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Comprehensive Molecular Characterization of Salivary Duct Carcinoma Reveals Actionable Targets and Similarity to Apocrine Breast Cancer Martin G

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Comprehensive Molecular Characterization of Salivary Duct Carcinoma Reveals Actionable Targets and Similarity to Apocrine Breast Cancer Martin G Published OnlineFirst April 21, 2016; DOI: 10.1158/1078-0432.CCR-16-0637 Personalized Medicine and Imaging Clinical Cancer Research Comprehensive Molecular Characterization of Salivary Duct Carcinoma Reveals Actionable Targets and Similarity to Apocrine Breast Cancer Martin G. Dalin1, Alexis Desrichard1, Nora Katabi2, Vladimir Makarov1, Logan A. Walsh1, Ken-Wing Lee1, Qingguo Wang1, Joshua Armenia1, Lyndsay West3, Snjezana Dogan2, Lu Wang2, Deepa Ramaswami1,AlanL.Ho4, Ian Ganly1,3, David B. Solit1,5,6, Michael F. Berger2,5, Nikolaus D. Schultz7, Jorge S. Reis-Filho1,2, Timothy A. Chan1,8, and Luc G.T. Morris1,3 Abstract Purpose: Salivary duct carcinoma (SDC) is an aggressive sal- receptor (AR) was overexpressed in 75%; several potential resis- ivary malignancy, which is resistant to chemotherapy and has tance mechanisms to androgen deprivation therapy (ADT) were high mortality rates. We investigated the molecular landscape of identified, including the AR-V7 splice variant (present in 50%, SDC, focusing on genetic alterations and gene expression profiles. often at low ratios compared with full-length AR) and FOXA1 Experimental Design: We performed whole-exome sequenc- mutations (10%). Consensus clustering and pathway analyses in ing, RNA sequencing, and immunohistochemical analyses in 16 transcriptome data revealed striking similarities between SDC and SDC tumors and examined selected alterations via targeted molecular apocrine breast cancer. sequencing of 410 genes in a second cohort of 15 SDCs. Conclusions: This study illuminates the landscape of genetic Results: SDCs harbored a higher mutational burden than many alterations and gene expression programs in SDC, identifying other salivary carcinomas (1.7 mutations/Mb). The most frequent numerous molecular targets and potential determinants of genetic alterations were mutations in TP53 (55%), HRAS (23%), response to AR antagonism. This has relevance for emerging PIK3CA (23%), and amplification of ERBB2 (35%). Most (74%) clinical studies of ADT and other targeted therapies in SDC. The tumors had alterations in either MAPK (BRAF/HRAS/NF1) genes similarities between SDC and apocrine breast cancer indicate that or ERBB2. Potentially targetable alterations based on supportive clinical data in breast cancer may generate useful hypotheses for clinical evidence were present in 61% of tumors. Androgen SDC. Clin Cancer Res; 1–11. Ó2016 AACR. Introduction cancers. The majority of cases originate in the parotid or sub- mandibular gland, with lymph node metastasis and facial nerve Salivary duct carcinoma (SDC) is one of the most aggressive palsy commonly present at diagnosis (1, 2). Standard treatment head and neck tumors, accounting for 2% of salivary gland includes surgical resection with or without adjuvant radiotherapy, but local disease recurrence and distant metastasis are common and rarely responsive to chemotherapy. Therefore, the overall 1Human Oncology and Pathogenesis Program, Memorial Sloan Ketter- 2 prognosis remains poor with a long-term survival of 30% to 55% ing Cancer Center, New York, New York. Department of Pathology, – Memorial Sloan Kettering Cancer Center, New York, New York. (1 3). 3Department of Surgery, Memorial Sloan Kettering Cancer Center, SDCs may arise de novo or develop as the malignant component 4 New York, New York. Head and Neck Medical Oncology Service, of a carcinoma ex-pleomorphic adenoma (denoted SDC ex-PA), Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. 5Marie-Josee and Henry R. Kravis Center for which is a cancer that has transformed from a longstanding Molecular Oncology, Memorial Sloan Kettering Cancer Center, New pleomorphic adenoma. Histologic findings include a hyalinized, York, New York. 6Genitourinary Oncology Service, Department of fibrous stroma infiltrated by neoplastic ducts, which resembles Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. 7Department of Epidemiology and Biostatistics, Memorial Sloan the morphology of invasive ductal carcinoma of the breast (4). Kettering Cancer Center, New York, New York. 8Department of Radi- SDC and breast cancer also share several IHC characteristics, ation Oncology, Memorial Sloan Kettering Cancer Center, New York, including positive staining for the androgen receptor (AR), which New York. is detected in a majority of both tumor types (3, 5–7). Several case Note: Supplementary data for this article are available at Clinical Cancer series have reported clinical benefit from androgen deprivation Research Online (http://clincancerres.aacrjournals.org/). therapy (ADT), which has been suggested as potential first-line Corresponding Authors: Luc G.T. Morris, Memorial Sloan Kettering Cancer therapy in patients with recurrent AR-positive SDC (8, 9). Center, 1275 York Avenue, New York, NY 10065. Phone: 212-639-3049; Fax: Amplification of ERBB2 (also known as HER2) has been 212-717-3278; E-mail: [email protected]; and Timothy A. Chan, detected in approximately one third of SDCs and is associated [email protected] with poor prognosis (3, 5, 10, 11). The ERBB2 inhibitor trastuzu- doi: 10.1158/1078-0432.CCR-16-0637 mab has been tested with reported cases of clinical response (12– Ó2016 American Association for Cancer Research. 14), although no controlled study has been performed. It has been www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst April 21, 2016; DOI: 10.1158/1078-0432.CCR-16-0637 Dalin et al. cases with sufficient tumor material were subjected to whole- Translational Relevance exome sequencing of tumor and normal DNA, as well as tumor Salivary duct carcinomas (SDC) often present with loco- RNA-Seq. regionally advanced disease or distant metastases. A majority For cohort 2 (denoted SDC17–SDC31), tumors were of patients ultimately succumb to treatment-resistant disease. sequenced using a clinical next-generation sequencing platform, Therapies such as androgen-deprivation therapy (ADT) and Memorial Sloan Kettering-Integrated Mutation Profiling of HER2 inhibition have achieved anecdotal responses, but the Actionable Cancer Targets (MSK-IMPACT; ref. 16). These were rarity of this disease and limited molecular data have impeded patients with advanced (all recurrent or metastatic) cancers who the design of rational clinical studies. To date, molecular were offered targeted tumor sequencing in the context of an IRB- profiling of SDCs has been restricted to ad hoc analyses of approved study (NCT01775072). For these cases, tumor DNA and only specific genes. Here, through whole-exome, targeted matched normal blood DNA were subjected to massively parallel capture, and transcriptome sequencing, we identified many sequencing, targeting the exons of 410 selected genes and selected targetable alterations, as well as potential ADT resistance intronic and regulatory regions (listed in Supplementary Table mechanisms. Our analysis also reveals a strong molecular S1), with technical details of this assay described previously (16). similarity to apocrine breast carcinoma, a tumor type in which ADT has demonstrated activity. Taken together, these data DNA and RNA extraction expand our knowledge of the biology of SDC, particularly DNA was extracted from fresh-frozen tissue or whole blood molecular features that have relevance to ADT, HER2 inhibi- using the DNeasy Blood and Tissue Kit (Qiagen) and quantified tion, and other targeted therapies. with the PicoGreen assay (Thermo Fisher Scientific). RNA was extracted using the RNeasy Mini kit (Qiagen) and quantified with the RiboGreen assay (Thermo Fisher Scientific). DNA and RNA quality and integrity were analyzed by BioAnalyzer (Agilent proposed that SDC, analogous to breast cancer, can be divided into Technologies) and Fragment Analyzer (Advanced Analytics). different subtypes based on receptor status: AR-positive, ERBB2- positive, and basal-like (AR- and ERBB2-negative) phenotypes (6). Whole-exome library preparation and sequencing However, this hypothesis is based on immunohistochemical data Whole-exome sequencing libraries were prepared using the only, and it is unclear whether SDC resembles breast cancer on a SureSelectXT Library Preparation Kit (Agilent). DNA was broader molecular level. sheared using an LE220 Focus-ultrasonicator (Covaris), and Previous genetic studies of SDC have focused on a limited the fragments were end-repaired, adenylated, ligated to Illu- fi number of genes and have found TP53 alterations in the majority mina sequencing adapters, and ampli ed by PCR. Exome of patients. Other recurrently mutated genes include KIT, PIK3CA, capture was performed using the SureSelectXT v4 51 Mb cap- and HRAS (5, 15). To date, no unbiased comprehensive molecular ture probe set (Agilent), and captured exome libraries were fi characterization of SDC with whole-exome or transcriptome enriched by PCR. Final libraries were quanti ed using the KAPA fi sequencing has been reported. Library Quanti cation Kit (KAPA Biosystems), Qubit Fluorom- In this study, we performed whole-exome sequencing of tumor eter (Life Technologies), and 2100 BioAnalyzer (Agilent) and and matched normal DNA, as well as tumor RNA sequencing were sequenced on a HiSeq2500 sequencer (Illumina) using 2 Â (RNA-Seq), and analyzed the spectrum of genetic alterations in 16 125 bp cycles. SDC patients. To classify SDC in comparison with breast cancer, global gene expression was analyzed and compared with pub- RNA library preparation and sequencing lished datasets
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