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BRCA1 secondary splice-site mutations drive exon-skipping and PARP inhibitor resistance.

Ksenija NesicJohn J KraisCassandra J VandenbergYifan WangPooja PatelTanya KwanElizabeth LieschkeGwo-Yaw HoHolly E BarkerJustin BedoSilvia CasadeiAndrew FarrellMarc RadkeKristy Shield-ArtinJocelyn S PeningtonFranziska GeisslerFan ZhangAlexander DobrovicInger OlesenRebecca KristeleitAmit OzaGayanie RatnayakeNadia Traficantenull nullAnna DeFazioDavid D L BowtellThomas C HardingKevin LinElizabeth M SwisherOlga KondrashovaClare L ScottNeil JohnsonMatthew J Wakefield
Published in: medRxiv : the preprint server for health sciences (2023)
BRCA1 splice isoforms Δ11 and Δ11q can contribute to PARP inhibitor (PARPi) resistance by splicing-out mutation-containing exons, producing truncated, partially-functional proteins. However, the clinical impact and underlying drivers of BRCA1 exon skipping remain undetermined. We analyzed nine ovarian and breast cancer patient derived xenografts (PDX) with BRCA1 exon 11 frameshift mutations for splice isoform expression and therapy response. This included a matched PDX pair derived from a patient pre-and post-chemotherapy/PARPi regimen. BRCA1 exon 11-deficient isoform expression was generally elevated in PARPi resistant PDX tumors. Two independent PDX models acquired secondary BRCA1 splice site mutations (SSMs), predicted in silico to drive exon skipping. Predictions were confirmed using qRT-PCR, RNA sequencing, western blots and BRCA1 minigene modelling. SSMs were also enriched in post-PARPi OC patient cohorts from the ARIEL2 and ARIEL4 clinical trials. We demonstrate that SSMs drive BRCA1 exon 11 skipping and PARPi resistance, and should be clinically monitored, along with frame-restoring secondary mutations.
Keyphrases
  • breast cancer risk
  • clinical trial
  • poor prognosis
  • dna damage
  • case report
  • young adults
  • single cell
  • study protocol
  • radiation therapy
  • squamous cell carcinoma
  • mesenchymal stem cells
  • south africa
  • molecular docking