Abstract GS1-05: Tandem duplicator phenotypes define 50% of triple negative breast cancers
Authors: ET Liu, F Menghi, F Barthel, V Yadav, M Tang, B Ji, G Carter, J Jonkers, R Verhaak
Journal: Cancer Research (2018)

Abstract Background. We recently discovered a unique chromotype, the Tandem Duplicator Phenotype (TDP), characterized by hundreds of somatic tandem duplications (TDs) scattered throughout the genome of a large percentage of triple negative breast cancers (TNBCs). Importantly, we observed that the TDP associates with a better response to cisplatin therapy in vitro and in vivo, suggesting that it is a tractable and quantitative biomarker of response to platinum-based therapy. Here, we expand on our initial findings by analyzing Whole-Genome (WG) sequences of over 2,700 tumors. Methods. TD coordinates from WG sequences relative to 2717 tumors were assembled from over 30 independent studies representing several cancer types, including 254 TNBCs. WG sequencing of mouse breast tumors was carried out using standard Illumina protocols. The number, distribution and span-size of somatic TDs from a training set of 992 tumors were used to develop a TDP classifier that identifies highly recurrent but clearly distinct TDP profiles. The TDP classifier was then applied to the remaining tumor sequences. WG mutation and copy number datasets were investigated to identify the genetic drivers associated with each TDP profile, and the genomic consequences of different TDPs were evaluated through identification of genomic hotspots for gene duplication and transection. Results. We describe six different TDPs featuring distinct TD span size distributions, with peaks at 10Kb (group 1), 300Kb (group 2) and 3Mb (group 3), or different combinations of these (mix12, mix13 and mix23). More than half of all TNBC display a TDP. Of these, 55% classify as group 1, 14% as group 2 and 15% as group mix12. Whereas all TDP groups show a higher TP53 mutation rate compared to non-TDP tumors, each TDP profile is characterized by specific additional gene perturbations, with loss of BRCA1 occurring in groups 1, mix12 and mix13; CCNE1 amplification in group 2; and CDK12 mutations in group mix23. We show that different TDPs are subject to the perturbation of specific oncogenic networks resulting from the duplication of oncogenes by larger TDs (&amp;gt;300Kb) or the disruption of tumor suppressors via double transections by shorter TDs (10Kb). Indeed, tumor suppressor genes such as PTEN, RB1 and MLL3 are frequently disrupted by TDs in TNBC TDP group 1 tumors, whereas TNBC TDP group 2 tumors commonly feature duplication of oncogenes such as MYC and MALAT1. Finally, through WG analyses of 18 mouse models (GEMMs) of breast cancer, we provide the first mechanistic evidence of the driving role of conjoint loss of TP53 and BRCA1, but not of BRCA2, in inducing the TDP group 1 profile. Conclusions. Our study shows a definitive genetic induction of one specific form of TDP (group 1) characterized by 10kb TD span. Different TDP profiles are characterized by alternative somatic genetic origins but always couple with disruptive TP53 mutations. The consequences of the massive TD formation in TDP TNBCs suggest a systems strategy to tumor induction involving heterogeneous combinations of oncogenes and tumor suppressors. That these TDP forms, accounting for ˜50% of TNBC, are associated with significant sensitivity to cisplatin suggest that this chromotype may identify TNBC patients who would benefit from upfront platinum-based chemotherapy. Citation Format: Liu ET, Menghi F, Barthel F, Yadav V, Tang M, Ji B, Carter G, Jonkers J, Verhaak R. Tandem duplicator phenotypes define 50% of triple negative breast cancers [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS1-05.