This is an edited version of an article reviewed Emilie Henderson, B.Sc., and published on News-Medical.Net Oct. 11, 2022
Two new discoveries led by Cedars-Sinai Cancer investigators help improve the understanding of what drives the development of ovarian cancer and why some women's tumors do not respond to therapy.
Scientists identify mutations tied to increase risk of ovarian cancer
The first study, published today in the Journal of the National Cancer Institute, identified four new regions of the human genome that harbor genetic variants or mutations that put women at an increased risk of developing epithelial ovarian cancer, the most common type of ovarian cancer.
"When it comes to ovarian cancer, prevention is how we're really going to impact mortality," said Michelle Jones, PhD, a research scientist in the Center for Bioinformatics and Functional Genomics and corresponding author of the study. "This study helps us accurately identify women who carry cancer-causing mutations, which can help physicians develop preventive strategies for these women."
To pinpoint the mutations, the team of investigators used new methods to analyze the structural variation of the genome, which is made up of 23 pairs of chromosomes where an individual's genetic code is stored.
While most research focuses on analyzing the change in the sequence of the gene, the team looked at the number of copies of the gene an individual has-;known as a copy number variant.
When the genome gets copied, structural variation can occur, and stretches of the genome can get deleted, duplicated or rearranged to another position. These changes can lead to diseases, like cancer.
The researchers collaborated with scientists at the University of Cambridge to specifically look at deletions and duplications in 13,000 women with ovarian cancer and compared them to 17,000 women without ovarian cancer from the Ovarian Cancer Association Consortium to identify copy number variants that were associated with ovarian cancer risk.
They found significant deletions and duplications in the BRCA1 gene, BRCA2 gene, and RAD51C gene, all of which are known to harbor changes in a patient's DNA sequence that increase risk for ovarian cancer. Also found: four new genes that have not been previously linked to an increased risk for ovarian cancer.
The study, which is the largest to date to evaluate the contribution of copy number variants to ovarian cancer risk, will likely lead to more accurate genetic testing for women.
"We have the technology that can pick up these deletions and duplications, but it's not always done consistently in clinical genetic testing," said Jones. "We hope these findings highlight the value of looking at copy number variants in clinical genetic testing."
Gene expression unlikely to drive chemotherapy resistance in ovarian cancer
The second study, published in the Journal of Experimental & Clinical Cancer Research, gives investigators a deeper understanding as to how ovarian tumors develop resistance to chemotherapy, which occurs in about 80% of high-grade serous ovarian cancer patients and ultimately leads to their succumbing to the disease.
Previously, researchers believed that ovarian tumors evolve after they are exposed to chemotherapy, and that they change their gene expression to adapt and survive through the treatment.
However, using whole genome sequencing, they found for the first time that this is not the case. Instead, it seems more likely that most high-grade serous ovarian tumors have the capacity to survive chemotherapy from a very early stage, said Jones, who is also the co-first author on this study.
"This study has changed our understanding of how tumors respond to chemotherapy," Jones said. "Previously it was thought that we could probably find a way to treat chemo-resistant tumors with other drugs after they have been treated with the standard therapy, but this study suggests that may not be the best approach."
"By improving our understanding as to how tumors ... survive chemotherapy, and even continue growing throughout treatment, as well as finding vulnerabilities in the tumors, will give us an opportunity to design better drugs and save the lives of women with ovarian cancer," added Gayther....
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