title: Genomic Complexity Profiling Reveals That HORMAD1 Overexpression Contributes to Homologous Recombination Deficiency in Triple-Negative Breast Cancers.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Johnathan
authors.initials: J
authors.lastname: Watkins
authors.affiliation: 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.
authors.forename: Daniel
authors.initials: D
authors.lastname: Weekes
authors.affiliation: 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.
authors.forename: Vandna
authors.initials: V
authors.lastname: Shah
authors.affiliation: 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.
authors.forename: Patrycja
authors.initials: P
authors.lastname: Gazinska
authors.affiliation: 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.
authors.forename: Shalaka
authors.initials: S
authors.lastname: Joshi
authors.affiliation: 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.
authors.forename: Bhavna
authors.initials: B
authors.lastname: Sidhu
authors.affiliation: 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.
authors.forename: Cheryl
authors.initials: C
authors.lastname: Gillett
authors.affiliation: 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.
authors.forename: Sarah
authors.initials: S
authors.lastname: Pinder
authors.affiliation: Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Fabio
authors.initials: F
authors.lastname: Vanoli
authors.affiliation: Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Maria
authors.initials: M
authors.lastname: Jasin
authors.affiliation: Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Markus
authors.initials: M
authors.lastname: Mayrhofer
authors.affiliation: Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Isaksson
authors.affiliation: Clinical Trials and Statistics Unit (ICR-CTSU), The Institute of Cancer Research, Surrey, United Kingdom.
authors.forename: Maggie C U
authors.initials: MC
authors.lastname: Cheang
authors.affiliation: 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.
authors.forename: Hasan
authors.initials: H
authors.lastname: Mirza
authors.affiliation: The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Jessica
authors.initials: J
authors.lastname: Frankum
authors.affiliation: The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lord
authors.affiliation: The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Alan
authors.initials: A
authors.lastname: Ashworth
authors.affiliation: Department of Medicine, Stanford University School of Medicine, Stanford, California.
authors.forename: Shaveta
authors.initials: S
authors.lastname: Vinayak
authors.affiliation: Department of Medicine, Stanford University School of Medicine, Stanford, California.
authors.forename: James M
authors.initials: JM
authors.lastname: Ford
authors.affiliation: Department of Medicine, Stanford University School of Medicine, Stanford, California.
authors.forename: Melinda L
authors.initials: ML
authors.lastname: Telli
authors.affiliation: 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.
authors.forename: Anita
authors.initials: A
authors.lastname: Grigoriadis
authors.affiliation: 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.
authors.forename: Andrew N J
authors.initials: AN
authors.lastname: Tutt
mesh_terms: D022981:Allelic Imbalance; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D043171:Chromosomal Instability; D016000:Cluster Analysis; D056915:DNA Copy Number Variations; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015870:Gene Expression; D020869:Gene Expression Profiling; D020868:Gene Silencing; D023281:Genomics; D059765:Homologous Recombination; D006801:Humans; D010984:Platinum / Q000008:administration & dosage; D020641:Polymorphism, Single Nucleotide; D034741:RNA, Small Interfering / Q000235:genetics; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology
chemical_list: D018797:Cell Cycle Proteins; C576915:HORMAD1 protein, human; D034741:RNA, Small Interfering; D010984:Platinum