A recent study from the University of Washington in Seattle indicates that microsatellite instability, classically associated with colorectal, stomach, and endometrial cancers, is a much more extensive phenotype than previously appreciated. The researchers developed MOSAIC, a method to assess microsatellite instability on a comprehensive, genome-wide scale, and identified tumors positive for this phenotype in 14 of 18 different cancers evaluated.

Recent research from the University of Washington in Seattle indicates that microsatellite instability (MSI), which may increase neoantigen production and thereby sensitivity to immunotherapy, is a much more extensive phenotype than previously appreciated. Until now, MSI has been classically associated with colorectal cancer, where it was discovered, as well as with stomach and endometrial cancers.

“We decided to cast the net more broadly and look for other cancers that might exhibit MSI,” says senior author Stephen Salipante, PhD. To do so, he and his team developed a method for assessing MSI on a comprehensive, genome-wide scale. The conventional assay, optimized for colorectal cancer, relies on just five microsatellite loci to classify MSI—“an extraordinarily small panel” that would have been limited in utility and far less informative, Salipante points out. Instead, his team built their MSI classifier, called MOSAIC, by examining 5,930 tumor exomes, representing 18 cancer types in The Cancer Genome Atlas, at more than 200,000 microsatellite loci.

The researchers used MOSAIC to classify tumors as positive (MSI-high) or negative (MSI-stable) for microsatellite instability. The former not only had large numbers of unstable microsatellite loci throughout the exome in general, but also had high rates of instability within the DEFB105A/B locus in particular. Unsurprisingly, of the 18 cancers evaluated, MSI-high specimens were most common in adenocarcinomas of the colon, rectum, and stomach, as well as in endometrial carcinoma. However, the team also identified MSI-high examples in another 10 cancer types, Salipante says, including renal clear cell carcinoma and epithelial ovarian carcinoma. Additionally, they found that different tumor types had their own MSI “fingerprint,” and that these signatures could be clustered into four major groups based on shared similarities.

Many of the unstable loci in MSI-high tumors were in or near cancer-associated genes such as RNF43 and KIF14, Salipante notes. “This suggests that MSI is not only a marker of genomic instability. It may have a role in driving carcinogenesis by influencing gene expression and generally helping tumors evolve,” he says.

In analyzing clinical outcomes data for several cancers, the researchers made another observation about MSI: When measured as a continuous variable, its positive correlation with patient survival was strong, but was less so when a tumor was simply classified as MSI-high or MSI-stable. “The degree of MSI in your tumor's genome, not its absolute presence or absence, is more indicative of survival,” Salipante explains. “We think MSI should be regarded as a continuum, not a line in the sand.”

Jeffrey Weitzel, MD, director of clinical cancer genetics at City of Hope Comprehensive Cancer Center in Duarte, CA, says this study provides “an amazingly in-depth look at the phenomenon of MSI, and a snapshot of all the different tumor types that may be involved.” Ideally, he says, MOSAIC could eventually be expanded into a “one-stop shop” that classifies MSI in tumors, analyzes underlying genetic features, and predicts which patients are more likely to respond to immunotherapy. –Alissa Poh

©2016 American Association for Cancer Research.
2016
American Association for Cancer Research.