Abstract 604: Impaired cell cycle arrest with concurrent epigenetic deregulation identified through next generation sequencing in patients with advanced carcinoma of unknown primary: Implications for personalized medicine
Authors: Subbiah Ishwaria M. , Varadhachary Gauri , Tsimberidou Apostolia M. , Wheler Jennifer J. , Subbiah Vivek , Janku Filip , Roy Chowdhuri Sinchita , Zinner Ralph , Hong David S. 
Published: August 2015

Abstract
Background: Patients with advanced carcinoma of unknown primary (CUP) have limited effective therapeutic options given the challenges of phenotypic and genotypic diversity. To identify future novel therapeutic strategies we conduct an ongoing exploratory analysis of next-generation sequencing (NGS) of relapsed, refractory CUP.
Methods: We identified CUP patients referred to our phase I clinic with adequate FFPE sections from archival tissue for a targeted CLIA-certified NGS assay (Foundation One, MA). Over 2000 exons of 186 cancer-related genes plus over 30 introns from 14 genes often rearranged in cancer were fully sequenced for point mutations, insertions/deletions, copy number alterations (CNAs) and select gene fusions.
Results: Of 19 patients seen (10 male, 9 female; median age at diagnosis 49 years), 17 demonstrated genomic alterations (median 3 aberrations/tumor, range 0 - 10); two patients had no reportable genomic alterations. Of the 71 detected aberrations, 17 (24%) have been implicated in impaired cell cycle regulation and arrest; specifically in genes which encode the cyclin-dependent kinases (CDK12 Q570*, CDKN2A/B loss, CDKN2A p16INK4a loss and p14ARF exon 2-3 loss) or their associated proteins including amplification of CCND1 and CCNE1 (n = 3). Of these 8 patients with impaired cell cycle regulation, 5 (63%) demonstrated concurrent mutations associated with epigenetic deregulation and impaired DNA methylation, most commonly ARID1A Y1211fs*5 and S1929fs*25, which encodes the AT-rich interactive domain-containing protein 1A, Arid1a, a member of the SWI/SNF chromatin remodeling complex); other mutations observed are CREBBP S893L (encoding a ubiquitously expressed transcriptional coregulatory protein controlling chromatin remodeling via its histone acetyltransferase activity); MLL2 R4904* (encoding an H3K4-specific histone methyltransferase) and KDM6A S466* (encoding the histone H3 lysine 27 demethylase UTX). Overall 5 of 19 (26%) patients with advanced relapsed CUP demonstrated a profile of aberrations that concurrently impact cell cycle arrest and epigenetic regulation.
Conclusion: Through NGS-based molecular profiling, we can a subset of patients with advanced carcinoma of unknown primary with coexisting mutations leading to impaired cell cycle arrest and epigenetic deregulation, highlighting a therapeutic combination with a cell cycle inhibitor (such as Cdk4/6 inhibitors currently in clinical trial) and histone deacetylase inhibitors.
Note: This abstract was not presented at the meeting.
Citation Format: Ishwaria M. Subbiah, Gauri Varadhachary, Apostolia M. Tsimberidou, Jennifer J. Wheler, Vivek Subbiah, Filip Janku, Sinchita Roy Chowdhuri, Ralph Zinner, David S. Hong. Impaired cell cycle arrest with concurrent epigenetic deregulation identified through next generation sequencing in patients with advanced carcinoma of unknown primary: Implications for personalized medicine. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 604. doi:10.1158/1538-7445.AM2015-604