Characterization of Clonal Evolution in Microsatellite Unstable Metastatic Cancers through Multiregional Tumor Sequencing
Open Access
- 23 November 2020
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Molecular Cancer Research
- Vol. 19 (3), 465-474
- https://doi.org/10.1158/1541-7786.mcr-19-0955
Abstract
Microsatellites are short, repetitive segments of DNA, which are dysregulated in mismatch repair-deficient (MMRd) tumors resulting in microsatellite instability (MSI). MSI has been identified in many human cancer types with varying incidence, and microsatellite instability-high (MSI-H) tumors often exhibit increased sensitivity to immune-enhancing therapies such as PD-1/PD-L1 inhibition. Next-generation sequencing (NGS) has permitted advancements in MSI detection, and recent computational advances have enabled characterization of tumor heterogeneity via NGS. However, the evolution and heterogeneity of microsatellite changes in MSI-positive tumors remains poorly described. We determined MSI status in 6 patients using our previously published algorithm, MANTIS, and inferred subclonal composition and phylogeny with Canopy and SuperFreq. We developed a simulated annealing-based method to characterize microsatellite length distributions in specific subclones and assessed the evolution of MSI in the context of tumor heterogeneity. We identified three to eight tumor subclones per patient, and each subclone exhibited MMRd-associated base substitution signatures. We noted that microsatellites tend to shorten over time, and that MMRd fosters heterogeneity by introducing novel mutations throughout the disease course. Some microsatellites are altered among all subclones in a patient, whereas other loci are only altered in particular subclones corresponding to subclonal phylogenetic relationships. Overall, our results indicate that MMRd is a substantial driver of heterogeneity, leading to both MSI and subclonal divergence. We leveraged subclonal inference to assess clonal evolution based on somatic mutations and microsatellites, which provides insight into MMRd as a dynamic mutagenic process in MSI-H malignancies.Keywords
Funding Information
- American Cancer Society (MRSG-12-194-01-TBG)
- NCI (UH2CA202971, UH2CA216432)
- NIGMS (T32GM068412)
- NCATS (TL1TR002735)
- NCI (K08CA241309)
This publication has 49 references indexed in Scilit:
- Regional Bias of Intratumoral Genetic Heterogeneity of Nucleotide Repeats in Colon Cancers with Microsatellite InstabilityPathology and Oncology Research, 2014
- Intratumor heterogeneity: Nature and biological significanceBiochemistry (Moscow), 2013
- The Landscape of Microsatellite Instability in Colorectal and Endometrial Cancer GenomesCell, 2013
- THetA: inferring intra-tumor heterogeneity from high-throughput DNA sequencing dataGenome Biology, 2013
- Secondary mutation in a coding mononucleotide tract in MSH6 causes loss of immunoexpression of MSH6 in colorectal carcinomas with MLH1/PMS2 deficiencyLaboratory Investigation, 2012
- Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion SequencingThe New England Journal of Medicine, 2012
- MissForest—non-parametric missing value imputation for mixed-type dataBioinformatics, 2011
- Destabilization of tracts of simple repetitive DNA in yeast by mutations affecting DNA mismatch repairNature, 1993
- Optimization by Simulated AnnealingScience, 1983
- Hereditary Factors in CancerArchives of Internal Medicine, 1966