Prognostic and histogenetic roles of gene alteration and the expression of key potentially actionable targets in salivary duct carcinomas

Abstract

// Tomotaka Shimura 1, 2, 14, * , Yuichiro Tada 3, * , Hideaki Hirai 2, * , Daisuke Kawakita 4 , Satoshi Kano 5 , Kiyoaki Tsukahara 6 , Akira Shimizu 6 , Soichiro Takase 6 , Yorihisa Imanishi 7 , Hiroyuki Ozawa 7 , Kenji Okami 8 , Yuichiro Sato 9 , Yukiko Sato 10 , Chihiro Fushimi 4 , Hideaki Takahashi 4 , Takuro Okada 6 , Hiroki Sato 6 , Kuninori Otsuka 7 , Yoshihiro Watanabe 7 , Akihiro Sakai 8 , Koji Ebisumoto 8 , Takafumi Togashi 9 , Yushi Ueki 9 , Hisayuki Ota 9 , Mizuo Ando 11 , Shinji Kohsaka 12 , Toyoyuki Hanazawa 13 , Hideaki Chazono 13 , Yoshiyuki Kadokura 14 , Hitome Kobayashi 1 and Toshitaka Nagao 2 1 Department of Otorhinolaryngology, Showa University School of Medicine, Tokyo, Japan 2 Department of Anatomic Pathology, Tokyo Medical University, Tokyo, Japan 3 Department of Head and Neck Oncology and Surgery, International University of Health and Welfare Mita Hospital, Tokyo, Japan 4 Department of Otolaryngology Head and Neck Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan 5 Department of Otolaryngology Head and Neck Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan 6 Department of Otolaryngology Head and Neck Surgery, Tokyo Medical University, Tokyo, Japan 7 Department of Otolaryngology Head and Neck Surgery, Keio University School of Medicine, Tokyo, Japan 8 Department of Otolaryngology Head and Neck Surgery, Tokai University School of Medicine, Isehara, Japan 9 Department of Head and Neck Surgery, Niigata Cancer Center Hospital, Niigata, Japan 10 Department of Pathology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan 11 Department of Otolaryngology Head and Neck Surgery, Faculty of Medicine, The University of Tokyo, Tokyo, Japan 12 Department of Medical Genomics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan 13 Department of Otolaryngology, Head and Neck Surgery, Chiba University Graduate School of Medicine, Chiba, Japan 14 Department of Otorhinolaryngology, Showa University Northern Yokohama Hospital, Yokohama, Japan * These authors contributed equally to this work Correspondence to: Toshitaka Nagao, email: nagao-t@tokyo-med.ac.jp Keywords: salivary duct carcinoma; TP53; PIK3CA; H-RAS; PI3K/Akt signaling pathway Received: August 25, 2017      Accepted: November 13, 2017      Published: December 04, 2017 ABSTRACT The molecular characteristics of therapeutically-relevant targets and their clinicopathological implications in salivary duct carcinomas (SDCs) are poorly understood. We investigated the gene alterations and the immunoexpression of crucial oncogenic molecules in 151 SDCs. The mutation rates that were identified, in order of frequency, were as follows: TP53 , 68%; PIK3CA , 18%; H-RAS , 16%; BRAF , 4%; and AKT1 , 1.5%. PIK3CA/H-RAS/BRAF mutations were more common in de novo SDC than in SDC ex-pleomorphic adenoma. Furthermore, these mutations were mutually exclusive for HER2 overexpression/amplification. TP53 mutations were frequently detected in cases with the aberrant p53 expression, and TP53 missense and truncating mutations were associated with p53-extreme positivity and negativity, respectively. DISH analysis revealed no cases of EGFR amplification. The rates of PI3K, p-Akt, and p-mTOR positivity were 34%, 22%, and 66%, respectively; PTEN loss was observed in 47% of the cases. These expressions were correlated according to the signaling axis. Cases with PI3K negativity and PTEN loss appeared to show a lower expression of androgen receptor. In the multivariate analysis, patients with SDC harboring TP53 truncating mutations showed shorter progression-free survival. Conversely, p-Akt positivity was associated with a favorable outcome. This study might provide information that leads to advances in personized therapy for SDC.