GermlineAPOBEC3Bdeletion in Asian women increases somatic hypermutation in breast cancer that is associated with Her2 subtype,PIK3CAmutations, immune activation, and increased survival

Abstract

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.Graphical Abstract

Germline copy number variations in BRCA1/2 negative families: Role in the molecular etiology of hereditary breast cancer in Tunisia

“…This locus was shown to be significantly associated with breast cancer risk in different populations including those of Chinese, Iranian, and European ancestries [ 18 , 47 , 48 ]. It was demonstrated also that deletion in the APOBEC3 loci disrupting APOBEC3A and APOBEC3B genes lead to the decreased expression of the corresponding genes [ 66 , 67 ]. Moreover, the association between GSTT1 gene deletion and breast cancer risk has been widely studied and it was demonstrated that GSTT1 null genotype is associated with increased breast cancer risk [ 68 ] and also with significant downregulation of GSTT1 gene resulting in loss of protein expression [ 69 – 71 ].…”

Restriction site associated DNA sequencing for tumour mutation burden estimation and mutation signature analysis

“…In carriers of the polymorphism, a high TMB is associated with increased immune infiltration and enrichment of an adaptive immune response signature 11,12,35,36 . In addition, in other cancer types such as lung cancer and cervical cancer, APOBEC hypermutation has been associated with these characteristics and improved response to immune checkpoint inhibition, even in samples that did not pass the ‘high TMB’ threshold of 10 mutations/Mb 10‐12,38‐41 . This suggests that it is possible that APOBEC hypermutation, may in itself be predictive of response to immunotherapy.…”

“… 11 , 12 , 35 , 36 In addition, in other cancer types such as lung cancer and cervical cancer, APOBEC hypermutation has been associated with these characteristics and improved response to immune checkpoint inhibition, even in samples that did not pass the ‘high TMB’ threshold of 10 mutations/Mb. 10 , 11 , 12 , 38 , 39 , 40 , 41 This suggests that it is possible that APOBEC hypermutation, may in itself be predictive of response to immunotherapy. Therefore, an APOBEC enrichment score, combined with a TMB estimate, may provide additional clinical utility compared to a TMB estimate alone.…”

Restriction site associated DNA sequencing for tumour mutation burden estimation and mutation signature analysis

“…In carriers of the polymorphism, a high TMB is associated with increased immune infiltration and enrichment of an adaptive immune response signature 13,14,39,40 . In addition, in other cancer types such as lung cancer and cervical cancer, APOBEC hypermutation has been associated with these characteristics and improved response to immune checkpoint inhibition, even in samples that did not pass the "high TMB" threshold of 10 mutations/Mb [12][13][14][42][43][44][45] . This suggests that it is possible that APOBEC hypermutation, may in itself be predictive of response to immunotherapy.…”