Abstract
Microsatellite instability (MSI) leads to accumulation of an excessive number of mutations in the genome, mostly small insertions and deletions. MSI colorectal cancers (CRCs), however, also contain more point mutations than microsatellite‐stable (MSS) tumors, yet they have not been as comprehensively studied. To identify candidate driver genes affected by point mutations in MSI CRC, we ranked genes based on mutation significance while correcting for replication timing and gene expression utilizing an algorithm, MutSigCV. Somatic point mutation data from the exome kit‐targeted area from 24 exome‐sequenced sporadic MSI CRCs and respective normals, and 12 whole‐genome‐sequenced sporadic MSI CRCs and respective normals were utilized. The top 73 genes were validated in 93 additional MSI CRCs. The MutSigCV ranking identified several well‐established MSI CRC driver genes and provided additional evidence for previously proposed CRC candidate genes as well as shortlisted genes that have to our knowledge not been linked to CRC before. Two genes, SMARCB1 and STK38L, were also functionally scrutinized, providing evidence of a tumorigenic role, for SMARCB1 mutations in particular.
Highlights
Colorectal cancer (CRC) is one of the most fatal cancers in Western countries leading to death in nearly 50% of the cases (Jemal et al, 2011)
In order to identify new candidates for driver genes affected by point mutations in Microsatellite instability (MSI) CRC, we analyzed sequencing data from a discovery set of 36 exome- or whole-genome-sequenced MSI CRCs and respective normals
MutSigCV analysis was performed on the somatic single-nucleotide variation (SNV) data to identify the genes most likely to display an excess of point mutations due to selection, and the resulting top 73 genes were further validated by MiSeq sequencing in a validation set of 93 additional MSI CRCs
Summary
Colorectal cancer (CRC) is one of the most fatal cancers in Western countries leading to death in nearly 50% of the cases (Jemal et al, 2011). 15% of CRCs exhibit microsatellite instability (MSI), which results from defective DNA mismatch repair (MMR) machinery (Boland & Goel, 2010). This is most often the result of a 2018 The Authors. The most common form of inherited predisposition is Lynch syndrome, where the individual inherits a germline mutation in one of the MMR genes (MLH1, MSH2, MSH6, PMS2) and is highly predisposed to CRC and endometrial cancer (Boland & Goel, 2010). Most of these have been flagged by missense mutation hot spots (e.g., BRAF, KRAS, CTNNB1, and PIK3CA), a mutation pattern typical of oncogenes (Fearon, 2011)
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