Comprehensive Molecular Characterization of Salivary Duct Carcinoma Reveals Actionable Targets and Similarity to Apocrine Breast Cancer.
OBJECTIVE
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.


METHODS
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 between SDC and 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. ©2016 AACR.
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
Martin G
MG
Dalin
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
Alexis
A
Desrichard
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
Nora
N
Katabi
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
Vladimir
V
Makarov
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
Logan A
LA
Walsh
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
Ken-Wing
KW
Lee
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
Qingguo
Q
Wang
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
Joshua
J
Armenia
Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
Lyndsay
L
West
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
Snjezana
S
Dogan
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
Lu
L
Wang
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
Deepa
D
Ramaswami
Head and Neck Medical Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
Alan L
AL
Ho
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
Ian
I
Ganly
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York. Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
David B
DB
Solit
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
Michael F
MF
Berger
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
Nikolaus D
ND
Schultz
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
Jorge S
JS
Reis-Filho
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York. morrisl@mskcc.org chant@mskcc.org.
Timothy A
TA
Chan
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York. morrisl@mskcc.org chant@mskcc.org.
Luc G T
LG
Morris
D000368:Aged; D000483:Alleles; D001050:Apocrine Glands / Q000378:metabolism / Q000473:pathology*; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D044584:Carcinoma, Ductal / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D056915:DNA Copy Number Variations; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D011944:Receptors, Androgen / Q000378:metabolism; D012008:Recurrence; D012468:Salivary Gland Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D015398:Signal Transduction; D016896:Treatment Outcome; D047368:Tumor Burden; D000073359:Exome Sequencing
D014408:Biomarkers, Tumor; D011944:Receptors, Androgen