title: Candidate driver genes in microsatellite-unstable colorectal cancer.
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.
authors.affiliation: Department of Medical Genetics, Genome-Scale Biology Research Program, Biomedicum Helsinki, University of Helsinki, Finland.
authors.forename: Pia
authors.initials: P
authors.lastname: Alhopuro
authors.forename: Heli
authors.initials: H
authors.lastname: Sammalkorpi
authors.forename: Iina
authors.initials: I
authors.lastname: Niittymäki
authors.forename: Mia
authors.initials: M
authors.lastname: Biström
authors.forename: Anniina
authors.initials: A
authors.lastname: Raitila
authors.forename: Juha
authors.initials: J
authors.lastname: Saharinen
authors.forename: Kari
authors.initials: K
authors.lastname: Nousiainen
authors.forename: Heli J
authors.initials: HJ
authors.lastname: Lehtonen
authors.forename: Elina
authors.initials: E
authors.lastname: Heliövaara
authors.forename: Jani
authors.initials: J
authors.lastname: Puhakka
authors.forename: Sari
authors.initials: S
authors.lastname: Tuupanen
authors.forename: Sónia
authors.initials: S
authors.lastname: Sousa
authors.forename: Raquel
authors.initials: R
authors.lastname: Seruca
authors.forename: Ana M
authors.initials: AM
authors.lastname: Ferreira
authors.forename: Robert M W
authors.initials: RM
authors.lastname: Hofstra
authors.forename: Jukka-Pekka
authors.initials: JP
authors.lastname: Mecklin
authors.forename: Heikki
authors.initials: H
authors.lastname: Järvinen
authors.forename: Ari
authors.initials: A
authors.lastname: Ristimäki
authors.forename: Torben F
authors.initials: TF
authors.lastname: Orntoft
authors.forename: Sampsa
authors.initials: S
authors.lastname: Hautaniemi
authors.forename: Diego
authors.initials: D
authors.lastname: Arango
authors.forename: Auli
authors.initials: A
authors.lastname: Karhu
authors.forename: Lauri A
authors.initials: LA
authors.lastname: Aaltonen
mesh_terms: D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics*; D016368:Frameshift Mutation; D045325:HCT116 Cells; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D053842:Microsatellite Instability; D018895:Microsatellite Repeats; D059645:Mutation Rate; D012044:Regression Analysis
chemical_list: D004273:DNA, Neoplasm