期刊
INTERNATIONAL JOURNAL OF CANCER
卷 130, 期 7, 页码 1558-1566出版社
WILEY-BLACKWELL
DOI: 10.1002/ijc.26167
关键词
microsatellite instability; colorectal cancer; frameshift mutation
类别
资金
- Academy of Finland
- Finnish Cancer Society
- Sigrid Juselius Foundation
- Association for International Cancer Research
- Helsinki University
- Biocentrum Helsinki
- European Commission
- Orion-Farmos Research Foundation
- AstraZeneca
- Finnish Medical Society
- Lilly Foundation
- Finnish Gastroenterology and Oncology Society
- Biomedicum Helsinki Foundation
- Paulo Foundation
- Maud Kuistila Foundation
- Ida Montin Foundation
Defects in the mismatch repair system lead to microsatellite instability (MSI), a feature observed in similar to 15% of all colorectal cancers (CRCs). Microsatellite mutations that drive tumourigenesis, typically inactivation of tumour suppressors, are selected for and are frequently detected in MSI cancers. Here, we evaluated somatic mutations in microsatellite repeats of 790 genes chosen based on reduced expression in MSI CRC and existence of a coding mononucleotide repeat of 6 similar to 10 bp in length. All the repeats were initially sequenced in 30 primary MSI CRC samples and whenever frameshift mutations were identified in >20%, additional 70 samples were sequenced. To distinguish driver mutations from passengers, we similarly analyzed the occurrence of frameshift mutations in 121 intronic control repeats and utilized a statistical regression model to determine cut-off mutation frequencies for repeats of all types (A/T and C/G, 610 bp). Along with several know target genes, including TGFBR2, ACVR2, and MSH3, six novel candidate driver genes emerged that harbored significantly more mutations than identical control repeats. The mutation frequencies in 100 MSI CRC samples were 51% in G8 of GLYR1, 47% in T9 of ABCC5, 43% in G8 of WDTC1, 33% in A8 of ROCK1, 30% in T8 of OR51E2, and 28% in A8 of TCEB3. Immunohistochemical staining of GLYR1 revealed defective protein expression in tumors carrying biallelic mutations, supporting a loss of function hypothesis. This is a large scale, unbiased effort to identify genes that when mutated are likely to contribute to MSI CRC development.
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