Tumor Heterogeneity May Be One Cause of Drug Resistance

New data are suggesting that deciphering the genomic diversity and evolution of tumors may provide a basis for identifying new targets and designing improved personalized medicine strategies.  

A new study has now identified more than 2,000 genetic mutations in tissue samples of esophageal tumors. The findings reveal that even different areas of individual tumors have various genetic patterns.   The study results, published in the journal Nature Genetics, may help explain why it is so difficult to cure cancer by targeting one specific genetic defect.

“A tumor is not a single disease,” said study investigator Dechen Lin, PhD, an assistant professor and research scientist in the Division of Hematology and Oncology in the Cedars-Sinai Department of Medicine in Los Angeles. “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.”

Lin and colleagues compiled genetic data on 51 tumor samples taken from 13 patients with esophageal squamous cell carcinoma (ESCC). The researchers investigated spatial intratumoral heterogeneity (ITH) and temporal clonal evolutionary processes, and found an average of 35.8% heterogeneous somatic mutations with strong evidence of ITH. In addition, the researchers found that approximately 50% of the driver mutations located on the branches of tumor phylogenetic trees targeted oncogenes. These oncogenes included PIK3CA, NFE2L2, MTOR, and others. They also found that the majority of truncal and clonal driver mutations occurred in tumor suppressor genes, and they included TP53, KMT2D, ZNF750, and others.

The findings suggest that the use of the single biopsy method, which is the standard approach in the clinic, may be suboptimal. The study’s investigators reconstructed a “biography” of the tumors, showing when some of these variations first appeared in the life cycle of the disease.

Study co-senior author Benjamin Berman, PhD, an associate professor of Biomedical Sciences and co-director of the Cedars-Sinai Center for Bioinformatics and Functional Genomics, said this is one of the first studies to look at epigenetic changes from different areas within a single tumor in a global way. The investigators plan to use this approach to investigate other cancers and to explore the significance of the genetic and epigenetic changes.

The researchers suggest that tumor heterogeneity may be one of the major causes of drug resistance and treatment failure in cancer and deciphering the genomic diversity and evolution of tumors can provide a basis for identifying new targets. They hope that integrated investigations of spatial ITH and clonal evolution may change how cancer is treated in the not too distant future.