Molecular patterns in salivary duct carcinoma identify prognostic subgroups

Müller, Simon A.; Gauthier, Marie-Emilie; Blackburn, James; Grady, John P.; Spiridoula, Kraitsek; Elektra, Hajdu; Dettmer, Matthias S.; Dahlstrom, Jane E.; Soon Lee, C.; Luk, Peter P.; Yu, Bing; Giger, Roland; Kummerfeld, Sarah; Clark, Jonathan R.; Gupta, Ruta; Cowley, Mark J. (2020). Molecular patterns in salivary duct carcinoma identify prognostic subgroups. Modern pathology, 33(10), pp. 1896-1909. Springer Nature 10.1038/s41379-020-0576-2

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Salivary duct carcinoma (SDCa) is a rare cancer with high rate of metastases and poor survival despite aggressive multimodality treatment. This study analyzes the genetic changes in SDCa, their impact on cancer pathways, and evaluates whether molecular patterns can identify subgroups with distinct clinical characteristics and outcome. Clinicopathologic details and tissue samples from 66 patients (48 males, 18 females) treated between 1995 and 2018 were obtained from multiple institutions. Androgen receptor (AR) was assessed by immunohistochemistry, and the Illumina TruSight 170 gene panel was used for DNA sequencing. Male gender, lympho-vascular invasion, lymph node metastasis, and smoking were significant predictors of disease-free survival. AR was present in 79%. Frequently encountered alterations were mutations in TP53 (51%), PIK3CA (32%) and HRAS (22%), as well as amplifications of CDK4/6 (22%), ERBB2 (21%), MYC (16%), and deletions of CDKN2A (13%). TP53 mutation and MYC amplifications were associated with decreased disease-free survival. Analysis of cancer pathways revealed that the PI3K pathway was most commonly affected. Alterations in the cell cycle pathway were associated with impaired disease-free survival (HR 2.6, P = 0.038). Three subgroups based on AR and ERBB2 status were identified, which featured distinct molecular patterns and outcome. Among AR positive SDCa, HRAS mutations were restricted to AR positive tumors without ERBB2 amplification and HRAS mutations featured high co-occurrence with PIK3CA alterations, which seems specific to SDCa. AR negative SDCa were associated with poor disease-free survival in multivariate analysis (HR 4.5, P = 0.010) and none of these tumors exhibited ERBB2 amplification or HRAS mutations. AR and ERBB2 status in SDCa thus classifies tumors with distinct molecular profiles relevant to future targeted therapy. Furthermore, clinical factors such as smoking and molecular features such as MYC amplification may serve as markers of poor prognosis of SDCa.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Head Organs and Neurology (DKNS) > Clinic of Ear, Nose and Throat Disorders (ENT)
04 Faculty of Medicine > Service Sector > Institute of Pathology

UniBE Contributor:

Müller, Simon Andreas; Dettmer, Matthias and Giger, Roland

Subjects:

600 Technology > 610 Medicine & health
500 Science > 570 Life sciences; biology
300 Social sciences, sociology & anthropology > 320 Political science

ISSN:

1530-0285

Publisher:

Springer Nature

Language:

English

Submitter:

Carmen Heimann

Date Deposited:

15 Dec 2020 16:00

Last Modified:

20 Dec 2020 02:56

Publisher DOI:

10.1038/s41379-020-0576-2

PubMed ID:

32457410

BORIS DOI:

10.7892/boris.148465

URI:

https://boris.unibe.ch/id/eprint/148465

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