Bottom Line:
Experts at Memorial Sloan Kettering Cancer Center (MSK) have identified genome doubling in cancer and have correlated it to a worse prognosis across cancer types. Using MSK-IMPACT™ to analyze matched tumor and normal DNA, MSK researchers were able to identify an abnormality in tumors known as genome doubling. This doubling occurs in 28 percent of all cancers and could have significant implications for treatment options in the future.
Findings:
Until now, genome doubling has remained an elusive area in the genetic research of human diseases. Researchers have not previously had the tools to study this genetic abnormality at a large scale.
Using MSK-IMPACT for the clinical sequencing of samples from people with advanced cancer, along with publicly available data on primary untreated cancers, researchers found that genome doubling was one of the most frequent and fundamental features of human tumors, in both treated and untreated cancers. From these findings, they were able to determine that people with genome doubling in their tumors had poorer prognoses than those who did not, regardless of cancer type and other clinical and molecular features. Researchers were able to make this determination using MSK-IMPACT because they also had matched clinical records and could examine how patients fared over time. This unprecedented combination of data enabled them to study the association with patient outcomes.
These findings were made possible in large part by comparing the tumor DNA with matched normal blood samples taken from patients at the same time. MSK experts hope that with additional study, the presence of genome doubling may be used in real-time clinical decision-making, so that doctors may recommend the most-aggressive treatments for those patients.
Corresponding Author Comments:
“This is an important example of how the clinical sequencing of people with cancer, used primarily to guide their clinical care, can be leveraged to make fundamental discoveries in basic translational science,” said Barry Taylor, PhD, Associate Director of the Marie Josée and Henry R. Kravis Center for Molecular Oncology at MSK and corresponding author of the study. “We never expected to be able to identify something as complex as genome doubling with this kind of targeted clinical sequencing data, so a discovery like this opens the door to leveraging patient clinical data for fundamental discoveries. Ultimately, we hope that future studies can transform this new knowledge into a predictive biomarker that could inform clinical decision-making in a rigorous way.”
Journal:
“Genome doubling shapes the evolution and prognosis of advanced cancers” published online July 16, 2018, in Nature Genetics.
About the MSK-IMPACT Team:
Since 2014, pathologists in the Molecular Diagnostics Service of the Department of Pathology have been using MSK-IMPACT to analyze the tumor DNA of essentially all MSK patients with advanced solid cancers. MSK-IMPACT sequencing has been approved by the New York State Department of Health as a clinical test and is performed in the clinical laboratories of the MSK Molecular Diagnostics Service, which is led by Marc Ladanyi, MD. Dr. Ladanyi played a key role in implementing MSK-IMPACT sequencing clinically and oversees this effort together with Maria Arcila, MD, Director of the Diagnostic Molecular Pathology Laboratory. The MSK-IMPACT team includes molecular pathologists, clinical bioinformaticians, genomic technology scientists, genomic variant curators, and highly specialized clinical laboratory technologists working together to ensure that the most-accurate and clinically useful information is obtained through this clinical tumor-sequencing program, possibly the largest of its kind anywhere.
Funding:
This work was supported by the National Institutes of Health awards P30 CA008748, U54 OD020355 (D.B.S, B.S.T), R01 CA207244 (D.M.H., B.S.T), and R01 CA204749 (B.S.T); the American Cancer Society; Cycle for Survival; the Sontag Foundation; the Prostate Cancer Foundation; and the Josie Robertson Foundation.
