Gene that drives ovarian cancer identified

Date:
September 11, 2020
Source:
Cornell University
Summary:
Scientists have pinpointed which specific genes drive - or delay -
high- grade serious ovarian carcinoma.



FULL STORY ========================================================================== 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 at the College of Veterinary Medicine 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 John Schimenti, professor of genetics in the Department of
Biomedical Sciences and senior author of the study, which published
Sept. 1 in Cell Reports.

Schimenti teamed with biomedical sciences colleague Alexander Nikitin, professor of pathology and director of the Cornell Stem Cell Program, and members of their respective labs to gain a better understanding of HGSOC.

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, Schimenti 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," he 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.

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," Schimenti 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," Nikitin said.

Schimenti 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," he 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." This work was supported
by grants from the Ovarian Cancer Research Fund, the New York State Stem
Cell Science Program, the National Institutes of Health and the National
Cancer Institute.


========================================================================== Story Source: Materials provided by Cornell_University. Original written
by Lauren Cahoon Roberts. Note: Content may be edited for style and
length.


========================================================================== Journal Reference:
1. Robert Joseph Yamulla, Shreya Nalubola, Andrea Flesken-Nikitin,
Alexander
Yu Nikitin, John C. Schimenti. Most Commonly Mutated Genes in
High-Grade Serous Ovarian Carcinoma Are Nonessential for Ovarian
Surface Epithelial Stem Cell Transformation. Cell Reports, 2020;
32 (9): 108086 DOI: 10.1016/j.celrep.2020.108086 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/09/200911110749.htm

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