A team of Dana-Farber scientists and their associates has identified 34 genes associated with an increased risk of developing earliest-stage ovarian cancer. The findings, published in the journal Nature Genetics, will both help identify women who have the highest risk of developing ovarian cancer and pave the way for identifying new therapies that can target these genes.

Currently, there is no effective screening test for ovarian cancer and the disease is notorious for being detected in later stages when survival rates are poor. However, if ovarian cancer is caught early, survival rates increase dramatically, underscoring the need to identify those who may be at risk for developing the disease.

The study, led by Dana-Farber’s Alexander Gusev, PhD, Simon Gayther, PhD, of Cedars-Sinai Medical Center in Los Angeles, and Bogdan Pasaniuc, PhD, of the University of California at Los Angeles, drew on genetic data gathered over more than a decade by the Ovarian Cancer Association Consortium. The researchers compared the genetic profiles of about 25,000 women with ovarian cancer and 45,000 women without the disease and found more than 30 regions of the genome associated with ovarian cancer.

The next task was to pick out the specific genes within those regions that are responsible for the increase in ovarian cancer risk.

“The main challenge has to do with the number of genes that are in one region of the genome,” explains Pasaniuc. “Whenever you inherit a piece of DNA from your parents, you don’t inherit just every base pair of the genome, you inherit big chunks. That means that if you inherit a gene mutation in a given region, you inherit the entire region, which can carry 10 to 20 genes at a time. This makes it very hard to pinpoint specific genes from specific regions.”

Detective work

The team compared the large-scale genetic data from the Ovarian Cancer Association Consortium with data on mutations that disrupt the genes in ovarian and other tissues. By putting these two pieces of information together, the researchers were able to identify 34 genes associated with an increased risk of developing ovarian cancer.

The study discovered that in women at greatest risk of ovarian cancer because of their genetic blueprint, “there is an interplay between their genetics and the specific genes that drive the very earliest stages of cancer development,” said Gayther. Ultimately, the findings may provide a basis for stratifying women based on their likelihood of developing the disease.

“One novelty of this work is that we looked at risk variants that operate through alternative splicing rather than just the total abundance of a gene, which led us to genes we would not have otherwise identified,” Gusev observes. “Beyond a better understanding, mechanisms that operate through splicing open up new drug-target opportunities.”

This article was originally published on August 14, 2019, by Dana-Farber Cancer Institute. It is republished with permission.