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

Jia Wern PanMuhammad Mamduh Ahmad ZabidiBoon-Keat ChongMei-Yee MengPei-Sze NgSiti Norhidayu HasanBethan SandeySaira BahnuPathmanathan RajaduraiCheng-Har YipOscar M RuedaCarlos CaldasSuet-Feung ChinSoo-Hwang Teo
Published in: International journal of cancer (2021)
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.
Keyphrases
  • polycystic ovary syndrome
  • dna repair
  • copy number
  • single cell
  • breast cancer risk
  • pregnancy outcomes
  • gene expression
  • rna seq
  • pregnant women
  • adipose tissue
  • young adults
  • insulin resistance
  • binding protein