title: Mutations in two short noncoding mononucleotide repeats in most microsatellite-unstable colorectal cancers.
abstract: DNA mismatch repair (MMR)-deficient cells typically accumulate mutations in short repetitive DNA tracts. This microsatellite instability (MSI) facilitates malignant transformation when affecting genes with growth-related and caretaker functions. To date, several putative MSI target genes have been proposed mainly based on high mutation frequency within their coding regions. However, some intronic repeat mutations have also been suggested to associate with MSI tumorigenesis, indicating the need for additional analyses on noncoding repeats. Here we have analyzed an intronic T9 repeat of semenogelin I (SEMG1) and report mutation frequencies of 51% (75 of 146) and 62% (8 of 13) in MMR-deficient primary colorectal cancers and cell lines, respectively. The putative effect of the SEMG1 mutations was assessed by RNA and protein level analyses, but no differences were detected between colorectal cancer cell lines with different SEMG1 status. Subsequently, the general background mutation frequency of MSI colorectal cancers was assessed by screening for intergenic T9 repeat alterations. One of 10 examined repeats was mutated in 70% (102 of 145) of the colorectal cancers evaluated. The frequencies observed here are notably higher than previously published in noncoding repeats shorter than 10 bp in MMR-deficient primary tumors. Our results indicate that high mutation frequencies, similar or higher than those observed in proposed and approved target genes, can be detected in repeat tracts of MSI tumors without any apparent selection pressure. These data call for urgent and thorough large-scale evaluation of mutation frequencies in neutral short repetitive sequences in MMR-deficient tumors.
authors.affiliation: Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, Finland.
authors.forename: Tuija
authors.initials: T
authors.lastname: Hienonen
authors.forename: Heli
authors.initials: H
authors.lastname: Sammalkorpi
authors.forename: Susa
authors.initials: S
authors.lastname: Enholm
authors.forename: Pia
authors.initials: P
authors.lastname: Alhopuro
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Barber
authors.forename: Rainer
authors.initials: R
authors.lastname: Lehtonen
authors.forename: Nina N
authors.initials: NN
authors.lastname: Nupponen
authors.forename: Heli
authors.initials: H
authors.lastname: Lehtonen
authors.forename: Reijo
authors.initials: R
authors.lastname: Salovaara
authors.forename: Jukka-Pekka
authors.initials: JP
authors.lastname: Mecklin
authors.forename: Heikki
authors.initials: H
authors.lastname: Järvinen
authors.forename: Riitta
authors.initials: R
authors.lastname: Koistinen
authors.forename: Diego
authors.initials: D
authors.lastname: Arango
authors.forename: Virpi
authors.initials: V
authors.lastname: Launonen
authors.forename: Bert
authors.initials: B
authors.lastname: Vogelstein
authors.forename: Auli
authors.initials: A
authors.lastname: Karhu
authors.forename: Lauri A
authors.initials: LA
authors.lastname: Aaltonen
mesh_terms: D000483:Alleles; D020137:Base Pair Mismatch / Q000235:genetics; D001483:Base Sequence; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism; D004260:DNA Repair / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D016368:Frameshift Mutation; D042822:Genomic Instability; D006801:Humans; D007438:Introns / Q000235:genetics; D018895:Microsatellite Repeats / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D029607:Seminal Vesicle Secretory Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism
chemical_list: D004273:DNA, Neoplasm; D012333:RNA, Messenger; D029607:Seminal Vesicle Secretory Proteins; C424482:seminal vesicle-specific antigen