Ovarian cancer accounts for about three percent of all cancers in women. This histopathological image shows serous adenocarcinoma in bilateral ovaries. Image: Wikimedia |
Scientists have developed the first comprehensive catalog of the genetic
aberrations responsible for an aggressive type of ovarian cancer that accounts
for 70% of all ovarian cancer deaths.
Hundreds of researchers from more than 80 institutions, including scientists
from the U.S. Department of Energy’s Lawrence Berkeley National Laboratory
(Berkeley Lab), deciphered the genome structure and gene expression patterns in
high-grade serous ovarian adenocarcinomas from almost 500 patients. They also
sequenced the protein-coding part of the genome in about 320 of these patients.
The result is the most expansive genomic analysis of any cancer to date and a
major step toward the personalized treatment of ovarian cancer. The research is
described in Nature.
Their work could lead to a day in which doctors treat high-grade serous
ovarian cancer by detecting the aberrant genes in a patient, and targeting
these genes with therapies that are most effective against the specific
mutations. It could also guide the development of new pharmaceuticals that are
specially tailored to fight mutations that cause ovarian cancer.
The project was conducted under the auspices of the The Cancer Genome Atlas,
an effort led by the National Institutes of Health’s National Cancer Institute
and National Human Genome Research Institute to improve cancer care by
understanding the genetic causes of the disease.
Paul Spellman of Berkeley Lab’s Life Sciences Division is the corresponding
author of the Nature article. Several other Berkeley Lab scientists
contributed to the research, including renowned cancer researcher Joe Gray, a
guest senior scientist in Berkeley Lab’s Life Sciences Division. The project
required collaboration among experts across the nation in tissue analysis,
genome sequencing, cancer genomics, and data analysis.
“The Cancer Genome Atlas is about giving a parts list to the cancer
community. Clinicians can use the data to propel the next wave of discoveries,
such as new cancer therapies and early-detection methods,” says Spellman. “We
are the first to systematically catalog the genetic mutations associated with
ovarian cancer.”
Ovarian cancer is the fifth leading cause of cancer death among women in the
U.S.,
with almost 22,000 new cases and 14,000 deaths estimated for 2010 according to
the National Cancer Institute. High-grade serous ovarian cancer, which begins
in the cells on the surface of the ovary, accounts for 90% of all ovarian
cancers and often remains undetected until it’s quite advanced.
The standard of care is aggressive surgery followed by platinum-taxane
chemotherapy. After therapy, however, platinum-resistant cancer recurs in
approximately 25% of patients within six months and the overall 5-year survival
rate is 31%. Because of this, scientists are seeking potent and targeted ways
to fight the disease, which requires a thorough understanding of its genetic
roots.
To do this, The Cancer Genome Atlas program brought together scientists from
a wide range of disciplines and research institutions. More than two dozen
sites provided tissue samples of ovarian tumors. Scientists at other sites
performed gene expression analysis, DNA sequencing, and other analyses. The
resulting data was fed to two repositories and analyzed by members of the
network including Berkeley Lab scientists.
Among their many findings, the team determined that the causes of ovarian
cancer are not confined to changes affecting individual genes. Large structural
changes in a cancer’s genome—in which genes are erroneously deleted or
duplicated—are also important. Scientists knew that ovarian cancer genomes have
gene copy errors, but they didn’t know these hiccups are such a big driver of
the disease.
They also found a possible new front in the fight against ovarian cancer.
They tallied a group of about 30 gene mutations that plays a role in the
disease, but which individually occur in only 1% to 2% of patients. A small
number of patients had mutations of the BRAF gene. Another small subset had
mutations of the Rb2 gene, which is common in breast cancer but not in ovarian
cancer. And yet another subset had a mutation in a gene that codes for the
production of the PI 3-kinase enzyme.
These mutations are quite rare by themselves, but together they’re found in
almost 20% of ovarian cancer patients. Therapies already exist for many of
these mutations, such as an inhibitor that silences the BRAF mutation, and
others are in development.
“These are actionable rare events,” says Spellman. “They are very specific
mutations that, if detected, clinicians can possibly go after—which opens up a
whole new way to fight the disease.”
They also determined that a network of genes that repairs damaged DNA is
defective in about half the tumors. Patients with this defect may benefit from
therapies that inhibit this errant function. And they found that the spectrum
of mutations in high-grade serous ovarian cancer is distinct from three other
ovarian cancer subtypes, which are themselves distinct from each other.
“This represents an opportunity to improve cancer care by approaching the
treatment of each subtype differently,” says Spellman.
Other findings include the fact that almost all patients with high-grade
serous ovarian cancers have a mutation in the TP53 gene, which codes for a tumor-suppressing
protein. This buttresses earlier research that underscored the importance of
the TP53 gene mutation in ovarian cancer. In addition, almost a quarter of
patients had BRCA1 or BRCA2 gene mutations, which also reaffirms earlier
research.
