Researchers at Moffitt Cancer Center, including Center Director Thomas A. Sellers, Ph.D., M.P.H., and 17 other co-authors, have discovered four new regions of the genome that influence the risk for developing ovarian cancer, according to two Moffitt-led studies published in the March 27 issue of the journals Nature Genetics and Nature Communications.
Ovarian cancer is the fifth leading cause of cancer death among women and accounts for 3 percent of all female cancers. Although mutations in the BRCA1 and BRCA2 genes remain the strongest genetic risk factors for ovarian cancer, these new findings taken with previously identified common genetic variants account for approximately 4 percent of the inherited component of this disease.
The two Moffitt-led studies are part of a coordinated series of 13 publications that resulted from collaborations involving researchers who are part of the Collaborative Oncological Gene-environment Study (COGS), the largest study of its kind to investigate the genetic basis of hormone-related cancers (ovarian, breast and prostate) by looking at DNA sequences of more than 250,000 individuals.
"Through this collaborative effort, we were able to conduct a large-scale analysis of more than 18,000 women with ovarian cancer and more than 26,000 healthy women, bringing us much closer to understanding the inherited factors that contribute to this disease," said Sellers, co-senior author on both Moffitt-led studies.
In the first study, Sellers and colleagues followed up on previous efforts where they scanned the entire genome to identify differences in the frequency of common spelling variation in the genetic code (known as single nucleotide polymorphisms or SNPs) between several thousand women who developed ovarian cancer and a similar number of women without ovarian cancer. "With the much larger study population in our collaboration, we were able to identify three new genomic regions on chromosomes 8, 10 and 17 that are strongly associated with ovarian cancer risk," said Catherine M. Phelan, Ph.D., M.D., co-first author and associate member in the Cancer Epidemiology Program at Moffitt.
"We present several lines of data that point to a small number of candidate gene targets in these regions that may play a role in ovarian cancer initiation and development. This represents an important discovery for the ovarian cancer community that needs to be followed up further," said Alvaro Monteiro, Ph.D., co-author and senior member in Moffitt's Cancer Epidemiology Program.
The second study was led by first-author Jennifer Permuth-Wey, Ph.D., a molecular epidemiologist at Moffitt. This study was designed to evaluate SNPs that lie in underexplored regions of the genome that may represent binding sites for microRNAs, small molecules that have been linked to the development and progression of ovarian cancer and other malignancies.
Using the same large series of ovarian cancer and healthy control samples as the first study, Permuth-Wey and colleagues identified several SNPs that were strongly associated with the most common and aggressive type of ovarian cancer, serous ovarian cancer. The risk-associated SNPs were located in a unique region of chromosome 17 known as 17q21.31.
"17q21.31 is a gene-rich region that has previously been linked to neurological diseases, and our collaboration was the first to report a link with ovarian cancer," Permuth-Wey said.
The authors went on to evaluate the frequency of SNPs in the entire 17q21.31 region and discovered even stronger associations with ovarian cancer risk for a set of SNPs that were not known to have functions related to microRNA binding.
"Further investigation of the 17q21.31 region highlighted several candidate genes and mechanisms that may contribute to ovarian cancer development, adding to the progress we are making in understanding this disease," said Monteiro, co-senior author of this study with Sellers and Simon Gayther, Ph.D., from the University of Southern California.
Moffitt researchers also contributed to additional publications in this series of 13 papers, including two papers that focused on the link between SNPs in genes known as HNF1B and TERT and ovarian cancer risk. Jong Park, Ph.D., associate member in Moffitt's Cancer Epidemiology Program, also co-authored several publications related to prostate cancer as part of this series.
"Although the current work provides compelling evidence for these new susceptibility regions, the actual genes and the mechanisms through which they influence risk remains to be determined," Sellers said. "We are funded by the NCI GAME-ON initiative to further refine these regions and unravel the biological basis for the observed associations. We also believe there are more gene variants to be discovered, particularly those that are rare in the population, and we are actively pursuing several strategies to identify them."
The hope is that this research could someday lead to targeted ovarian cancer prevention and screening strategies, new treatments, and a better understanding of how and why ovarian cancer develops.
Additional Moffitt researchers who are co-authors in this series of publications include Melissa Buckley; Gregory C. Bloom, Ph.D.; Renato Carvalho, Ph.D.; Y. Ann Chen, Ph.D.; Zhihua Chen; Jin Q. Cheng, M.D., Ph.D.; David Fenstermacher, Ph.D.; Anxhela Gjyshi, M.P.H.; Heather S. Jim, Ph.D.; Johnathan M. Lancaster, M.D., Ph.D.; Xiaotao Qu, Ph.D.; Ya-Yu Tsai, Ph.D.; Aneliya Velkova, Ph.D.; and Nicholas Woods, Ph.D.
About Moffitt Cancer Center
Located in Tampa, Moffitt is one of only 41 National Cancer Institute-designated Comprehensive Cancer Centers, a distinction that recognizes Moffitt's excellence in research, its contributions to clinical trials, prevention and cancer control. Since 1999, Moffitt has been listed in U.S. News & World Report as one of "America's Best Hospitals" for cancer. With more than 4,200 employees, Moffitt has an economic impact on the state of nearly $2 billion. For more information, visit MOFFITT.org, and follow the Moffitt momentum on Facebook, twitter and YouTube.
Journal
Nature Genetics