Mapping molecular subtype specific alterations in breast cancer brain metastases identifies clinically relevant vulnerabilities

TL;DR

This study explores how different breast cancer subtypes develop brain metastases and finds that a DNA repair defect called homologous recombination deficiency is a key weakness in some cases.

Contribution

The study identifies subtype-specific molecular alterations and validates homologous recombination deficiency as a therapeutic vulnerability in brain metastases.

Findings

Luminal brain metastases show homologous recombination deficiency with specific mutational signatures.

PARP inhibition was effective in patient-derived brain metastatic tumor explants with HRD.

Transcriptional programs and hub genes were identified that are specific to brain metastasis subtypes.

Abstract

The molecular events and transcriptional plasticity driving brain metastasis in clinically relevant breast tumor subtypes has not been determined. Here we comprehensively dissect genomic, transcriptomic and clinical data in patient-matched longitudinal tumor samples, and unravel distinct transcriptional programs enriched in brain metastasis. We report on subtype specific hub genes and functional processes, central to disease-affected networks in brain metastasis. Importantly, in luminal brain metastases we identify homologous recombination deficiency operative in transcriptomic and genomic data with recurrent breast mutational signatures A, F and K, associated with mismatch repair defects, TP53 mutations and homologous recombination deficiency (HRD) respectively. Utilizing PARP inhibition in patient-derived brain metastatic tumor explants we functionally validate HRD as a key vulnerability. Here, we demonstrate a functionally relevant HRD evident at genomic and transcriptomic levels pointing to genomic instability in breast cancer brain metastasis which is of potential translational significance.

The molecular landscape of breast cancer brain metastases (BCBM) is still understudied, especially for different breast cancer subtypes. Here, the authors characterise subtype-specific BCBMs using genomics and transcriptomics and identify homologous recombination deficiency as a key therapeutic vulnerability.

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