Analysis of chromosomal changes in serous ovarian carcinoma using high-resolution array comparative genomic hybridization: Potential predictive markers of chemoresistant disease

Abstract

The mechanism of drug resistance in cancer is multifactorial, and the accumulation of multiple genetic changes may lead to drug-resistant phenotypes. This study sought to determine characteristic genetic changes in chemoresistant serous ovarian carcinomas using high-resolution array comparative genomic hybridization (aCGH), and identified genomic aberrations that could be used as predictive markers of chemoresistant disease. Seventeen primary ovarian tumors from optimally debulked stage IIIc serous ovarian carcinoma patients were analyzed using aCGH. Ten patients had chemoresistant disease (progression within 12 months of initial chemotherapy), whereas seven patients had chemosensitive disease (no recurrence for more than 36 months). Receiver operating characteristics curve analysis was used to select chromosomal aberrations that could help distinguish chemoresistant disease from chemosensitive disease. In 17 tumors, frequent increases in DNA copy number were seen on 1p36.33, 3q26.2, 8q24.3, 10q26.3, 12p11.21, 20q13.33, and 21q22.3, and frequent losses were observed on 4p12, 5q13.2, 7q11.21, 8p23.1, 14q32.33, Xq13.3, and Xq21.31. The gains on 5p15.33 and 14q11.2, and losses on 4q34.2, 4q35.2, 5q15, 8p21.1, 8p21.2, 11p15.5, 13q14.13, 13q14.2, 13q32.1, 13q34, 16q22.2, 17p11.2, 17p12, and 22q12.3 were more frequent in chemoresistant disease. The losses on 13q32.1 and 8p21.1 had the largest areas under the curve (AUC 0.90 and 0.85, respectively). The most reliable combination of chromosomal aberrations for detecting chemoresistant disease was the loss on 13q32.1 and 8p21.1 (AUC 0.950). Our findings suggest that these chromosomal aberrations are potential predictive markers of chemoresistant disease in patients with serous ovarian carcinomas.