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

Tomotaka Shimura, Yuichiro Tada, Hideaki Hirai, Daisuke Kawakita, Satoshi Kano, Kiyoaki Tsukahara, Akira Shimizu, Soichiro Takase, Yorihisa Imanishi, Hiroyuki Ozawa, Kenji Okami, Yuichiro Sato, Yukiko Sato, Chihiro Fushimi, Hideaki Takahashi, Takuro Okada, Hiroki Sato, Kuninori Otsuka, Yoshihiro Watanabe, Akihiro Sakai, Koji Ebisumoto, Takafumi Togashi, Yushi Ueki, Hisayuki Ota, Mizuo Ando, Shinji Kohsaka, Toyoyuki Hanazawa, Hideaki Chazono, Yoshiyuki Kadokura, Hitome Kobayashi and Toshitaka Nagao _

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Oncotarget. 2018; 9:1852-1867. https://doi.org/10.18632/oncotarget.22927

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Abstract

Tomotaka Shimura1,2,14,*, Yuichiro Tada3,*, Hideaki Hirai2,*, Daisuke Kawakita4, Satoshi Kano5, Kiyoaki Tsukahara6, Akira Shimizu6, Soichiro Takase6, Yorihisa Imanishi7, Hiroyuki Ozawa7, Kenji Okami8, Yuichiro Sato9, Yukiko Sato10, Chihiro Fushimi4, Hideaki Takahashi4, Takuro Okada6, Hiroki Sato6, Kuninori Otsuka7, Yoshihiro Watanabe7, Akihiro Sakai8, Koji Ebisumoto8, Takafumi Togashi9, Yushi Ueki9, Hisayuki Ota9, Mizuo Ando11, Shinji Kohsaka12, Toyoyuki Hanazawa13, Hideaki Chazono13, Yoshiyuki Kadokura14, Hitome Kobayashi1 and Toshitaka Nagao2

1Department of Otorhinolaryngology, Showa University School of Medicine, Tokyo, Japan

2Department of Anatomic Pathology, Tokyo Medical University, Tokyo, Japan

3Department of Head and Neck Oncology and Surgery, International University of Health and Welfare Mita Hospital, Tokyo, Japan

4Department of Otolaryngology Head and Neck Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

5Department of Otolaryngology Head and Neck Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan

6Department of Otolaryngology Head and Neck Surgery, Tokyo Medical University, Tokyo, Japan

7Department of Otolaryngology Head and Neck Surgery, Keio University School of Medicine, Tokyo, Japan

8Department of Otolaryngology Head and Neck Surgery, Tokai University School of Medicine, Isehara, Japan

9Department of Head and Neck Surgery, Niigata Cancer Center Hospital, Niigata, Japan

10Department of Pathology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan

11Department of Otolaryngology Head and Neck Surgery, Faculty of Medicine, The University of Tokyo, Tokyo, Japan

12Department of Medical Genomics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

13Department of Otolaryngology, Head and Neck Surgery, Chiba University Graduate School of Medicine, Chiba, Japan

14Department 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.


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