Colorectal Cancer Metastasis: A Game of Clones


Yang Figure

Diagram of genomic changes observed during tumor evolution in a single colorectal cancer patient.

Colorectal cancer is highly prevalent worldwide, and metastasis of colorectal cancer to distant sites accounts for ~90% of the mortality associated with this disease. Researchers at the Sidney Kimmel Cancer Center at Jefferson (SKCC), along with collaborators at several other institutions, tracked genomic changes that occur as colorectal tumors progress and metastasize to distant sites — providing important insights into how these tumors evolve as they metastasize within a patient.

The study was recently published in Annals of Oncology. Senior authors are Hushan Yang, PhD, Associate Professor of Medical Oncology, and Dr. Bingshan Li at Vanderbilt University. Other contributors from SKCC include Drs. James A. Posey, Ronald E. Myers, Scott A. Waldman, Bing-Hua Jiang, Juan P. Palazzo, and Atrayee Basu-Mallick.

The researchers analyzed progressively early to late stages of colorectal cancer including primary tumors, matched metastatic tumors, and distant lymph node tumors from four colorectal cancer patients using a strategy called multiregion whole-exome sequencing. In this approach, regions of the genome known to harbor all human protein-coding genes (i.e. exome) are extensively sequenced to identify which mutations are present in different portions of the same tumor in each of the tumor samples. Consistent with studies of other cancer types, the team found that each colorectal cancer sample was actually a patchwork of genetically distinct cancer cells that arose by separate mutations in founder cells, a concept known as clonal expansion. As cancer cells accumulate mutations and proliferate, one group of cells (a clone) carries a particular set of mutations, while another clone bears a different spectrum of mutations. As a result, these constantly evolving clones carry distinct genetic aberrations in different cancer cells, often called subclones.

A remarkable observation from the study was that all metastatic tumors inherited multiple genetically distinct subclones from their primary tumors, although the relative frequency of subclones changed significantly during tumor progression (see Figure 3). Some subclones expanded and made a larger contribution to the metastatic tumor, while others were diminished. These changes in the subclonal architecture of colorectal cancer have important implications for the clinical analysis of metastatic colorectal cancer and ultimately its treatment. As noted by Yang, the subclone frequency alterations that occur as tumors progress from primary to metastatic stages suggest that “the subclonal structure of primary tumors may not be particularly relevant in understanding or treating metastasis.” Conversely, the high degree of genetic similarity among metastatic tumors that originate from the same primary tumor indicates that “to guide the treatment of colorectal cancer metastasis, high-depth sequencing of a single metastatic tumor sample may be more cost-effective than analyzing multiple samples.”

“The findings of this study suggest that colorectal cancer metastasis may involve a multi-clonal effect in that genomic aberrations in different subclones cooperate to promote metastasis,” Yang added. “Given the importance of understanding colorectal cancer metastasis in order to devise effective treatment strategies, the novel genes and mutations identified in this study warrant further functional characterization.”

Another finding with potentially important clinical implications is that in one patient who also had positive lymph nodes analyzed, the lung metastasis exhibited a drastically different genomic landscape than the three positive lymph nodes. This observation strongly suggested that genetically distinct subclones from the primary tumor might have migrated to the lung and given rise to the lung metastasis, likely independent from lymph node invasion. Metastasis can be either sequential, in which cancer cells metastasize to lymph node first and thence to distant organs, or parallel, in which cancer cells migrate from the primary tumor along parallel but separate routes to lymph nodes and distant organs. Data in this study supported the existence of parallel metastasis in colorectal cancer, in addition to the well-established sequential metastasis mechanism that is mediated through lymph nodes. This innovative finding, although derived using data from a single patient, was strongly confirmed by a much larger study that was subsequently published in Science, showing that 65% of colorectal cancer metastasis was not mediated by lymph nodes. Taken together, these emerging clues about the origins of metastatic colorectal cancer might have a profound clinical impact on the prevention and treatment of colorectal metastasis.

The study offers promising new directions for further research. The team noted that “an important next-step direction would be to develop circulating tumor DNA (ctDNA)-based and circulating tumor cell (CTC)-based liquid biopsy assays that can help us track tumor progression and guide treatment in a non-invasive manner.” Because the study utilized a relatively small sample size of four patients, the researchers predict that it will be highly informative to expand the sample size and perform more in-depth explorations of colorectal cancer genetic heterogeneity.

Looking further ahead, understanding the role of the high-frequency subclones that arise in metastatic colorectal cancer is an area of importance. As tumors progress, subclones in close proximity within the tumor compete with one another for growth and survival. Hence, those subclones that increase in frequency are likely to represent cells with potent tumor growth-promoting abilities and are thought to be responsible for helping tumors acquire resistance to chemotherapy and other treatments: a major complication in cancer therapy. Thus, gaining a more complete picture of how the subclonal architecture of colorectal tumors contributes to their metastatic potential will have important implications for preventing and managing the lethal consequences of this disease.