September 22, 2017

Genetic Heterogeneity in Colorectal Cancer Metastases

Despite recent progress in early diagnosis and treatment, colorectal cancer remains a major cause of morbidity and mortality, with 90% of the deaths attributable to metastatic disease. We now know that cancer is largely a disease of genetic mutations and that most cancers harbor large numbers of different mutations. More recently, extensive whole genome sequencing has revealed that many tumors comprise multiple subclones of cells, each carrying a distinct set of genetic mutations – a property known as intratumor heterogeneity (ITH). ITH plays an important role in a cancer’s response to therapy and its ability to develop resistance to therapy, yet most studies of ITH have focused only on the primary tumor, yielding little information regarding the all-important metastases. This led Vanderbilt Basic Sciences investigator Bingshan Li, his collaborator Hushan Yang (Jefferson University, Philadelphia, PA) and their colleagues to conduct a detailed genomic analysis of 10 primary tumor, 3 positive lymph node, 10 metastatic tumor, and 5 normal tissue samples from 4 patients. Their results show that there is greater intertumor heterogeneity between patients than ITH within a given patient’s primary tumor. Furthermore, metastatic tumors demonstrate lower levels of ITH than their corresponding primary tumors. Of greater interest, however, was the finding that the metastatic tumors from a single patient are genetically distinct from each other and appear to have arisen from multiple clones within the primary tumor. Similarly, metastatic tumors appear to have distinct origins from cancer cells found within a positive lymph node from the same patient. These findings support the hypothesis that individual colorectal cancer metastases result from multiple separate seeding events, and that few arise from tumor cells present in lymph nodes. The relatively low level of ITH within metastases suggests that an individual sample might yield adequate genetic information to predict its response to therapy, but there is no guarantee that any individual sample will be representative of either the complete primary tumor or all metastatic foci. The work is published in the journal Annals of Oncology [Q. Wei, et al., (2017) Ann. Oncol., 28, 2138].