Amplification of the ch19p13.2 NACC1 locus in ovarian high-grade serous carcinoma.
On the basis of digital karyotyping, we have identified a new, discrete amplified region at ch19p13.2 in a high-grade ovarian serous carcinoma. To further characterize this region, we determined the frequency and biological significance of ch19p13.2 amplification by analyzing 341 high-grade serous carcinomas from The Cancer Genome Atlas (TCGA) and found an increased DNA copy number at this locus in 18% of cases. We correlated the DNA and RNA copy number by analyzing the TCGA data set for all amplified genes and detected seven genes within ch19p13.2 that were significantly correlated (R≥0.54) and were, in fact, listed as the top 100 potential 'driver' genes at a genome-wide scale. Interestingly, one of the seven genes, NACC1, encoding NAC1 was previously reported to be involved in the development of tumor recurrence in ovarian serous carcinoma and to have a causal role in the development of paclitaxel resistance. Therefore, we selected NACC1 for validation in an independent cohort. On the basis of fluorescence in situ hybridization, we found that 35 (20%) of 175 high-grade serous carcinomas had an increased DNA copy number at the NACC1 locus, and those amplified cases were associated with early disease recurrence within 6 months (P=0.013). A significantly high level of NAC1 protein expression based on immunohistochemistry was detected in amplified tumors as compared with non-amplified tumors (P<0.005). In summary, our data suggest that amplification at the ch19p13.2 NACC1 locus, leading to NAC1 overexpression, is one of the molecular genetic alterations associated with early tumor recurrence in ovarian cancer.
Departments of Pathology, Oncology and Gynecology/Obstetrics, Johns Hopkins Medical Institutions, 1550 Orleans Street, Baltimore, MD 21231, USA. ishih@jhmi.edu
Ie-Ming
IeM
Shih
Kentaro
K
Nakayama
Gang
G
Wu
Naomi
N
Nakayama
Jinghui
J
Zhang
Tian-Li
TL
Wang
D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002888:Chromosomes, Human, Pair 19; D018284:Cystadenocarcinoma, Serous / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005784:Gene Amplification; D018628:Gene Dosage; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D009364:Neoplasm Recurrence, Local; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism
D014408:Biomarkers, Tumor; C516477:NACC1 protein, human; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins
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