A research team at Seoul National University Bundang Hospital (SNUBH) has developed an algorithm that uses tumor gene panel data to identify patients who require additional testing for hereditary gynecologic cancer, addressing a longstanding challenge in selecting candidates for genetic screening.
Professor Kim Ki-dong
Led by Professor Kim Ki-dong of the Department of Obstetrics and Gynecology, the team developed the algorithm using tumor gene panel tests routinely performed in clinical practice to flag patients who may require further genetic evaluation.
Hereditary cases account for only about 10 percent of all gynecologic cancer patients. Until now, expensive genetic tests were either conducted too broadly or hereditary cancer patients were repeatedly missed, highlighting the need for clearer screening criteria.
Hereditary cancers are caused by mutations in germ cells. The problem is that germ cells are passed down to the next generation, meaning that if the cells mutate, they can be transmitted to children, raising their risk of developing hereditary cancer.
For instance, if parents have mutations in their BRCA1/2 genes, the mutation is highly likely to be passed on to their offspring, significantly increasing the children's risk of breast or ovarian cancer.
Therefore, identifying hereditary mutations holds important clinical significance as it allows for the selection of appropriate targeted therapies for the specific mutation type and, more importantly, provides a basis for regular screenings for early detection among family members, including the children of patients with hereditary cancer.
However, determining whether a cancer is hereditary has not been easy until now.
The standard tumor gene panel test can only confirm the presence of gene mutations, but it cannot distinguish whether the mutation is located in a germ cell or a general cell.
Confirming the distinction requires a separate hereditary genetic test. It is practically difficult to administer a test costing 500,000 won ($329.67) to 1,000,000 won per session to every patient just to find the roughly 10 percent who have hereditary gynecologic cancer. The reality highlighted the urgent need for clear screening criteria.
Accordingly, the research team focused on two pieces of information obtainable from the tumor gene panel test.
One is the gene mutation tier, a method of evaluating mutations based on their association with cancer. The team set tier one and tier two, the stages that trigger hereditary cancer, as the standard.
The other factor is the variant allele frequency, or VAF, which is the proportion of a specific gene mutation within the total DNA, as germ cell mutations are present in all cells, the VAF appears relatively high.
As a result, general cell mutations only occur in cancer cells, resulting in a relatively lower VAF in DNA excluding cancer cells. The team established a standard of a VAF of 40 percent or higher.
Combining the two criteria, the research team completed an algorithm targeting mutations found in 11 genes known to be related to hereditary gynecologic cancer.
The researchers explained that they reduced unnecessary false detections by narrowing the testing scope to the 11 genes, which have a confirmed direct association with hereditary causes of ovarian and endometrial cancers.
To verify the algorithm's reliability, the team applied it to 702 gynecologic cancer patients who had undergone the tumor gene panel test.
The results showed that 19 patients, or 2.7 percent, were candidates for hereditary genetic testing.
Among them, all four patients who actually took the hereditary genetic test were confirmed to be hereditary gynecologic cancer patients. The algorithm demonstrated high accuracy, yielding a positive predictive value of 100 percent among the selected patients.
The team explained that the study is highly significant as it is the first attempt to present clear, algorithm-based criteria for germ cell genetic testing, which had previously been conducted without specific standards.
If future prospective studies supplement and improve the algorithm, the team expects to more accurately identify patients requiring germ cell genetic testing and contribute to improving the reliability of hereditary cancer screening.
"The algorithm is a practical tool that bridges the diagnostic gap between the tumor gene panel test and the germ cell test,” Kim said. “By systematically selecting patients who absolutely need genetic counseling and germ cell testing using tumor test data, our goal is to help high-risk hereditary cancer patients receive appropriate care while efficiently utilizing medical resources."
The research was published in the SCIE international journal Gynecologic Oncology.
Source: https://www.koreabiomed.com/news/articleView.html?idxno=31178
