TY - JOUR
T1 - Proteogenomic analysis of salivary adenoid cystic carcinomas defines molecular subtypes and identifies therapeutic targets
AU - Ferrarotto, Renata
AU - Mitani, Yoshitsugu
AU - McGrail, Daniel J.
AU - Li, Kaiyi
AU - Karpinets, Tatiana V.
AU - Bell, Diana
AU - Frank, Steven J.
AU - Song, Xingzhi
AU - Kupferman, Michael E.
AU - Liu, Bin
AU - Jack Lee, J.
AU - Glisson, Bonnie S.
AU - Zhang, Jianhua
AU - Aster, Jon C.
AU - Lin, Shiaw Yih
AU - Andrew Futreal, P.
AU - Heymach, John V.
AU - El-Naggar, Adel K.
N1 - Funding Information:
This work was supported by grants from the Conquer Cancer Foundation of the American Society of Clinical Oncology (to R. Ferrarotto), Adenoid Cystic Carcinoma Research Foundation (to R. Ferrarotto), Khalifa Bin Zayed Al Nahyan Foundation Khalifa Scholar fellowship program (to R. Ferrarotto), the NIH National Institute of Dental and Craniofacial Research and the Salivary Gland Tumor Biorepository (HHSN268200900039C 04), NCI grant K99CA240689 (to D.J. McGrail), and by the NIH/NCI under award number P30 CA016672, which supports the Sequencing and Microarray Facility. The authors thank Stephanie P. Deming of Scientific Publications, Research Medical Library, MD Anderson Cancer Center, for editorial assistance and The Adenoid Cystic Carcinoma Research Foundation for critically reviewing the article.
Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2021/2/1
Y1 - 2021/2/1
N2 - Purpose: Salivary gland adenoid cystic carcinoma (ACC) has heterogeneous clinical behavior. Currently, all patients are treated uniformly, and no standard-of-care systemic therapy exists for metastatic ACC. We conducted an integrated proteogenomic analyses of ACC tumors to identify dysregulated pathways and propose a classification with therapeutic implications. Experimental Design: RNA/DNA sequencing of 54 flash-frozen salivary ACCs and reverse phase protein array (RPPA) in 38 specimens were performed, with validation by Western blotting and/or IHC. Three independent ACC cohorts were used for validation. Results: Both unbiased RNA sequencing (RNA-seq) and RPPA analysis revealed two molecular subtypes: ACC-I (37%) and ACC-II (63%). ACC-I had strong upregulation of MYC, MYC target genes, and mRNA splicing, enrichment of NOTCH-activating mutations, and dramatically worse prognosis. ACC-II exhibited upregulation of TP63 and receptor tyrosine kinases (AXL, MET, and EGFR) and less aggressive clinical course. TP63 and MYC were sufficient to assign tumors to ACC subtypes, which was validated in one independent cohort by IHC and two additional independent cohorts by RNA-seq. Furthermore, IHC staining for MYC and P63 protein levels can be used to identify ACC subtypes, enabling rapid clinical deployment to guide therapeutic decisions. Our data suggest a model in which ACC-I is driven by MYC signaling through either NOTCH mutations or direct amplification, which in turn suppress P63 signaling observed in ACC-II, producing unique therapeutic vulnerabilities for each subtype. Conclusions: Cooccurrence of multiple actionable protein/pathways alterations in each subtype indicates unique therapeutic vulnerabilities and opportunities for optimal combination therapy for this understudied and heterogeneous disease.
AB - Purpose: Salivary gland adenoid cystic carcinoma (ACC) has heterogeneous clinical behavior. Currently, all patients are treated uniformly, and no standard-of-care systemic therapy exists for metastatic ACC. We conducted an integrated proteogenomic analyses of ACC tumors to identify dysregulated pathways and propose a classification with therapeutic implications. Experimental Design: RNA/DNA sequencing of 54 flash-frozen salivary ACCs and reverse phase protein array (RPPA) in 38 specimens were performed, with validation by Western blotting and/or IHC. Three independent ACC cohorts were used for validation. Results: Both unbiased RNA sequencing (RNA-seq) and RPPA analysis revealed two molecular subtypes: ACC-I (37%) and ACC-II (63%). ACC-I had strong upregulation of MYC, MYC target genes, and mRNA splicing, enrichment of NOTCH-activating mutations, and dramatically worse prognosis. ACC-II exhibited upregulation of TP63 and receptor tyrosine kinases (AXL, MET, and EGFR) and less aggressive clinical course. TP63 and MYC were sufficient to assign tumors to ACC subtypes, which was validated in one independent cohort by IHC and two additional independent cohorts by RNA-seq. Furthermore, IHC staining for MYC and P63 protein levels can be used to identify ACC subtypes, enabling rapid clinical deployment to guide therapeutic decisions. Our data suggest a model in which ACC-I is driven by MYC signaling through either NOTCH mutations or direct amplification, which in turn suppress P63 signaling observed in ACC-II, producing unique therapeutic vulnerabilities for each subtype. Conclusions: Cooccurrence of multiple actionable protein/pathways alterations in each subtype indicates unique therapeutic vulnerabilities and opportunities for optimal combination therapy for this understudied and heterogeneous disease.
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U2 - 10.1158/1078-0432.CCR-20-1192
DO - 10.1158/1078-0432.CCR-20-1192
M3 - Article
C2 - 33172898
AN - SCOPUS:85100400245
SN - 1078-0432
VL - 27
SP - 852
EP - 864
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 3
ER -