In a genome-wide association study, researchers found three new risk loci specifically associated with mucinous ovarian cancer, which provide the first clues to the biology of this uncommon disease.
Historically, ovarian cancer has been treated as one disease. However, molecular studies indicate four main tumor subtypes of malignant disease that show distinct responses to treatment: serous, clear-cell, endometrioid, and mucinous ovarian carcinomas.
To find germline variants that might flag individual susceptibility—and new therapeutic targets—for these tumor types, researchers turned to genome-wide association studies (GWAS). One recent study, published in Nature Genetics, describes three new genetic loci specifically associated with the risk for mucinous ovarian carcinoma (MOC).
“Once you find genetic loci that affect the risk, it's like giving clues to Sherlock Holmes for where to look next, and what aspects of the biology to study,” says Andrew Berchuck, MD, director of gynecologic oncology at Duke University School of Medicine in Durham, NC, and senior author of the study. “These variants could shed some light on the pathogenesis of this disease.”
Many clinical trials currently focus on therapeutically targeting germline mutations, such as BRCA1 and BRCA2, known high-risk factors for high-grade serous ovarian cancer (HGSOC), the most common of all the subtypes. However, only 3% of women diagnosed with ovarian cancer have primary, invasive MOC, leaving researchers with a dearth of data to analyze.
In this study from the Ovarian Cancer Association Consortium, researchers compared genotypes from 1,644 women with MOC to those of 21,693 unaffected controls and discovered three new risk loci. One variant, near the HOXD9 gene, is in a region of the genome that predisposes women to the HGSOC subtype; the other two lie near the INFL3 and PAX8 genes, both implicated in the development of colorectal cancer.
With this information, researchers can follow dysfunctional cell pathways which, in turn, may point toward the cancer's origins. Previous studies have shown that HOXD9 belongs to a family of transcription factors that control cell differentiation. The precise functions of INFL3 and PAX8 aren't known, but data suggest that their expression may help maintain a malignant state.
“This study is really a starting point to try to understand the biology of mucinous ovarian cancer, particularly if they can identify the biological relevance for these genes,” says Elizabeth Swisher, MD, a professor of obstetrics and gynecology at the University of Washington and medical director of the Breast and Ovarian Cancer Prevention Program at the Seattle Cancer Care Alliance.
One caveat with GWAS is that each locus may have many single-nucleotide variants that could be responsible for the risk association, notes Berchuck. Although researchers can test the correlation between each variant and the level of expression of the gene, such laboratory-based simulations aren't definitive evidence of causality. In the future, gene-editing methods may allow researchers to mimic the variants, to more accurately assess the biologic effects.
“This is just the start,” says Simon Gayther, PhD, a professor of preventive medicine at the University of Southern California's Keck School of Medicine in Los Angeles and corresponding author of the study. “The more we do these studies focusing on MOC, the more it will become clear that this cancer has its own biology, its own genetic susceptibility, its own prevention approaches and therapies that need to be developed.”