TY - JOUR
T1 - Whole-genome sequencing of common Salivary Gland carcinomas
T2 - Subtype-restricted and shared genetic alterations
AU - Karpinets, Tatiana V.
AU - Mitani, Yoshitsugu
AU - Liu, Bin
AU - Zhang, Jianhua
AU - Pytynia, Kristen B.
AU - Sellen, Linton D.
AU - Karagiannis, Danice T.
AU - Ferrarotto, Renata
AU - Futreal, Andrew P.
AU - El-Naggar, Adel K.
N1 - Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/7/15
Y1 - 2021/7/15
N2 - Purpose: Salivary gland carcinomas (SGCs) are pathologically classified into several widely diverse subtypes, of which adenoid cystic carcinoma (ACC), mucoepidermoid carcinoma (MEC), and salivary duct carcinoma (SDC) are the most commonly encountered. A comparative genetic analysis of these subtypes provides detailed information on the genetic alterations that are associated with their tumorigenesis and may lead to the identification of biomarkers to guide tumor-specific clinical trials. Experimental Design: Whole-genome sequencing of 58 common SGCs (20 ACCs, 20 SDCs, and 18 MECs) was performed to catalog structural variations, copy number, rearrangements, and driver mutations. Data were bioinformatically analyzed and correlated with clinicopathologic parameters, and selected targets were validated. Results: Novel and recurrent type–specific and shared genetic alterations were identified within and among 3 subtypes. Mutually exclusive canonical fusion and nonfusion genomic alterations were identified in both ACC and MEC. In ACCs, loss of chromosome 12q was dominant in MYB or MYBL1 fusion–positive tumors and mutations of NOTCH pathway were more common in these fusion negatives. In MECs, CRTC1-MAML2 fusion–positive tumors showed frequent BAP1 mutation, and tumors lacking this fusion were enriched with LRFN1 mutation. SDCs displayed considerable genetic instability, lacked recurrent chromosomal rearrangements, and demonstrated non-overlapping TP53 mutation and ERBB2 amplification in a subset of tumors. Limited genetic alterations, including focal amplifications of 8q21-q23, were shared by all subtypes and were associated with poor survival. Conclusions: This study delineates type-specific and shared genetic alterations that are associated with early phenotypic commitment and the biologic progression of common SGCs. These alterations, upon validation, could serve as biomarkers in tumor-specific clinical trials.
AB - Purpose: Salivary gland carcinomas (SGCs) are pathologically classified into several widely diverse subtypes, of which adenoid cystic carcinoma (ACC), mucoepidermoid carcinoma (MEC), and salivary duct carcinoma (SDC) are the most commonly encountered. A comparative genetic analysis of these subtypes provides detailed information on the genetic alterations that are associated with their tumorigenesis and may lead to the identification of biomarkers to guide tumor-specific clinical trials. Experimental Design: Whole-genome sequencing of 58 common SGCs (20 ACCs, 20 SDCs, and 18 MECs) was performed to catalog structural variations, copy number, rearrangements, and driver mutations. Data were bioinformatically analyzed and correlated with clinicopathologic parameters, and selected targets were validated. Results: Novel and recurrent type–specific and shared genetic alterations were identified within and among 3 subtypes. Mutually exclusive canonical fusion and nonfusion genomic alterations were identified in both ACC and MEC. In ACCs, loss of chromosome 12q was dominant in MYB or MYBL1 fusion–positive tumors and mutations of NOTCH pathway were more common in these fusion negatives. In MECs, CRTC1-MAML2 fusion–positive tumors showed frequent BAP1 mutation, and tumors lacking this fusion were enriched with LRFN1 mutation. SDCs displayed considerable genetic instability, lacked recurrent chromosomal rearrangements, and demonstrated non-overlapping TP53 mutation and ERBB2 amplification in a subset of tumors. Limited genetic alterations, including focal amplifications of 8q21-q23, were shared by all subtypes and were associated with poor survival. Conclusions: This study delineates type-specific and shared genetic alterations that are associated with early phenotypic commitment and the biologic progression of common SGCs. These alterations, upon validation, could serve as biomarkers in tumor-specific clinical trials.
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U2 - 10.1158/1078-0432.CCR-20-4071
DO - 10.1158/1078-0432.CCR-20-4071
M3 - Article
C2 - 34011559
AN - SCOPUS:85110074730
SN - 1078-0432
VL - 27
SP - 3960
EP - 3969
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 14
ER -