Two new studies are helping to improve our understanding of ovarian cancer

Two new studies are helping to improve our understanding of ovarian cancer

Two new discoveries led by Cedars-Sinai cancer researchers are helping to advance our understanding of what drives the development of ovarian cancer and why some tumors in women do not respond to therapy.

Understanding the relationship between molecular profiles and the clinical presentation of ovarian cancer can not only help develop personalized therapeutic approaches, but also help us identify women at highest risk so we can intervene before the cancer even develops.”

Simon Gayther, PhD, professor of biomedical sciences, director of the Center for Bioinformatics and Functional Genomics at Cedars-Sinai and senior author of both studies

Scientists identify mutations that increase the 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 increased risk of developing epithelial ovarian cancer, the most common type of ovarian cancer.

“When it comes to ovarian cancer, prevention is the way we can actually impact mortality,” said Michelle Jones, PhD, research associate at the Center for Bioinformatics and Functional Genomics and corresponding author of the study. “This study will help us accurately identify women who carry cancer-causing mutations, which may help doctors develop prevention strategies for these women.”

To locate the mutations, the research team used new methods to analyze the structural variation of the genome, which consists of 23 pairs of chromosomes in which an individual's genetic code is stored.

While most research focuses on analyzing the change in the gene sequence, the team examined the number of copies of the gene an individual has - a so-called copy number variant.

When the genome is copied, structural variations can occur and parts of the genome can be deleted, duplicated, or rearranged to a different position. These changes can lead to diseases such as cancer.

The researchers worked with scientists at the University of Cambridge to specifically look at deletions and duplications in 13,000 women with ovarian cancer and compared them with 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, which are known to harbor changes in a patient's DNA sequence that increase the risk of ovarian cancer. Also found: four new genes that have not previously been associated with an increased risk of ovarian cancer.

The largest study to date to assess the contribution of copy number variants to ovarian cancer risk is likely to lead to more accurate genetic testing for women.

“We have the technology that can detect these deletions and duplications, but that is not always done consistently in clinical genetic testing,” Jones said. “We hope these results highlight the value of studying copy number variants in clinical genetic testing.”

Gene expression is unlikely to promote chemotherapy resistance in ovarian cancer

The second study, published in the Journal of Experimental & Clinical Cancer Research, gives researchers a deeper understanding of how ovarian tumors develop resistance to chemotherapy, which occurs in about 80% of high-grade serous ovarian cancer patients and ultimately leads to their death from the disease.

Previously, researchers assumed that ovarian tumors develop after exposure to chemotherapy and change their gene expression to adapt to treatment and survive.

However, using whole genome sequencing, they discovered for the first time that this was not the case. Instead, it appears more likely that most high-grade serous ovarian tumors have the ability to survive chemotherapy at a very early stage, said Jones, who is also co-first author of this study.

“This study has changed our understanding of how tumors respond to chemotherapy,” Jones said. "It was previously thought that we could probably find a way to treat chemoresistant tumors with other drugs after treating them with standard therapy, but this study suggests that this may not be the best approach."

“By improving our understanding of how tumors survive chemotherapy and even continue to grow during treatment, as well as finding weak points in the tumors, we have the opportunity to develop better drugs and save the lives of women with ovarian cancer,” added Gayther.

High Risk BRCA Cedars-Sinai Cancer Clinic

While researchers at Cedars-Sinai Cancer study how to more accurately identify women who carry cancer-causing mutations, clinicians are also working to monitor BRCA-positive patients and treat them quickly if necessary.

Led by BJ Rimel, MD, a gynecologic oncologist and medical director of the Cedars-Sinai Cancer Clinical Trials Office, Cedars-Sinai recently opened a high-risk BRCA clinic – known as the Previvor Clinic – for BRCA1 and 2 carriers at high risk of developing ovarian cancer.

Rimel says the goal is to provide BRCA-positive patients with regular screenings and risk-reducing prevention strategies in a one-stop clinic setting.

“Our multidisciplinary care team, including a reproductive and infertility medicine doctor, a gynecologist-oncologist and a genetic counselor, spends time with each high-risk patient during the clinic visit,” Rimel said. “We provide on-site transvaginal screening, review the results of relevant lab work, and ensure questions are answered in real time.”

Modeled after an existing and highly successful high-risk BRCA breast cancer program, the ovarian cancer screening clinic remains a key focus at Cedars-Sinai.

“Changes in genes like BRCA either in the cancer or in the patient’s germline have profound implications for treatment and prevention,” said Dan Theodorescu, MD, PhD, director of Cedars-Sinai Cancer and the PHASE ONE Foundation Distinguished Chair and professor of surgery and pathology and laboratory medicine. “As our research evolves, so do our translational insights that impact and improve patients’ lives.”

Source:

Cedar Sinai

References:

• DeVries, AA, et al. (2022) Kopienzahlvarianten sind Risikoallele für Eierstockkrebs an bekannten und neuen Risikoorten. Zeitschrift des National Cancer Institute. doi.org/10.1093/jnci/djac160.
• Gull, N., et al. (2022) DNA-Methylierung und transkriptomische Merkmale bleiben während des Krankheitsrezidivs und der Chemoresistenz bei hochgradigem serösem Eierstockkrebs erhalten. Zeitschrift für experimentelle und klinische Krebsforschung. doi.org/10.1186/s13046-022-02440-z.

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