Candidate driver genes in microsatellite-unstable colorectal cancer

Pia Alhopuro, Heli Sammalkorpi, Iina Niittymäki, Mia Biström, Anniina Raitila, Juha Saharinen, Kari Nousiainen, Heli J. Lehtonen, Elina Heliövaara, Jani Puhakka, Sari Tuupanen, Sõnia Sousa, Raquel Seruca, Ana M. Ferreira, Robert M.W. Hofstra, Jukka Pekka Mecklin, Heikki Järvinen, Ari Ristimäki, Torben F. Ørntoft, Sampsa HautaniemiDiego Arango, Auli Karhu, Lauri A. Aaltonen

    Research output: Contribution to journalArticleResearchpeer-review

    59 Citations (Scopus)

    Abstract

    Defects in the mismatch repair system lead to microsatellite instability (MSI), a feature observed in ∼ 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 6-10 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, 6-10 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. Copyright © 2011 UICC.
    Original languageEnglish
    Pages (from-to)1558-1566
    JournalInternational Journal of Cancer
    Volume130
    Issue number7
    DOIs
    Publication statusPublished - 1 Apr 2012

    Keywords

    • colorectal cancer
    • frameshift mutation
    • microsatellite instability

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