Dataset Information

Comprehensive evaluation of coding region point mutations in microsatellite-unstable colorectal cancer.

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.

SUBMITTER: Kondelin J

PROVIDER: S-EPMC6402450 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Comprehensive evaluation of coding region point mutations in microsatellite-unstable colorectal cancer.

Kondelin Johanna J Salokas Kari K Saarinen Lilli L Ovaska Kristian K Rauanheimo Heli H Plaketti Roosa-Maria RM Hamberg Jiri J Liu Xiaonan X Yadav Leena L Gylfe Alexandra E AE Cajuso Tatiana T Hänninen Ulrika A UA Palin Kimmo K Ristolainen Heikki H Katainen Riku R Kaasinen Eevi E Tanskanen Tomas T Aavikko Mervi M Taipale Minna M Taipale Jussi J Renkonen-Sinisalo Laura L Lepistö Anna A Koskensalo Selja S Böhm Jan J Mecklin Jukka-Pekka JP Ongen Halit H Dermitzakis Emmanouil T ET Kilpivaara Outi O Vahteristo Pia P Turunen Mikko M Hautaniemi Sampsa S Tuupanen Sari S Karhu Auli A Välimäki Niko N Varjosalo Markku M Pitkänen Esa E Aaltonen Lauri A LA

EMBO molecular medicine 20180901 9

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 utilizi ...[more]

PMID: 30108113

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Project description:The search for immunotherapy biomarkers in Microsatellite Instability High/Deficient Mismatch Repair system (MSI-H/dMMR) metastatic colorectal cancer (mCRC) is an unmet need. Sixteen patients with mCRC and MSI-H/dMMR (determined by either immunohistochemistry or polymerase chain reaction) treated with PD-1/PD-L1 inhibitors at our institution were included. According to whether the progression-free survival with PD-1/PD-L1 inhibitors was longer than 6 months or shorter, patients were clustered into the IT-responder group (n: 9 patients) or IT-resistant group (n: 7 patients), respectively. In order to evaluate determinants of benefit with PD-1/PD-L1 inhibitors, we performed multimodal analysis including genomics (through NGS panel tumour-only with 431 genes) and the immune microenvironment (using CD3, CD8, FOXP3 and PD-L1 antibodies). The following mutations were more frequent in IT-resistant compared with IT-responder groups: B2M (4/7 versus 2/9), CTNNB1 (2/7 versus 0/9), and biallelic PTEN (3/7 versus 1/9). Biallelic ARID1A mutations were found exclusively in the IT-responder group (4/9 patients). Tumour mutational burden did not correlate with immunotherapy benefit, neither the rate of indels in homopolymeric regions. Of note, biallelic ARID1A mutated tumours had the highest immune infiltration and PD-L1 scores, contrary to tumours with CTNNB1 mutation. Immune microenvironment analysis showed higher densities of different T cell subpopulations and PD-L1 expression in IT-responders. Misdiagnosis of MSI-H/dMMR inferred by discordances between immunohistochemistry and polymerase chain reaction was only found in the IT-resistant population (3/7 patients). Biallelic ARID1A mutations and Wnt signalling activation through CTNNB1 mutation were associated with high and low T cell immune infiltrates, respectively, and deserve special attention as determinants of response to PD-1/PD-L1 inhibitors. The non-MSI-H phenotype in dMMR is associated with poor benefit to immunotherapy. Our results suggest that mechanisms of resistance to immunotherapy are multi-factorial.

Dataset Information

Comprehensive evaluation of coding region point mutations in microsatellite-unstable colorectal cancer.

Publications

Comprehensive evaluation of coding region point mutations in microsatellite-unstable colorectal cancer.

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