Mutations in two short noncoding mononucleotide repeats in most microsatellite-unstable colorectal cancers

Tuija Hienonen, Heli Sammalkorpi, Susa Enholm, Pia Alhopuro, Thomas D Barber, Rainer Lehtonen, Nina N Nupponen, Heli Lehtonen, Reijo Salovaara, Jukka-Pekka Mecklin, Heikki J Järvinen, Riitta Koistinen, Diego Arango, Virpi Launonen, Bert Vogelstein, Auli Karhu, Lauri A Aaltonen

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Sammanfattning

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 (SEMGI) 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 lip 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.
Originalspråkengelska
TidskriftCancer Research
Volym65
Utgåva11
Sidor (från-till)4607-4613
Antal sidor7
ISSN0008-5472
DOI
StatusPublicerad - 2005
MoE-publikationstypA1 Tidskriftsartikel-refererad

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    Hienonen, Tuija ; Sammalkorpi, Heli ; Enholm, Susa ; Alhopuro, Pia ; Barber, Thomas D ; Lehtonen, Rainer ; Nupponen, Nina N ; Lehtonen, Heli ; Salovaara, Reijo ; Mecklin, Jukka-Pekka ; Järvinen, Heikki J ; Koistinen, Riitta ; Arango, Diego ; Launonen, Virpi ; Vogelstein, Bert ; Karhu, Auli ; Aaltonen, Lauri A. / Mutations in two short noncoding mononucleotide repeats in most microsatellite-unstable colorectal cancers. I: Cancer Research. 2005 ; Vol. 65, Nr. 11. s. 4607-4613.
    @article{f5619c8a6aec42a1be186647e6ad948d,
    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 (SEMGI) 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 lip 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.",
    keywords = "REPAIR-DEFICIENT CANCERS, SOMATIC FRAMESHIFT MUTATIONS, NONPOLYPOSIS COLON-CANCER, TUMOR-CELL-LINES, TARGET GENES, MUTATOR PHENOTYPE, SEMENOGELIN-I, HUMAN-SEMEN, GASTROINTESTINAL CANCER, BETA RECEPTOR",
    author = "Tuija Hienonen and Heli Sammalkorpi and Susa Enholm and Pia Alhopuro and Barber, {Thomas D} and Rainer Lehtonen and Nupponen, {Nina N} and Heli Lehtonen and Reijo Salovaara and Jukka-Pekka Mecklin and J{\"a}rvinen, {Heikki J} and Riitta Koistinen and Diego Arango and Virpi Launonen and Bert Vogelstein and Auli Karhu and Aaltonen, {Lauri A}",
    year = "2005",
    doi = "10.1158/0008-5472.CAN-05-0165",
    language = "English",
    volume = "65",
    pages = "4607--4613",
    journal = "Cancer Research",
    issn = "0008-5472",
    publisher = "American Association for Cancer Research",
    number = "11",

    }

    Hienonen, T, Sammalkorpi, H, Enholm, S, Alhopuro, P, Barber, TD, Lehtonen, R, Nupponen, NN, Lehtonen, H, Salovaara, R, Mecklin, J-P, Järvinen, HJ, Koistinen, R, Arango, D, Launonen, V, Vogelstein, B, Karhu, A & Aaltonen, LA 2005, 'Mutations in two short noncoding mononucleotide repeats in most microsatellite-unstable colorectal cancers' Cancer Research, vol. 65, nr. 11, s. 4607-4613. https://doi.org/10.1158/0008-5472.CAN-05-0165

    Mutations in two short noncoding mononucleotide repeats in most microsatellite-unstable colorectal cancers. / Hienonen, Tuija; Sammalkorpi, Heli; Enholm, Susa; Alhopuro, Pia; Barber, Thomas D; Lehtonen, Rainer; Nupponen, Nina N; Lehtonen, Heli; Salovaara, Reijo; Mecklin, Jukka-Pekka; Järvinen, Heikki J; Koistinen, Riitta; Arango, Diego; Launonen, Virpi; Vogelstein, Bert; Karhu, Auli; Aaltonen, Lauri A.

    I: Cancer Research, Vol. 65, Nr. 11, 2005, s. 4607-4613.

    Forskningsoutput: TidskriftsbidragArtikelVetenskapligPeer review

    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 J

    AU - Koistinen, Riitta

    AU - Arango, Diego

    AU - Launonen, Virpi

    AU - Vogelstein, Bert

    AU - Karhu, Auli

    AU - Aaltonen, Lauri A

    PY - 2005

    Y1 - 2005

    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 (SEMGI) 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 lip 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.

    AB - 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 (SEMGI) 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 lip 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.

    KW - REPAIR-DEFICIENT CANCERS

    KW - SOMATIC FRAMESHIFT MUTATIONS

    KW - NONPOLYPOSIS COLON-CANCER

    KW - TUMOR-CELL-LINES

    KW - TARGET GENES

    KW - MUTATOR PHENOTYPE

    KW - SEMENOGELIN-I

    KW - HUMAN-SEMEN

    KW - GASTROINTESTINAL CANCER

    KW - BETA RECEPTOR

    U2 - 10.1158/0008-5472.CAN-05-0165

    DO - 10.1158/0008-5472.CAN-05-0165

    M3 - Article

    VL - 65

    SP - 4607

    EP - 4613

    JO - Cancer Research

    JF - Cancer Research

    SN - 0008-5472

    IS - 11

    ER -