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

PARP inhibitor (PARPi) therapy has transformed outcomes for patients with homologous recombination DNA repair (HRR) deficient ovarian cancers, for example those with BRCA1 or BRCA2 gene defects. Unfortunately, PARPi resistance is common. Multiple resistance mechanisms have been described, including secondary mutations that restore the HR gene reading frame.

Integrating deep mutational scanning and low-throughput mutagenesis data to predict the impact of amino acid variants.

Background: Evaluating the impact of amino acid variants has been a critical challenge for studying protein function and interpreting genomic data. High-throughput experimental methods like deep mutational scanning (DMS) can measure the effect of large numbers of variants in a target protein, but because DMS studies have not been performed on all proteins, researchers also model DMS data computationally to estimate variant impacts by predictors.

Results: In this study, we extended a linear regression-based predictor to explore whether incorporating data from alanine scanning (AS), a widely used low-throughput mutagenesis method, would improve prediction results.

A Matched Molecular and Clinical Analysis of the Epithelioid Haemangioendothelioma Cohort in the Stafford Fox Rare Cancer Program and Contextual Literature Review.

Background: Epithelioid haemangioendothelioma (EHE) is an ultra-rare malignant vascular tumour with a prevalence of 1 per 1,000,000. It is typically molecularly characterised by a gene fusion in approximately 90% of cases, or a gene fusion in approximately 10% of cases. EHE cases are typically refractory to therapies, and no anticancer agents are reimbursed for EHE in Australia.

Targeting homologous recombination deficiency in uterine leiomyosarcoma.

Background: Uterine leiomyosarcoma (uLMS) is a rare and aggressive gynaecological malignancy, with individuals with advanced uLMS having a five-year survival of < 10%. Mutations in the homologous recombination (HR) DNA repair pathway have been observed in ~ 10% of uLMS cases, with reports of some individuals benefiting from poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi) therapy, which targets this DNA repair defect. In this report, we screened individuals with uLMS, accrued nationally, for mutations in the HR repair pathway and explored new approaches to therapeutic targeting.

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

splice isoforms Δ11 and Δ11q can contribute to PARP inhibitor (PARPi) resistance by splicing-out the mutation-containing exon, producing truncated, partially-functional proteins. However, the clinical impact and underlying drivers of exon skipping remain undetermined. We analyzed nine ovarian and breast cancer patient derived xenografts (PDX) with exon 11 frameshift mutations for exon skipping and therapy response, including a matched PDX pair derived from a patient pre- and post-chemotherapy/PARPi.