Genomic Complexity Profiling Reveals That HORMAD1 Overexpression Contributes to Homologous Recombination Deficiency in Triple-Negative Breast Cancers

Johnathan Watkins, Daniel Weekes, Vandna Shah, Patrycja Gazinska, Shalaka Joshi, Bhavna Sidhu, Cheryl Gillett, Sarah Pinder, Fabio Vanoli, Maria Jasin, Markus Mayrhofer, Anders Isaksson, Maggie C U Cheang, Hasan Mirza, Jessica Frankum, Christopher J Lord, Alan Ashworth, Shaveta Vinayak, James M Ford, Melinda L TelliAnita Grigoriadis, Andrew N J Tutt

Research output: Contribution to journalArticlepeer-review

92 Citations (Scopus)

Abstract

Triple-negative breast cancers (TNBC) are characterized by a wide spectrum of genomic alterations, some of which might be caused by defects in DNA repair processes such as homologous recombination (HR). Despite this understanding, associating particular patterns of genomic instability with response to therapy has been challenging. Here, we show that allelic-imbalanced copy-number aberrations (AiCNA) are more prevalent in TNBCs that respond to platinum-based chemotherapy, thus providing a candidate predictive biomarker for this disease. Furthermore, we show that a high level of AiCNA is linked with elevated expression of a meiosis-associated gene, HORMAD1. Elevated HORMAD1 expression suppresses RAD51-dependent HR and drives the use of alternative forms of DNA repair, the generation of AiCNAs, as well as sensitizing cancer cells to HR-targeting therapies. Our data therefore provide a mechanistic association between HORMAD1 expression, a specific pattern of genomic instability, and an association with response to platinum-based chemotherapy in TNBC.

Significance: Previous studies have shown correlation between mutational “scars” and sensitivity to platinums extending beyond associations with BRCA1/2 mutation, but do not elucidate the mechanism. Here, a novel allele-specific copy-number characterization of genome instability identifies and functionally validates the inappropriate expression of the meiotic gene HORMAD1 as a driver of HR deficiency in TNBC, acting to induce allelic imbalance and moderate platinum and PARP inhibitor sensitivity with implications for the use of such “scars” and expression of meiotic genes as predictive biomarkers.
Original languageEnglish
Pages (from-to)488-505
Number of pages18
JournalCancer discovery
Volume5
Issue number5
Early online date13 Mar 2015
DOIs
Publication statusPublished - 1 May 2015

Fingerprint

Dive into the research topics of 'Genomic Complexity Profiling Reveals That HORMAD1 Overexpression Contributes to Homologous Recombination Deficiency in Triple-Negative Breast Cancers'. Together they form a unique fingerprint.

Cite this