Yale: DNA mutations can cause cancer but in some cases, more mutations may mean a better prognosis for patients. A Yale-led comprehensive genomic analysis of more than 700 brain tumors has revealed one such subtype of the most malignant brain tumor, called glioblastoma, or GBM. This subtype possesses thousands of tumor-specific DNA errors or mutations instead of dozens observed in most glioblastoma cases. It is also associated with longer survival.
The findings, reported in Journal
Neuro-Oncology, suggest it may be possible to develop personalized
treatments for more aggressive forms of brain cancer, including
immunotherapy for these hyper- or ultra-mutated tumors, said Murat
Günel, professor and chair of neurosurgery, who leads the Brain Tumor
Research Program at Yale and Smilow Cancer Hospital at Yale-New Haven
“We have been able to translate various complementary
cutting-edge genomic technologies, which were once solely research
tools, to our clinical programs to analyze individual cancers,” said
Günel, who is also a professor of genetics and a researcher for the Yale
Cancer Center. “We can now gain comprehensive understanding of the
molecular make-up of a cancer to pinpoint specific vulnerabilities and
leverage these weak spots for precision treatments in our Recurrent
Brain Tumor Treatment Program.”
While as many as 10,000 mutations
were found in the newly described subset of glioblastomas, a more
typical tumor contains less than 100. This counterintuitive pattern has
also been observed in gynecological and colon cancers: An extraordinary
number of mutations means a better chance of survival.
holds that cells with greater number of mutations are able to trigger an
aggressive immune system response against cancer cells, while cells
with fewer mutations might escape detection, Gunel said.
the number of GBMs in this newly identified group is small, the use of
standard chemotherapy in some cases has been shown to inadvertently
result in a hyper-mutated tumor. Indeed, the drug temozolomide, used as
the first line of chemotherapy in GBM, has been shown to sometimes
“But perhaps the naïve immune system is not strong enough to eliminate the cancer cells in these brain tumors,” Gunel noted.
if a new generation of immunotherapy drugs called checkpoint inhibitors
were used in these hyper-mutated tumors, perhaps more cancer cells
might be targeted for destruction, he said. Clinical trials currently
underway might be improved by considering the molecular genetic make-up
of the individual tumor, he concluded.
The Gregory Kiez and Mehmet Kutman Foundation funded the work.
Zeynep Erson-Omay and Ahmet Okay Çağlayan from Yale co-first authored the paper.