PO-228 Comprehensive molecular characterisation of TNBCs expressing HORMAD1, a driver of homologous recombination deficiency

• Published in: ESMO open Vol. 3; no. Suppl 2; p. A316
• Main Authors: Quist, J, Mirza, H, Weekes, D, Nowinski, S, Cheang, MCU, Lord, CJ, Tutt, ANJ, Grigoriadis, A
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 01-07-2018
• ISSN: 2059-7029; 2059-7029
• DOI: 10.1136/esmoopen-2018-EACR25.745

IntroductionTriple-negative breast cancers (TNBCs) are characterised by increased tumour-infiltrating lymphocytes and the presence of complex compositions of structural and single nucleotide variations. We previously described HORMAD1, a Cancer/Testis (CT) antigen, as a novel driver of homologous recombination (HR) deficiency. Our ultimate aim was to identify biomarkers in HORMAD1 positive TNBCs that could be used to stratify patients for immunomodulatory and/or DNA damage response (DDR) targeted agents. In order to do this, we first defined the transcriptomics and genomics features of HORMAD1 positive TNBCs.Material and methodsHORMAD1 positive TNBCs were identified using either microarray or RNA-sequencing data. Gene set enrichment analysis was used to identify hyper- or hypo-activated pathways. Whole-exome sequencing (WES) from TCGA TNBCs was used to identify genes exclusively mutated in HORMAD1 positive TNBCs. Mutational signatures in tumours were delineated using whole-genome sequencing from ICGC TNBCs.Results and discussionsIn six independent TNBC cohorts (total n=719) HORMAD1 expression was bimodal. More than 50% of the TNBCs were identified as HORMAD1 positive and tended to display PAM50 basal-like, intClust 10, or a basal-like 1 TNBCtype-4 subtype (P value<0.05). In HORMAD1 positive TNBCs, genes involved in DNA repair by HR or DNA mismatch repair displayed increased expression (Q value<0.05). WES from TCGA TNBCs (n=75) indicated that missense mutations in PIK3CA were found exclusively in HORMAD1 negative TNBCs (P value=0.002). Mutational signature 3 and rearrangement signature 5, previously associated with HR deficiency in BRCA1- and BRCA2-deficient tumours, were more prevalent in HORMAD1 positive ICGC TNBCs (n=72, Q value=0.049 and 0.028 respectively), as was an increase in substitution burden (P value=0.032). HORMAD1 positive TNBCs also displayed a transcriptomic signature reminiscent of activated CD4 +T cells (Q value<0.05). It is possible that the DNA damage caused by ectopic HORMAD1 expression, or its role as a CT antigen, or both, could drive an adaptive immune response, thus explaining this CD4 +T cell signature.ConclusionTaken together, the molecular profiles of HORMAD1 positive TNBCs indicate not only the underlying biology of this TNBC subset, but also opportunities for therapeutic exploitation, including agents that target the DDR and immune system.