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Mutations in two short noncoding mononucleotide repeats in most microsatellite-unstable colorectal cancers.
Cancer Res. 2005 Jun 01; 65(11):4607-13.CR

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+Show Affiliations

Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, Finland.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15930278

Citation

Hienonen, Tuija, et al. "Mutations in Two Short Noncoding Mononucleotide Repeats in Most Microsatellite-unstable Colorectal Cancers." Cancer Research, vol. 65, no. 11, 2005, pp. 4607-13.
Hienonen T, Sammalkorpi H, Enholm S, et al. Mutations in two short noncoding mononucleotide repeats in most microsatellite-unstable colorectal cancers. Cancer Res. 2005;65(11):4607-13.
Hienonen, T., Sammalkorpi, H., Enholm, S., Alhopuro, P., Barber, T. D., Lehtonen, R., Nupponen, N. N., Lehtonen, H., Salovaara, R., Mecklin, J. P., Järvinen, H., Koistinen, R., Arango, D., Launonen, V., Vogelstein, B., Karhu, A., & Aaltonen, L. A. (2005). Mutations in two short noncoding mononucleotide repeats in most microsatellite-unstable colorectal cancers. Cancer Research, 65(11), 4607-13.
Hienonen T, et al. Mutations in Two Short Noncoding Mononucleotide Repeats in Most Microsatellite-unstable Colorectal Cancers. Cancer Res. 2005 Jun 1;65(11):4607-13. PubMed PMID: 15930278.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mutations in two short noncoding mononucleotide repeats in most microsatellite-unstable colorectal cancers. AU - Hienonen,Tuija, AU - Sammalkorpi,Heli, AU - Enholm,Susa, AU - Alhopuro,Pia, AU - Barber,Thomas D, AU - Lehtonen,Rainer, AU - Nupponen,Nina N, AU - Lehtonen,Heli, AU - Salovaara,Reijo, AU - Mecklin,Jukka-Pekka, AU - Järvinen,Heikki, AU - Koistinen,Riitta, AU - Arango,Diego, AU - Launonen,Virpi, AU - Vogelstein,Bert, AU - Karhu,Auli, AU - Aaltonen,Lauri A, PY - 2005/6/3/pubmed PY - 2005/7/29/medline PY - 2005/6/3/entrez SP - 4607 EP - 13 JF - Cancer research JO - Cancer Res VL - 65 IS - 11 N2 - 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. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/15930278/Mutations_in_two_short_noncoding_mononucleotide_repeats_in_most_microsatellite_unstable_colorectal_cancers_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=15930278 DB - PRIME DP - Unbound Medicine ER -