In finding new ways to fight ovarian cancer, researchers and scientists are constantly seeking to find ways to detect cancer precursors that are known to be dangerous from those which are benign and unlikely to become deadly. In working to achieve this goal, researchers at the Johns Hopkins Kimmel Cancer Center made progress after a 7-year study, uncovering how certain precancerous lesions become cancerous (J Pathol 2018; https://doi.org/10.1002/path.5219).
This study was unique because it was the largest of its kind focused specifically on early precancerous lesions. Together, researchers used select skill sets to assess and analyze patient specimens and the likelihood that their lesions would in fact progress into cancer.
More specifically, the researchers noted this study of cancer genetics using fallopian tube tissue demonstrated that the most common and lethal type of ovarian cancer arises from individual growths unrelated to each other, and not from precancerous lesions. To come to this conclusion, the study included the evaluation of many precursor lesions without cancer present to provide a unique molecular landscape of ovarian cancer precursors in place before ovarian cancer actually develops.
Research Methodology
Beginning their study, researchers analyzed fallopian tube and ovarian tissue from 15 women seen at the Johns Hopkins Hospital. While 11 of these women had no evidence of cancer when these organs were removed prophylactically to reduce their cancer risk, the other four already were diagnosed with high-grade serous carcinomas (HGSCs).
"This cancer is incredibly hard to beat because it's usually diagnosed at a late stage since earlier stages have few to no symptoms," stated study leader Tian-Li Wang, PhD, Director of the Molecular Genetics Laboratory of Female Reproductive Cancer and Professor of Pathology, Oncology, and Gynecology and Obstetrics at the Johns Hopkins University School of Medicine.
Alternatively, Wang suggested that ovarian cancers actually arise from precancerous lesions in the fallopian tubes. Yet, even she remains uncertain as to how exactly this progression proceeds from precancerous lesions to active cancer.
However, today, as much as 70 percent of all ovarian cancers are known to be HGSCs and account for the vast majority of the 14,000 women who die of ovarian cancer each year in the U.S. For this reason, determining how ovarian cancer originates in a woman's body is integral to finding solutions that yield successful outcomes and can work to end the prevalence of the disease.
Throughout their studies pertaining to these precursors, researchers first identified a variety of different precancerous lesions clustered in three groups using high-powered microscopes and according to pathological diagnostic markers on the women's fallopian tubes. Using a technique called laser capture microdissection, they then removed cells from these lesions to determine if and how fast the cells in each of the lesions were dividing. By removing the cells, they were also able to perform an analysis of their genetic mutations.
According to the researchers involved, throughout this study they found that these precancerous lesions were in a variety of stages of activity. Whereas some were dormant and not actively proliferating, others were proliferating but were not yet cancerous.
By the study's conclusion, genetic analyses of the participants yielded on 24 lesions in 11 women identified mutations in 12 different cancer-related genes. Additionally, one cancer-free woman had multiple precursor tubal lesions and each appeared to be driven by different sets of mutations, reportedly suggesting that they weren't derived from a common primary lesion and had each arisen independently.
Additionally, the researchers were able to link the instances of active ovarian cancer of the four women with a primary precursor lesion on their fallopian tubes. In one case, however, the researchers could not find a genetic link with co-existing precancerous lesions. This reinforces the idea that, while many precancerous lesions arise in women at risk for ovarian cancer, only some progress to active cancers. Yet, the inconclusiveness of this study further emphasizes the need for future studies, using this information to formulate a more advanced hypothesis.
"We were able to find out that precancerous lesions are probably multiple, and it is likely that many are different than the ones that cause cancer," Wang said. "In young women, they may already have precancerous lesions, but some of them will not progress to cancer. It may take time for one to progress to cancer."
Study Intentions
Wang stated that this information gives her and the other researchers hope for a possible window for detection for patients in the future. Once the precancerous lesions get to a certain stage, she explains that they can then rapidly progress. In some cases, it can take upwards of 6 years for a precancerous lesion to progress to cancer, according to Wang.
"We are still very interested in pursuing further analysis to learn which early precancerous lesions specifically are the ones which are likely to progress into cancer," Wang shared. "We are especially interested in working with patients who are known to have genetic dispositions and dormant lesions, and those who are aging and have varied immune systems."
Although, Wang made note that coming to the point where they are able to identify which precancerous lesions are likely to progress to cancer will require a longer term of study. She says the research team's ultimate goal is to be able to do a risk projection based on the information they have, and to then inform the patients who may be at risk.
Overall, the research team discovered strong evidence that the longstanding notion that cancer steadily progresses from any and all precancerous lesions is potentially incorrect, or at least in some circumstances. With this knowledge, researchers and health care teams can thereby further identify windows of time to intervene before cancers become even more advanced and difficult to treat.
"This has led to the rise of molecular genetic testing within the emerging markets, which currently has a billion dollars of market value," stated Ren-Chin Wu, PhD, an author of the study and Associate Professor at Chang Gung University School of Medicine in Taiwan. "Genetic testing can be used to detect a mutation, which can occur in normal cells (including skin cells from UV exposure) and can acquire the cancer gene mutations."
Wu further explained that, likewise, within the gastrointestinal tract, many tissues and cells can produce age-related mutations. He emphasized that as humans grow older, mutations can begin to grow within their bodies at a higher rate.
"Due to these factors and the results of our study, the major implication and take-home message is that we need to be prudent in our research and findings to know how we can interpret molecule results for diagnostic test purposes," Wu shared. "Pure mutation analysis cannot be the only answer, but should be combined with protein biomarkers and epigenetic biomarkers to come up with a more comprehensive, holistic panel for cancer diagnosis and predictions."
He added that personal health history is also an extremely important factor to addressing early detection and the subsequent diagnosis of cancerous cells. In addition to health histories, noting factors such as the exposure to carcinogens and lifestyle (like obesity), which can carry very substantial weight into cancer development and currents.
"Molecular tests, especially genetic tests based on mutations, are only a small part of the whole story," Wu stressed. "We must be more comprehensive in our minds how to design the best tests in the future. I think that's really the take-home message from this study."
Lindsey Nolen is a contributing writer.