American Association for Cancer Research
00085472can170682-sup-178396_1_supp_4059381_zqrpzs.pdf (1.75 MB)

Supplementary Figures 1-19, supplementary methods and extended literature evaluation of the candidate genes from Comprehensive Evaluation of Protein Coding Mononucleotide Microsatellites in Microsatellite-Unstable Colorectal Cancer

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journal contribution
posted on 2023-03-31, 00:41 authored by Johanna Kondelin, Alexandra E. Gylfe, Sofie Lundgren, Tomas Tanskanen, Jiri Hamberg, Mervi Aavikko, Kimmo Palin, Heikki Ristolainen, Riku Katainen, Eevi Kaasinen, Minna Taipale, Jussi Taipale, Laura Renkonen-Sinisalo, Heikki Järvinen, Jan Böhm, Jukka-Pekka Mecklin, Pia Vahteristo, Sari Tuupanen, Lauri A. Aaltonen, Esa Pitkänen

Figures describing the following; length distribution of somatic insertions and deletions in the exome sequencing data, coverage of mononucleotide microsatellite sites in both exome and MiSeq sequencing data, mutation frequencies at mononucleotide microsatellite sites in the exome sequencing data, number of somatic deletions and insertions in the exome sequencing data, model p-values, expected -log10(p) values, mutation frequency, significance and normalized allelic fraction (NAF) of the top genes, overlap between validation sets 1,2, and 3, and mapped base pairs in the MiSeq sequencing data as well as the supplementary methods and extended literature evaluation of the candidate genes.


Academy of Finland

Jane and Aatos Erkko Foundation

Biomedicum Helsinki Foundation

Otto Malm Foundation

Ida Montin Foundation

Orion-Farmos Research Foundation

Oskar Öflunds Stiftelse

Maud Kuistila Memorial Foundation

University of Helsinki





Approximately 15% of colorectal cancers exhibit microsatellite instability (MSI), which leads to accumulation of large numbers of small insertions and deletions (indels). Genes that provide growth advantage to cells via loss-of-function mutations in microsatellites are called MSI target genes. Several criteria to define these genes have been suggested, one of them being simple mutation frequency. Microsatellite mutation rate, however, depends on the length and nucleotide context of the microsatellite. Therefore, assessing the general impact of mismatch repair deficiency on the likelihood of mutation events is paramount when following this approach. To identify MSI target genes, we developed a statistical model for the somatic background indel mutation rate of microsatellites to assess mutation significance. Exome sequencing data of 24 MSI colorectal cancers revealed indels at 54 million mononucleotide microsatellites of three or more nucleotides in length. The top 105 microsatellites from 71 genes were further analyzed in 93 additional MSI colorectal cancers. Mutation significance and estimated clonality of mutations determined the most likely MSI target genes to be the aminoadipate-semialdehyde dehydrogenase AASDH and the solute transporter SLC9A8. Our findings offer a systematic profiling of the somatic background mutation rate in protein-coding mononucleotide microsatellites, allowing a full cataloging of the true targets of MSI in colorectal cancer. Cancer Res; 77(15); 4078–88. ©2017 AACR.

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