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

Research output: Contribution to journalArticleScientificpeer-review

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.
Original languageEnglish
JournalCancer Research
Volume65
Issue number11
Pages (from-to)4607-4613
Number of pages7
ISSN0008-5472
DOIs
Publication statusPublished - 2005
MoE publication typeA1 Journal article-refereed

Fields of Science

  • REPAIR-DEFICIENT CANCERS
  • SOMATIC FRAMESHIFT MUTATIONS
  • NONPOLYPOSIS COLON-CANCER
  • TUMOR-CELL-LINES
  • TARGET GENES
  • MUTATOR PHENOTYPE
  • SEMENOGELIN-I
  • HUMAN-SEMEN
  • GASTROINTESTINAL CANCER
  • BETA RECEPTOR

Cite this

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. In: Cancer Research. 2005 ; Vol. 65, No. 11. pp. 4607-4613.
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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, no. 11, pp. 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.

In: Cancer Research, Vol. 65, No. 11, 2005, p. 4607-4613.

Research output: Contribution to journalArticleScientificpeer-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 -