Histotype-specific copy-number alterations in ovarian cancer
- Equal contributors
1 Department of Obstetrics & Gynaecology, National University Hospital, 5 Lower Kent Ridge Road, Singapore, 119074, Singapore
2 Cancer Science Institute, National University of Singapore, Centre for Life Sciences, #02-07 28 Medical Drive, Singapore, 117456, Singapore
3 Cancer & Stem Cell Biology, Duke-National University of Singapore Graduate Medical School, 8 College road, Rm 6-32, Singapore, 169857, Singapore
4 Department of Gynecology and Obstetrics, Kyoto University Graduate Medical School, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan
5 National Defense Medical Center, Taiwan, 114 No.161, Sec. 6, Minquan E. Rd., Neihu Dist, Taipei City, 114, Taiwan
6 Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Singapore, 138673, Singapore
7 Department of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610, Singapore
8 Saw Swee Hock School of Public Health, Yong Loo Lin School of Medicine, National University of Singapore, MD3, 16 Medical Drive, Singapore, 117597, Singapore
BMC Medical Genomics 2012, 5:47 doi:10.1186/1755-8794-5-47Published: 18 October 2012
Epithelial ovarian cancer is characterized by multiple genomic alterations; most are passenger alterations which do not confer tumor growth. Like many cancers, it is a heterogeneous disease and can be broadly categorized into 4 main histotypes of clear cell, endometrioid, mucinous, and serous. To date, histotype-specific copy number alterations have been difficult to elucidate. The difficulty lies in having sufficient sample size in each histotype for statistical analyses.
To dissect the heterogeneity of ovarian cancer and identify histotype-specific alterations, we used an in silico hypothesis-driven approach on multiple datasets of epithelial ovarian cancer.
In concordance with previous studies on global copy number alterations landscape, the study showed similar alterations. However, when the landscape was de-convoluted into histotypes, distinct alterations were observed. We report here significant histotype-specific copy number alterations in ovarian cancer and showed that there is genomic diversity amongst the histotypes. 76 cancer genes were found to be significantly altered with several as potential copy number drivers, including ERBB2 in mucinous, and TPM3 in endometrioid histotypes. ERBB2 was found to have preferential alterations, where it was amplified in mucinous (28.6%) but deleted in serous tumors (15.1%). Validation of ERBB2 expression showed significant correlation with microarray data (p=0.007). There also appeared to be reciprocal relationship between KRAS mutation and copy number alterations. In mucinous tumors where KRAS mutation is common, the gene was not significantly altered. However, KRAS was significantly amplified in serous tumors where mutations are rare in high grade tumors.
The study demonstrates that the copy number landscape is specific to the histotypes and identification of these alterations can pave the way for targeted drug therapy specific to the histotypes.