Clonal Evolution in MSI-H Colorectal Cancer Suggests Repeated Molecular Testing May Be Necessary

When genes that regulate DNA, also known as mismatch repair genes, do not work properly in correcting errors in DNA as cells divide, DNA could become unstable. A person with this condition is said to have microsatellite instability-high (MSI-H) status. According to study results presented at the 2018 Gastrointestinal Cancer Symposium, people who have microsatellite instability-high (MSI-H) colorectal cancer may undergo a distinct pattern of clonal evolution, which would affect the use of targeted and immunologic therapies.

Molecular profiling is a way to test for whether patients have MSI-H or as microsatellite stable (MSS) tumors.

Although MSI-H status in tumors means there is likely a hereditary risk for malignancies, such as colorectal cancer (CRC), it also means patients can have a positive response to immune-checkpoint therapies.

Clonal evolution is the hierarchical differentiation of cells. In this case, each unique cancer evolves over time, and in any one patient, the clonal structure, genotype, and phenotype shifts over time. In turn, oncologists can change cancer clone dynamics dramatically by introducing targeted therapies.

Researchers from The University of Texas MD Anderson Cancer Center hypothesized that MSI status may confer a higher rate of somatic alteration, which would result in clonal evolution over time compared with microsatellite stable patients.

In total, 139 patients with metastatic CRC consented to a prospective genomic matching protocol, of which archived tumor DNA from primary or metastatic tissue was sequenced on a 46- to 50-gene panel.

Six patients had MSI-H metastatic colorectal tumors. In total, the researchers detected 471 mutations in either tissue or circulating tumor DNA.

Mutations detected in MSI-H patients showed a significantly greater discordance compared with MSS patients. The researchers validated this finding using an independent evaluation of 17 MSI-H patients.

In addition, among the recurrently altered genes found, MSI-H cases appeared to be significantly more likely to have gained new TP53 mutations and to have lost PIK3CA mutations compared to MSS cases.

“MSI correlates with discordance between tissue DNA and circulating tumor DNA-based mutation profiling, which suggests that MSI-H CRC undergoes distinct patterns of clonal evolution including acquisition of new TP53 mutations,” the researchers wrote. “This may have implications for targeted and immunologic therapies in this unique population, and suggests a utility for repeated molecular testing.”