Amplification of The ch19p13.2 NACC1 Locus in Ovarian High-grade Serous Carcinoma

Based on 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 dataset for all amplified genes and detected 7 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 7 genes, NACC1, encoding NAC1 was previously reported to be involved in the development of tumor recurrence in ovarian serous carcinoma and to play a causal role in the development of paclitaxel resistance. Therefore, we selected NACC1 for validation in an independent cohort. Based on 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 to 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.