that germlineA3Bdeletion polymorphism leads to expression of theA3A-Bhybrid isoform and increased APOBEC-associated somatic hypermutation. Hypermutated tumours, regardless ofA3Bgermline status, were associated with the Her2 molecular subtype andPIK3CAmutations. Compared to non-hypermutated tumours, hypermutated tumours also had higher neoantigen burden, tumour heterogeneity and immune activation. Taken together, our results suggest that the germlineA3Bdeletion polymorphism, via theA3A-Bhybrid isoform, contributes to APOBEC-mutagenesis in a significant proportion of Asian breast cancers. In addition, APOBEC somatic hypermutation, regardless ofA3Bbackground, may be an important clinical biomarker for Asian breast cancers.Graphical Abstract

International audience; • Background and Aims Seedling herbivory is an important selective filter in many plant communities. The re- moval of preferred food plants by both vertebrate and, more commonly, invertebrate herbivores can destroy entire seedling cohorts, and consequently dictate plant community assembly. Nevertheless, our understanding of how and why some seedlings are more prone to herbivore attack than their neighbours remains limited. For seedlings, where even minor tissue damage is fatal, avoiding contact with herbivores is probably advantageous and, on this basis, volatile organic compounds (VOCs) are strong candidates to fulfil a primary defensive role.• Methods We quantified seedling selection by snails (Cornu aspersum) for 14 common, European grassland species. Seedling acceptability was subsequently compared with species-specific expression of constitutive sec- ondary defence metabolites (CSDMs), and VOCs to determine their relative influence on seedling selection. • Results We found no relationship between seedling acceptability and CSDMs, but seedling selection was strongly associated with VOC profiles. Monoterpenes (specifically à-ocimene) were identified as likely attractants, while green leaf volatiles (GLVs) (3-hexen-1-ol acetate) were strongly associated with low seedling acceptability. • Conclusions ByelucidatingarelationshipbetweenVOCsandseedlingacceptability,wecontradictalong-held, but poorly tested, assumption that seedling selection by herbivores in (semi-)natural plant communities centres on CSDMs. Instead, our results corroborate recent work showing how GLVs, including 3-hexen-1-ol acetate, deter crop seedling selection by molluscs. Although our failure to establish any early-ontogenetic relationship between VOCs and CSDMs also suggests that the former do not ‘advertise’ possession of the latter, we nevertheless reveal the role that VOCs play in defending seedlings against herbivory before lethal damage occurs.