Ovarian Cancer in Uganda
Ovarian cancer is often deadly; less than 45% of women diagnosed with ovarian cancer survive five years after diagnosis. Ovarian tumors are highly complex, making solutions more challenging to find. Research at Norris Cotton Cancer Center, led by Principal Investigators Jennifer Doherty, PhD and Casey Greene, PhD and a multidisciplinary team, are using new approaches in bioinformatics to look for commonalities in ovarian tumors from women with diverse genetic and reproductive histories. It may be in those commonalities that Doherty and Greene find the most essential drivers to ovarian tumors. "If we can figure out what pathways are shared in ovarian tumors from women with very different genetic backgrounds and reproductive histories, then we’ll have information key to developing therapies targeted at those essential components of the tumor," said Doherty.
The Odd Similarity: Ovarian Cancer in LMIC
It is commonly understood that women in low- and middle-income countries (LMIC) have a lower burden of ovarian cancer than women in high income countries including the United States (though it is likely that ovarian cancer is underreported in LMIC). The more pregnancies a woman has, the lower her risk of ovarian cancer, so the lower rates in LMIC are likely to be attributable to the differences in reproductive experiences. However, in Uganda, a country where women typically have six or more pregnancies (women in the U.S. average less than two pregnancies each), the rates of ovarian cancer are almost the same as those in the U.S.
Epidemiology, Genetics, Bioinformatics, and Pathology
To investigate what could make the ovarian cancer burden so similar in places where conventional wisdom says it should be quite different, Doherty and Greene formed a multidisciplinary group to attack the question in what NCCC calls a "team science" approach. Adding pathologist Laura Tafe, MD and gynecologic oncologist Evelyn Fleming, MD, they have a team with strengths and tools ranging from molecular pathology to Dartmouth's supercomputer Discovery. In 2013, they named the project Searching for Common Drivers of Molecular Subtypes of Ovarian Cancer across Diverse Populations and received NCCC funding through a Prouty Pilot Funding Award.
A Novel Approach in Ovarian Cancer Research
Doherty and Greene hypothesized that it is what the ovarian tumors from such different populations have in common that is the core to their power to wreak havoc. To test their hypothesis, they would need ovarian tumors from Ugandan women to compare with ovarian tumors from U.S. women who are of European descent.
Ovarian Cancer and the Fallopian Tubes
Ovarian cancers are a heterogeneous group of tumors with different histologies and different pathways of carcinogenesis. In recent years there has been a shift in how we think about the origins of ovarian cancer. High-grade serous carcinoma, the most common and deadly type of ovarian cancer, is now believed to arise from fallopian tube epithelium, predominantly of the fimbriae, that becomes neoplastic and involves the ovary. It has been shown that, in U.S. women with sporadic serous carcinoma, 40-60% have tubal intraepithelial precursor lesions, (TP53 signature lesions and intraepithelial carcinoma), many of which harbor the identical TP53 mutation as the corresponding cancers, supporting the theory that high-grade serous carcinomas arise from the fallopian tube. This theory of ovarian cancer pathogenesis has largely been studied in women of European descent, and one goal of the Uganda study is to understand if this is substantiated across populations.
Uganda Cancer Research Institute (UCI)
The Dartmouth team turned to colleagues at the Uganda Cancer Institute (UCI)/Hutchinson Cancer Center Alliance in Kampala, Uganda to form a research partnership. Meeting with surgeon Martin Origa, MD, study coordinator Constance Namirembe, in addition to many other team members, they formed a bi-national study team to approach the question: What irregularities in gene expression do the ovarian tumors have in common? "This is a new way to think about these types of problems," said Greene whose work in bioinformatics involves finding meaning in massive and frequently dissimilar data sets. "Here we started by looking at two very different population groups to pull out common themes." Transcriptomics, the study of mRNA and how much of each gene is expressed by a particular tumor is central to Greene's approach.
Drs. Doherty and Greene received an NCCC Prouty Pilot Award to set up the overall study. These awards are funded by philanthropy directed to NCCC through the Friends of Norris Cotton Cancer Center. Other funding was supplied by the Hitchcock Foundation, the American Cancer Society, and the Institute for Quantitative Biomedical Sciences at Dartmouth.