UCSD: A team of 18 University of California San Diego School of Medicine and Moores Cancer Center researchers has developed a new tool to analyze an often overlooked aspect of cancer genetics — an alteration that results in the loss or gain in a copy of a gene. This change, known as somatic copy-number alterations, may be key to disease progression and might offer new therapeutic approaches for ovarian cancer and other malignancies.
“When most people think about cancer genetics, they think about
single key mutations that foster tumor formation — very specific things
like the BRCA genes,” said Joe R. Delaney, PhD, a fellow in the Clinical
Translation program at UC San Diego Moores Cancer Center and lead
author of the paper published February 15 in Nature Communications.
“These changes are often referred to as tumor drivers but these are not
the only deviations that impact cancer growth. We explored other
More than 90 percent of genetic changes in cancer cells involve the
loss or gain of a single copy of a gene, rather than a mutation. A tumor
cell might have one copy or three instead of the normal two copies —
one provided by each parent. This area has not been explored in depth,
since experience with other diseases has taught scientists that the loss
of one gene copy might not lead to disease symptoms because the second
copy provided by the other parent fills in.
Delaney and team wondered if this were true if several single gene
copies that cooperated for the same cellular function were lost, and
what the patterns might be in different cancers. The team designed the
Haploinsufficient/Triplosensitive Gene (HAPTRIG) computational tool to
identify pathways significantly disrupted by the loss and gain of genes.
Ovarian cancer in particular is fraught with these alterations — with
more than 60 percent of genes affected. When the team analyzed this
malignancy using HAPTRIG, the pathway that stood out was autophagy — a
natural process of cell death that helps maintain normal cellular
health. Ovarian cancer cells use autophagy all of the time, but also
lose several copies of autophagy genes resulting in a compromised
The researchers then used a combination of existing United States
Food and Drug Administration-approved drugs to target autophagy and
found ovarian cancer cells to be highly sensitive to these drugs in
several different mouse cancer models — even among cells resistant to
standard chemotherapy. The combination of drugs appeared less toxic than
standard chemotherapy, were relatively inexpensive and should be
clinically evaluated, said Dwayne G. Stupack, PhD, the study’s senior
author and associate professor in the Division of Gynecologic Oncology
at Moores Cancer Center.
With further work, said the authors, this finding could lead to new
approaches to treat chemotherapy-resistant disease, and could enhance
treatment of other cancers as well.
“Our study suggests that a roadmap of targetable genetic changes in
tumors should not be limited to mutations,” said Stupack. “HAPTRIG may
reveal additional targetable pathways across cancer types. We have
provided a free web-tool to allow the community to easily perform a HAPTRIG analysis on 21 cancer types.”
Study co-authors include: Chandni B. Patel, Katelyn McCabe Willis,
Mina Haghighiabyaneh, Joshua Axelrod, Isabelle Tancioni, Dan Lu, Jaidev
Bapat, Shanique Young, Octavia Cadassou, Alena Bartakova, Parthiv Sheth,
Carley Haft, Sandra Hui, Cheryl Saenz, David D. Schlaepfer, and Olivier
Harismendy, UC San Diego
This research was funded, in part, by National Cancer Institute
(CA107263, CA102310, CA177519) and by funding from the Nine Girls Ask