42O - Profiles of genome complexity identify HORMAD1 as a driver of homologous recombination deficiency and platinum therapy response in triple-negative b...

Date 07 May 2015
Event IMPAKT 2015
Session Best abstracts session
Topics Anti-Cancer Agents & Biologic Therapy
Breast Cancer
Pathology/Molecular Biology
Translational Research
Presenter Anita Grigoriadis
Citation Annals of Oncology (2015) 26 (suppl_3): 15-24. 10.1093/annonc/mdv117
Authors A. Grigoriadis1, D. Weekes1, J.A. Watkins1, P. Gazinska1, J. Frankum2, C. Lord2, A. Ashworth2, J.M. Ford3, M. Telli3, A. Tutt4
  • 1Breakthrough Breast Cancer Research Unit, King's College London Guy's Hospital, SE1 9RT - London/UK
  • 2Cancer Genomics And Therapeutics, Institute of Cancer Research ICR, SW7 3RP - London/UK
  • 3Division Of Oncology, Stanford University School of Medicine, 94305-5151 - Stanford/US
  • 4Breakthrough Breast Cancer Research Unit, King's College London School of Medicine, SE1 9RT - London/UK

Abstract

Body

Triple negative breast cancers (TNBCs) are characterised by complex numerical and structural DNA alterations. While in some TNBCs, these changes result from defects in known homologous recombination (HR) repair proteins, such as BRCA1 and BRCA2, the possible aetiology and consequences of these genomic patterns have yet to be determined in the majority of cases. To identify and functionally validate a candidate driver of specific genomic instability forms in TNBCs, we established 3 measures of chromosomal instability scarring (SCINS): allelic imbalanced copy number aberrations (AiCNAs); copy neutral losses of heterozygosity (CnLOH); and allelic balanced copy number aberrations based on SNP microarray allele-specific copy number profiles, and applied them to 331 TNBCs, 38 breast cell lines, and 299 TCGA high-grade serous ovarian tumours. Among TNBCs, 3 groups with distinctive genomic patterns were identified: high in AiCNA, high in CnLOH and low for all SCINS measures. Gene expression analysis revealed high levels of HORMAD1, a cancer testis antigen involved in double strand DNA break processing during meiosis, in groups with high AiCNA and CnLOH, with AiCNA being strongly correlated with its expression. Western blotting and immunohistochemistry confirmed its protein expression. Immunofluorescence validated its nuclear localisation. By overexpressing HORMAD1 in cell lines, cytogenetic abnormalities and AiCNA were increased. DR-GFP and EJ5 non-homologous end-joining (NHEJ) reporter assays revealed reduced HR and increased NHEJ efficiency in such cells. Induced HORMAD1 expression sensitised cells to cisplatin and two PARP inhibitors. In PrECOG0105, a neoadjuvant platinum chemotherapy trial, bimodality analysis identified HORMAD1-low and -high expressing tumours, the latter were more likely to respond to treatment in both unselected and BRCA1/2 wildtype TNBCs. Our measures of SCINS have proven to be useful tools to uncover HORMAD1 as potential driver of specific patterns of genomic instability and as a possible biomarker for platinum and PARP inhibitor sensitivity caused by its ability to induce HR deficiency and upregulation of NHEJ.

Disclosure: All authors have declared no conflicts of interest.