Researchers at Cedars-Sinai Medical Center (CSMC) in Los Angeles recently highlighted the challenges of treating cancer due to tumor heterogeneity by identifying more than 2,000 genetic mutations in tissue samples of esophageal cancer. The results, published in Nature Genetics, help explain why the treatment of cancer is so complex and how tissue biopsies only provide a partial picture of any single patient’s cancer.
"A tumor is not a single disease," said Dechen Lin, Ph.D., assistant professor and research scientist in the division of hematology and oncology, CSMC. "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."
For the project, the CSMC team studied esophageal squamous cell carcinoma. To create the catalog of mutations for this cancer, the researchers used an informatics and computational approach to compile genetic data on 51 tumor samples taken from 13 patients. Using complex algorithms, identified the genes and the biological processes that turned the genes' activities both on and off within the cancer cells.
This approach identified 2,178 genetic variations among the tumor samples, including dozens of variations involving genes known to be associated with cancer development. Notably, the researchers pointed out, many important mutations were detected in some areas of the tumor and not others, highlighting the shortcoming of using a single-biopsy method of cancer diagnosis.
"This study is on the leading edge of looking within a tumor for heterogeneity, or variations, across patients and within the same patient,” said Benjamin Berman, PhD, the study's co-senior author, associate professor of biomedical sciences and co-director of the Cedars-Sinai Center for Bioinformatics and Functional Genomics. “It also is one of the very first studies to look at epigenetic changes from different areas within a single tumor in a global way.”
To build upon this latest research, the team at CSMC will use the analytic techniques developed to examine other cancers and to explore the significance of the genetic and epigenetic changes that they have so far identified. The ultimate goal is to help develop individualized cancer therapies and unlock the challenges of drug resistance faced by many cancer patients during the course of the disease.
"Evidence suggests that tumor heterogeneity is one of the major causes of drug resistance and treatment failure in cancer," concluded H. Phillip Koeffler, M.D., professor of medicine and the Mark Goodson chair in oncology research at CSMC and a co-author of the study. "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."