Genetic heterogeneity among cells of the same tumor represents a significant underlying cause of why many cancers are extremely difficult to treat. Now, a new study by investigators at Cedars-Sinai dramatically illustrates this complexity by identifying more than 2000 genetic mutations in tissue samples of esophageal tumors. The findings reveal that even different areas of individual tumors have various genetic patterns. The new study results help explain why it is so difficult to battle cancer by targeting a particular genetic defect.
“A tumor is not a single disease,” noted co-author and project coordinator Dechen Lin, Ph.D., assistant professor and research scientist in the division of hematology and oncology in the Cedars-Sinai Department of Medicine. “It's many diseases within the same person and over time. There are millions of cells in a tumor, and a significant proportion of them are different from each other.”
The research team chose to study esophageal squamous cell carcinoma, as it is especially difficult to treat. The disease attacks the esophagus and has a 5-year survival of about 20%, according to the American Cancer Society.
To assemble the catalog of mutations, investigators relied on bioinformatic software to compile genetic data on 51 tumor samples taken from 13 patients. Through sophisticated algorithms, they analyzed both the genetic and epigenetic mechanisms that turned the genes' activities on and off within the cancer cells.
Using these techniques, the research team identified 2178 genetic variations in the sampled tumors. Dozens of the variations involved genes known to be associated with enabling the development of cancer. The most striking finding was that many significant mutations were detected only in some areas of a tumor, further highlighting the complexity of the cancer cells. This result also demonstrated the potential for inaccurate interpretation of cancer's genetic makeup using the single-biopsy method, which is the standard approach in the clinic.
The findings from this study were published recently in Nature Genetics in an article entitled “Spatial Intratumoral Heterogeneity and Temporal Clonal Evolution in Esophageal Squamous Cell Carcinoma.”
“This study is on the leading edge of looking within a tumor for heterogeneity, or variations, across patients and within the same patient. It also is one of the very first studies to examine epigenetic changes from different areas within a single tumor in a global way,” explained co-senior author Benjamin Berman, Ph.D., associate professor of biomedical sciences and co-director of the Cedars-Sinai Center for Bioinformatics and Functional Genomics.
In the future, the investigators are looking to apply their analytic techniques to other cancers and explore the significance of the genetic and epigenetic changes that they have so far identified. They view their work as fundamental to developing effective, individualized therapies to combat the drug resistance that many cancer patients face during the course of their disease.
“Evidence suggests that tumor heterogeneity is one of the major causes of drug resistance and treatment failure in cancer,” remarked co-senior author Phillip Koeffler, M.D., professor of medicine and chair in oncology research at Cedars-Sinai. “In light of this situation, deciphering the genomic diversity and evolution of tumors can provide a basis for identifying new targets and designing personalized medicine strategies.”