TY - JOUR
T1 - Whole-exome sequencing characterizes the landscape of somatic mutations and copy number alterations in adrenocortical carcinoma
AU - Juhlin, C. Christofer
AU - Goh, Gerald
AU - Healy, James M.
AU - Fonseca, Annabelle L.
AU - Scholl, Ute I.
AU - Stenman, Adam
AU - Kunstman, John W.
AU - Brown, Taylor C.
AU - Overton, John D.
AU - Mane, Shrikant M.
AU - Nelson-Williams, Carol
AU - Bäckdahl, Martin
AU - Suttorp, Anna Carinna
AU - Haase, Matthias
AU - Choi, Murim
AU - Schlessinger, Joseph
AU - Rimm, David L.
AU - Höög, Anders
AU - Prasad, Manju L.
AU - Korah, Reju
AU - Larsson, Catharina
AU - Lifton, Richard P.
AU - Carling, Tobias
N1 - Publisher Copyright:
Copyright © 2015 by the Endocrine Society.
PY - 2015/3/1
Y1 - 2015/3/1
N2 - Context: Adrenocortical carcinoma (ACC) is a rare and lethal malignancy with a poorly defined etiology, and the molecular genetics of ACC are incompletely understood. Objective: To utilize whole-exome sequencing for genetic characterization of the underlying somatic mutations and copy number alterations present in ACC. Design: Screening for somatic mutation events and copy number alterations (CNAs) was performed by comparative analysis of tumors and matched normal samples from 41 patients with ACC. Results: In total, 966 nonsynonymous somatic mutations were detected, including 40 tumors with a mean of 16 mutations per sample and one tumor with 314 mutations. Somatic mutations in ACC-associated genes included TP53 (8/41 tumors, 19.5%) and CTNNB1 (4/41, 9.8%). Genes with potential disease-causing mutations included GNAS , NF2, and RB1 , and recurrently mutated genes with unknown roles in tumorigenesis comprised CDC27 , SCN7A , and SDK1 . Recurrent CNAs included amplification at 5p15.33 including TERT (6/41, 14.6%) and homozygous deletion at 22q12.1 including the Wnt repressors ZNRF3 and KREMEN1 (4/41 9.8% and 3/41, 7.3%, respectively). Somatic mutations in ACC-established genes and recurrent ZNRF3 and TERT loci CNAs were mutually exclusive in the majority of cases. Moreover, gene ontology identified Wnt signaling as the most frequently mutated pathway in ACCs. Conclusions: These findings highlight the importance of Wnt pathway dysregulation in ACC and corroborate the finding of homozygous deletion of Wnt repressors ZNRF3 and KREMEN1. Overall, mutations in either TP53 or CTNNB1 as well as focal CNAs at the ZNRF3 or TERT loci denote mutually exclusive events, suggesting separate mechanisms underlying the development of these tumors.
AB - Context: Adrenocortical carcinoma (ACC) is a rare and lethal malignancy with a poorly defined etiology, and the molecular genetics of ACC are incompletely understood. Objective: To utilize whole-exome sequencing for genetic characterization of the underlying somatic mutations and copy number alterations present in ACC. Design: Screening for somatic mutation events and copy number alterations (CNAs) was performed by comparative analysis of tumors and matched normal samples from 41 patients with ACC. Results: In total, 966 nonsynonymous somatic mutations were detected, including 40 tumors with a mean of 16 mutations per sample and one tumor with 314 mutations. Somatic mutations in ACC-associated genes included TP53 (8/41 tumors, 19.5%) and CTNNB1 (4/41, 9.8%). Genes with potential disease-causing mutations included GNAS , NF2, and RB1 , and recurrently mutated genes with unknown roles in tumorigenesis comprised CDC27 , SCN7A , and SDK1 . Recurrent CNAs included amplification at 5p15.33 including TERT (6/41, 14.6%) and homozygous deletion at 22q12.1 including the Wnt repressors ZNRF3 and KREMEN1 (4/41 9.8% and 3/41, 7.3%, respectively). Somatic mutations in ACC-established genes and recurrent ZNRF3 and TERT loci CNAs were mutually exclusive in the majority of cases. Moreover, gene ontology identified Wnt signaling as the most frequently mutated pathway in ACCs. Conclusions: These findings highlight the importance of Wnt pathway dysregulation in ACC and corroborate the finding of homozygous deletion of Wnt repressors ZNRF3 and KREMEN1. Overall, mutations in either TP53 or CTNNB1 as well as focal CNAs at the ZNRF3 or TERT loci denote mutually exclusive events, suggesting separate mechanisms underlying the development of these tumors.
UR - http://www.scopus.com/inward/record.url?scp=84924995394&partnerID=8YFLogxK
U2 - 10.1210/jc.2014-3282
DO - 10.1210/jc.2014-3282
M3 - Article
C2 - 25490274
AN - SCOPUS:84924995394
SN - 0021-972X
VL - 100
SP - E493-E502
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 3
ER -