Posted: September 29, 2011
TCGA Research Data Used to Characterize Amplified Region at ch19p13.2 in Ovarian Cancer
Emma J. Spaulding
Ovarian cancer is cancer of a woman’s reproductive system, specifically the ovary. It is also the fifth leading cause of death among women. A major and dangerous type of ovarian cancer is ovarian serous cystadenocarcinoma. This type is associated with frequent tumor reoccurrence and sadly, high mortality.
A research group based at the Johns Hopkins Medical Institutions is working to identify new cancer associated genes that might contribute to pathogenesis of ovarian serous cystadenocarcinoma. They found an amplified region in chromosome 19. This is called DNA copy number variation (CNV) and in this case, means there are more copies of the region than usual. This region contained a gene, NACC1, known to contribute to chemoresistance or a cell’s development of resistance to chemotherapy treatment. NACC1 upregulates its own expression when amplified meaning that when NACC1 is amplified, it makes more of its protein, NAC1. This finding increases the likelihood that NACC1 participates in carcinogenesis. Amplification of NACC1 correlates significantly with patients that show early tumor reoccurrence.
TCGA Data Used to Examine CNV Frequency
The finding that interested the group was made in previous research. While examining DNA copy number in ovarian serous cystadenocarcinomas, the researchers found a nearly two Mb region repeated 17 times in one of their seven samples. This is an example of copy number variation. This caused the group to wonder if other ovarian serous tumor samples would show a similar change. Fortunately for the research group, this is one type of datum that The Cancer Genome Atlas (TCGA) analyzes and makes available. Using data from the TCGA Data Portal , the research group found that 18 percent of samples showed increased DNA copy number. It seemed that something in the amplified region was contributing to the ovarian cancer.
To find out what it was, the researchers reasoned that amplified genes that “drive” cancer, called “driver” genes, would upregulate their expression, how often genes are actualized to proteins. Genes in the amplified region that did not contribute to cancer but were “along for the ride,” so-called “passenger” genes, would not change gene expression. The researchers examined links between corresponding mRNA expression levels and DNA copy number. Of the seven genes that showed significant correlation, NACC1 was chosen because its biological role had already been reported. The protein of NACC1, NAC1 has been shown to participate in the development of chemoresistant tumors.
Patients Display Earlier Tumor Reoccurrence
Using genetic analysis data and follow-up information from their patients, the Hopkins-based research group examined if there was a connection between NACC1 amplification and time until tumor reoccurrence. They found there was; Patients with an increase of DNA copy number at the chromosome 19 region had an earlier reoccurrence of tumors than those without the increase. As NACC1 contributes to chemoresistance, this conclusion seems logical. Tumors with usual copy numbers of NACC1 grow back; if there are more copies, the tumors are able to grow back even faster.
Because TCGA has collected and analyzed many samples, the data can be used to add context to findings. Researchers used TCGA data to learn that nearly 20 percent of patients have a similar increase in copy number. This methodology demonstrates a different strategy for distilling “driver” genes from “passenger” genes: examining which genes upregulate themselves. In the future, controlling gene expression might become a new treatment.
Shih, I.M., Nakayama, K., Wu, G., Nakayama, N. and Wang, T.L. (2011) Amplification of the ch19p13.2 NACC1 locus in ovarian high-grade serous carcinoma. Mod. Path. 24(5):638-645. Read the full article.