High-grade serious ovarian carcinoma (HGSOC) is the fifth-leading cause of cancer-related deaths in women in the United States, yet little is known about the origins of this disease. Now, scientists have collaborated on a study that pinpoints which specific genes drive - or delay - this deadly cancer.

"We've taken the enormous collection of genomic mutation data that's been mined on cancer genetics and tried to make functional sense of it," said the senior author of the study, which published in Cell Reports.

Cancer researchers have known for a while that the disease is almost always caused by multiple genetic "hits." One mutation alone does not turn a cell cancerous; generally at least two or three are required, and often different combinations of genes can cause the same cancer.

Adding complexity, the author said, is the fact that once one key genome-destabilizing mutation arises, others will follow. Sequenced tumors yield a plethora of mutations -- some are the originators of the cancer itself, while many others are spinoffs.

"It's a longstanding issue in cancer research," the author said. "What are the genetic drivers, and what are the passengers in the process?"

To address these complexities, the researchers wanted to test combinations of possible genetic suspects, and then parse out which of the many associated mutations were sparking the cancer.

To do so, they turned to the Cancer Genome Atlas, an international collaborative database that compiles the genetic information from patient tumor samples and the mutated genes associated with them. They took a list of 20 genes known to mutate in HGSOC and, using CRISPR gene-editing technology, created random combinations of these mutations in cultured cells from the ovary surface, including regular epithelial cells and epithelial stem cells, to see which cell type was more susceptible to the mutations.

The researchers then noted which combination of mutations turned which group of cells cancerous - pinpointing both the genes driving the process and which cell type the cancer originated in.

The study revealed what the team had originally suspected - that ovarian surface stem cells were more apt to become cancerous when hit with mutations. The disruption of TP53 and PTEN, combined with RB1 disruption, constitutes a core set of mutations driving efficient transformation in vitro. They also unexpectedly discovered genes that had the opposite effect.

"We found there were various genes that would help the process along, but interestingly, there were other genes that, when mutated, actually inhibited the cancer initiation process," the author said.

Knowing which are the cells of origin and which genes are necessary in initiating this highly aggressive form of ovarian cancer can be powerful information, both for ovarian and other types of cancers. "The cancer driver screening methodology we used should be applicable to answering the same kinds of questions for cells and cancers in other organs and tissues," another author said.

The author said the findings could be particularly useful for ovarian cancer patients who have their tumors biopsied and sequenced for genetic data.

"In the past, you would know which genes were mutated but you wouldn't know what role they played," the author said. "Now you know which ones are important. And eventually, you could develop drugs to target the mutated genes that you know are causing the problem."

https://news.cornell.edu/stories/2020/09/veterinary-college-team-ids-gene-drives-ovarian-cancer

https://www.cell.com/cell-reports/fulltext/S2211-1247(20)31075-5

http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Fmost-commonly-mutated&filter=22