Comprehensive molecular characterization of salivary duct carcinoma reveals actionable targets and similarity to apocrine breast cancer

Martin G. Dalin, Alexis Desrichard, Nora Katabi, Vladimir Makarov, Logan A. Walsh, Ken Wing Lee, Qingguo Wang, Joshua Armenia, Lyndsay West, Snjezana Dogan, Lu Wang, Deepa Ramaswami, Alan L. Ho, Ian Ganly, David B. Solit, Michael F. Berger, Nikolaus D. Schultz, Jorge S. Reis-Filho, Timothy A. Chan, Luc G T Morris

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: Salivary duct carcinoma (SDC) is an aggressive salivary malignancy, which is resistant to chemotherapy and has high mortality rates. We investigated the molecular landscape of SDC, focusing on genetic alterations and gene expression profiles. Experimental Design: We performed whole-exome sequencing, RNA sequencing, and immunohistochemical analyses in 16 SDC tumors and examined selected alterations via targeted sequencing of 410 genes in a second cohort of 15 SDCs. Results: SDCs harbored a higher mutational burden than many other salivary carcinomas (1.7 mutations/Mb). The most frequent genetic alterations were mutations in TP53 (55%), HRAS (23%), PIK3CA (23%), and amplification of ERBB2 (35%). Most (74%) tumors had alterations in either MAPK (BRAF/HRAS/NF1) genes or ERBB2. Potentially targetable alterations based on supportive clinical evidence were present in 61% of tumors. Androgen receptor (AR) was overexpressed in 75%; several potential resistance mechanisms to androgen deprivation therapy (ADT) were identified, including the AR-V7 splice variant (present in 50%, often at low ratios compared with full-length AR) and FOXA1 mutations (10%). Consensus clustering and pathway analyses in transcriptome data revealed striking similarities betweenSDCand molecular apocrine breast cancer. Conclusions: This study illuminates the landscape of genetic alterations and gene expression programs in SDC, identifying numerous molecular targets and potential determinants of response to AR antagonism. This has relevance for emerging clinical studies of ADT and other targeted therapies in SDC. The similarities between SDC and apocrine breast cancer indicate that clinical data in breast cancer may generate useful hypotheses for SDC. Clin Cancer Res; 22(18); 4623-33.

Original languageEnglish
Pages (from-to)4623-4633
Number of pages11
JournalClinical Cancer Research
Volume22
Issue number18
DOIs
Publication statusPublished - Sep 15 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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