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Cancer Discov. 2015 May;5(5):488-505. doi: 10.1158/2159-8290.CD-14-1092. Epub 2015 Mar 13.

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

Author information

1
Breakthrough Breast Cancer Research Unit, King's College London, London, United Kingdom. Institute for Mathematical and Molecular Biomedicine, King's College London, London, United Kingdom. Department of Research Oncology, King's Health Partners AHSC, Life Sciences and Medicine, King's College London, London, United Kingdom.
2
Breakthrough Breast Cancer Research Unit, King's College London, London, United Kingdom. Department of Research Oncology, King's Health Partners AHSC, Life Sciences and Medicine, King's College London, London, United Kingdom.
3
Department of Research Oncology, King's Health Partners AHSC, Life Sciences and Medicine, King's College London, London, United Kingdom. King's Health Partners Cancer Biobank, King's College London, London, United Kingdom.
4
Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
5
Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
6
Clinical Trials and Statistics Unit (ICR-CTSU), The Institute of Cancer Research, Surrey, United Kingdom.
7
The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
8
Department of Medicine, Stanford University School of Medicine, Stanford, California.
9
Breakthrough Breast Cancer Research Unit, King's College London, London, United Kingdom. Department of Research Oncology, King's Health Partners AHSC, Life Sciences and Medicine, King's College London, London, United Kingdom. The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom. andrew.tutt@kcl.ac.uk.

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.

PMID:
25770156
PMCID:
PMC4490184
DOI:
10.1158/2159-8290.CD-14-1092
[Indexed for MEDLINE]
Free PMC Article

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