TY - JOUR
T1 - Chromosome 19 amplification correlates with advanced disease in adrenocortical carcinoma
AU - Rubinstein, Jill C.
AU - Brown, Taylor C.
AU - Goh, Gerald
AU - Juhlin, C. Christofer
AU - Stenman, Adam
AU - Korah, Reju
AU - Carling, Tobias
N1 - Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2016/1/1
Y1 - 2016/1/1
N2 - Background Familial syndromes with specific genetic drivers account for a subset of adrenocortical carcinomas (ACCs), but the genomic underpinnings of sporadic cases remain poorly understood. Recent advances in copy number variation (CNV) prediction from exome sequencing are facilitating exploration of genomic rearrangements common to these carcinomas. Methods ACC and matched, nontumor samples underwent exome sequencing. CNVs were predicted using coverage-depth comparison. Clinicopathologic characteristics of amplification- and deletion-dominant samples were compared and pathway enrichment analysis performed for regions with significant variation. Results CNVs are distributed broadly across the ACC genome. Individual signatures demonstrate amplification or deletion dominance. Areas of recurrent amplification include chromosomes 5, 12, 19, and 20, whereas chromosomes 1, 10, 18, and 22 are deletion prone. Large-scale amplification of chromosome 19 occurred in 12 of 19 cases (63%), including 6 of 8 amplification-dominant samples (75%) and was associated with stage III/IV disease (P =.002). Genes within this amplified region are overrepresented among the adrenal hyperplasia and steroid biosynthesis pathways (P = 4.2-5 and 2.5-5, respectively). Conclusion CNV detection via exome sequencing allows high-resolution cataloging of structural variations in ACC. Large-scale, recurrent amplifications encompassing known adrenal-specific gene pathways correlate with tumor stage. Further functional analysis of individual genes within these regions could provide mechanistic insight into specific drivers underlying pathogenesis and progression of ACC.
AB - Background Familial syndromes with specific genetic drivers account for a subset of adrenocortical carcinomas (ACCs), but the genomic underpinnings of sporadic cases remain poorly understood. Recent advances in copy number variation (CNV) prediction from exome sequencing are facilitating exploration of genomic rearrangements common to these carcinomas. Methods ACC and matched, nontumor samples underwent exome sequencing. CNVs were predicted using coverage-depth comparison. Clinicopathologic characteristics of amplification- and deletion-dominant samples were compared and pathway enrichment analysis performed for regions with significant variation. Results CNVs are distributed broadly across the ACC genome. Individual signatures demonstrate amplification or deletion dominance. Areas of recurrent amplification include chromosomes 5, 12, 19, and 20, whereas chromosomes 1, 10, 18, and 22 are deletion prone. Large-scale amplification of chromosome 19 occurred in 12 of 19 cases (63%), including 6 of 8 amplification-dominant samples (75%) and was associated with stage III/IV disease (P =.002). Genes within this amplified region are overrepresented among the adrenal hyperplasia and steroid biosynthesis pathways (P = 4.2-5 and 2.5-5, respectively). Conclusion CNV detection via exome sequencing allows high-resolution cataloging of structural variations in ACC. Large-scale, recurrent amplifications encompassing known adrenal-specific gene pathways correlate with tumor stage. Further functional analysis of individual genes within these regions could provide mechanistic insight into specific drivers underlying pathogenesis and progression of ACC.
UR - http://www.scopus.com/inward/record.url?scp=84951764206&partnerID=8YFLogxK
U2 - 10.1016/j.surg.2015.09.001
DO - 10.1016/j.surg.2015.09.001
M3 - Article
C2 - 26453132
AN - SCOPUS:84951764206
SN - 0039-6060
VL - 159
SP - 296
EP - 301
JO - Surgery (United States)
JF - Surgery (United States)
IS - 1
ER -