Analysis of somatic microsatellite indels identifies driver events in human tumors.

Yosef E Maruvka,Yehuda Brody,Prasanna Parasuraman,Andre Bernards,Atanas Kamburov,Kent W Mouw,Esther Rheinbay,Amnon Koren,Rosa Karlic,Lior Z Braunstein,Michael S Lawrence,Paz Polak,Gad Getz,Nicholas J Haradhvala,Julian M Hess,Adam Bass,Franziska Michor,Alan D'Andrea

doi:10.1038/nbt.3966

Yosef E Maruvka, Yehuda Brody + Show 16 more

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https://doi.org/10.1038/nbt.3966

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Microsatellites (MSs) are tracts of variable-length repeats of short DNA motifs that exhibit high rates of mutation in the form of insertions or deletions (indels) of the repeated motif. Despite their prevalence, the contribution of somatic MS indels to cancer has been largely unexplored, owing to difficulties in detecting them in short-read sequencing data. Here we present two tools: MSMuTect, for accurate detection of somatic MS indels, and MSMutSig, for identification of genes containing MS indels at a higher frequency than expected by chance. Applying MSMuTect to whole-exome data from 6,747 human tumors representing 20 tumor types, we identified >1,000 previously undescribed MS indels in cancer genes. Additionally, we demonstrate that the number and pattern of MS indels can accurately distinguish microsatellite-stable tumors from tumors with microsatellite instability, thus potentially improving classification of clinically relevant subgroups. Finally, we identified seven MS indel driver hotspots: four in known cancer genes (ACVR2A, RNF43, JAK1, and MSH3) and three in genes not previously implicated as cancer drivers (ESRP1, PRDM2, and DOCK3).

Highlights

Microsatellites (MSs), are regions of the genome characterized by repetition of a short sequence motif[1]
The microsatellite instability (MSI) phenotype has been observed across tumor types, it appears to be most common in colon adenocarcinoma (COAD), stomach adenocarcinoma (STAD), and uterine corpus endometrial carcinoma (UCEC)[8]
Previous reports[20,21,22] have identified a small fraction of MSI cases in cohorts of cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), uterine carcinosarcoma (UCS) and adrenocortical carcinoma (ACC), and our analysis identified MS indels in these tumor types

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Microsatellites (MSs), are regions of the genome characterized by repetition of a short sequence motif (usually 1-6 bp)[1]. Rates of insertions and deletions (indels) in MSs are significantly higher than rates of single nucleotide substitutions elsewhere in the genome (10-4-10-3 compared to ~10-8 per locus per generation, respectively)[2]. The increased mutation rate within MS indels is thought to arise due to DNA polymerase slippage during replication, leading to changes in the number of repeats. MS indels frequently result in frameshift mutations and can dramatically alter protein function or expression[1]. Tumors with microsatellite instability (MSI) have dramatically increased numbers of MS indels owing to loss of normal mismatch repair (MMR) function[8]. Given the important prognostic and therapeutic implications of MSI status, many clinical centers perform PCR- or immunohistochemistry-based MSI testing for these tumor types 9–12

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