Identification of novel prognostic and predictive biomarkers in salivary duct carcinoma via comprehensive molecular profiling

Author:

Kohsaka ShinjiORCID,Tada YuichiroORCID,Ando MizuoORCID,Nakaguro Masato,Shirai Yukina,Ueno ToshihideORCID,Kojima Shinya,Hirai Hideaki,Saigusa Natsuki,Kano Satoshi,Tsukahara Kiyoaki,Togashi Takafumi,Ozawa Hiroyuki,Kondo Takahito,Okami Kenji,Takahashi Hideaki,Kawakita Daisuke,Fushimi Chihiro,Suzuki Takayoshi,Shimizu Akira,Okamoto Isaku,Okada Takuro,Sato Yuichiro,Imanishi YorihisaORCID,Watanabe Yoshihiro,Sakai Akihiro,Ebisumoto Koji,Sato YukikoORCID,Urano Makoto,Honma Yoshitaka,Yamazaki Keisuke,Ueki Yushi,Hanazawa Toyoyuki,Saito Yuki,Shimura Tomotaka,Nagao ToshitakaORCID,Mano HiroyukiORCID

Abstract

AbstractMolecular targets and predictive biomarkers for prognosis in salivary duct carcinoma (SDC) have not been fully identified. We conducted comprehensive molecular profiling to discover novel biomarkers for SDC. A total of 67 SDC samples were examined with DNA sequencing of 464 genes and transcriptome analysis in combination with the clinicopathological characteristics of the individuals. Prognostic biomarkers associated with response to combined androgen blockade (CAB) treatment were explored using mRNA expression data from 27 cases. Oncogenic mutations in receptor tyrosine kinase (RTK) genes or genes in the MAPK pathway were identified in 55 cases (82.1%). Alterations in the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway were identified in 38 cases (56.7%). Interestingly, patient prognosis could be predicted using mRNA expression profiles, but not genetic mutation profiles. The risk score generated from the expression data of a four-gene set that includes the ADAMTS1, DSC1, RNF39, and IGLL5 genes was a significant prognostic marker for overall survival in the cohort (HR = 5.99, 95% confidence interval (CI) = 2.73–13.1, p = 7.8 × 10−6). Another risk score constructed from the expression of CD3E and LDB3 was a strong prognostic marker for progression-free survival for CAB treatment (p = 0.03). Mutations in RTK genes, MAPK pathway genes, and PI3K/AKT pathway genes likely represent key mutations in SDC tumorigenesis. The gene expression profiles identified in this study may be useful for stratifying patients who are good candidates for CAB treatment and may benefit from additional systemic therapies.

Funder

Japan Agency for Medical Research and Development

MEXT | Japan Society for the Promotion of Science

Publisher

Springer Science and Business Media LLC

Subject

Cancer Research,Oncology

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