Neurofibromatosis type 1 gene as a mutational target in a mismatch repair-deficient cell type

Qing Wang, Gilles Mountmain, Eric Ruano, Meena Upadhyaya, Sandra Dudley, R. Michael Liskay, Stephen N Thibodeau, Alain Puisieux

Research output: Contribution to journalArticle

73 Citations (Scopus)

Abstract

DNA mismatch repair (MMR) is the process by which incorrectly paired DNA nucleotides are recognized and repaired. A germline mutation in one of the genes involved in the process may be responsible for a dominantly inherited cancer syndrome, hereditary nonpolyposis colon cancer. Cancer progression in predisposed individuals results from the somatic inactivation of the normal copy of the MMR gene, leading to a mutator phenotype affecting preferentially repeat sequences (microsatellite instability, MSI). Recently, we identified children with a constitutional deficiency of MMR activity attributable to a mutation in the hMLHl gene. These children exhibited a constitutional genetic instability associated with clinical features of de novo neurofibromatosis type 1 (NF1) and early onset of extracolonic cancer. Based on these observations, we hypothesized that somatic NF1 gene mutation was a frequent and possibly early event in MMR-deficient cells. To test this hypothesis, we screened for NF1 mutations in cancer cells. Genetic alterations were identified in five out of ten tumor cell lines with MSI, whereas five MMR-proficient tumor cell lines expressed a wild-type NF1 gene. Somatic NF1 mutations were also detected in two primary tumors exhibiting an MSI phenotype. Finally, a 35-bp deletion in the murine Nf1 coding region was identified in mlh1 -/- mouse embryonic fibroblasts. These observations demonstrate that the NF1 gene is a mutational target of MMR deficiency and suggest that its inactivation is an important step of the malignant progression of MMR-deficient cells.

Original languageEnglish (US)
Pages (from-to)117-123
Number of pages7
JournalHuman Genetics
Volume112
Issue number2
StatePublished - Feb 2003

Fingerprint

Neurofibromatosis 1 Genes
Neurofibromatosis 1
DNA Mismatch Repair
Microsatellite Instability
Mutation
Neoplasms
Tumor Cell Line
Genes
Phenotype
Hereditary Nonpolyposis Colorectal Neoplasms
Germ-Line Mutation
Nucleotides
Fibroblasts
DNA

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Wang, Q., Mountmain, G., Ruano, E., Upadhyaya, M., Dudley, S., Liskay, R. M., ... Puisieux, A. (2003). Neurofibromatosis type 1 gene as a mutational target in a mismatch repair-deficient cell type. Human Genetics, 112(2), 117-123.

Neurofibromatosis type 1 gene as a mutational target in a mismatch repair-deficient cell type. / Wang, Qing; Mountmain, Gilles; Ruano, Eric; Upadhyaya, Meena; Dudley, Sandra; Liskay, R. Michael; Thibodeau, Stephen N; Puisieux, Alain.

In: Human Genetics, Vol. 112, No. 2, 02.2003, p. 117-123.

Research output: Contribution to journalArticle

Wang, Q, Mountmain, G, Ruano, E, Upadhyaya, M, Dudley, S, Liskay, RM, Thibodeau, SN & Puisieux, A 2003, 'Neurofibromatosis type 1 gene as a mutational target in a mismatch repair-deficient cell type', Human Genetics, vol. 112, no. 2, pp. 117-123.
Wang Q, Mountmain G, Ruano E, Upadhyaya M, Dudley S, Liskay RM et al. Neurofibromatosis type 1 gene as a mutational target in a mismatch repair-deficient cell type. Human Genetics. 2003 Feb;112(2):117-123.
Wang, Qing ; Mountmain, Gilles ; Ruano, Eric ; Upadhyaya, Meena ; Dudley, Sandra ; Liskay, R. Michael ; Thibodeau, Stephen N ; Puisieux, Alain. / Neurofibromatosis type 1 gene as a mutational target in a mismatch repair-deficient cell type. In: Human Genetics. 2003 ; Vol. 112, No. 2. pp. 117-123.
@article{80ac387e7ceb48d28b70868298b65c48,
title = "Neurofibromatosis type 1 gene as a mutational target in a mismatch repair-deficient cell type",
abstract = "DNA mismatch repair (MMR) is the process by which incorrectly paired DNA nucleotides are recognized and repaired. A germline mutation in one of the genes involved in the process may be responsible for a dominantly inherited cancer syndrome, hereditary nonpolyposis colon cancer. Cancer progression in predisposed individuals results from the somatic inactivation of the normal copy of the MMR gene, leading to a mutator phenotype affecting preferentially repeat sequences (microsatellite instability, MSI). Recently, we identified children with a constitutional deficiency of MMR activity attributable to a mutation in the hMLHl gene. These children exhibited a constitutional genetic instability associated with clinical features of de novo neurofibromatosis type 1 (NF1) and early onset of extracolonic cancer. Based on these observations, we hypothesized that somatic NF1 gene mutation was a frequent and possibly early event in MMR-deficient cells. To test this hypothesis, we screened for NF1 mutations in cancer cells. Genetic alterations were identified in five out of ten tumor cell lines with MSI, whereas five MMR-proficient tumor cell lines expressed a wild-type NF1 gene. Somatic NF1 mutations were also detected in two primary tumors exhibiting an MSI phenotype. Finally, a 35-bp deletion in the murine Nf1 coding region was identified in mlh1 -/- mouse embryonic fibroblasts. These observations demonstrate that the NF1 gene is a mutational target of MMR deficiency and suggest that its inactivation is an important step of the malignant progression of MMR-deficient cells.",
author = "Qing Wang and Gilles Mountmain and Eric Ruano and Meena Upadhyaya and Sandra Dudley and Liskay, {R. Michael} and Thibodeau, {Stephen N} and Alain Puisieux",
year = "2003",
month = "2",
language = "English (US)",
volume = "112",
pages = "117--123",
journal = "Human Genetics",
issn = "0340-6717",
publisher = "Springer Verlag",
number = "2",

}

TY - JOUR

T1 - Neurofibromatosis type 1 gene as a mutational target in a mismatch repair-deficient cell type

AU - Wang, Qing

AU - Mountmain, Gilles

AU - Ruano, Eric

AU - Upadhyaya, Meena

AU - Dudley, Sandra

AU - Liskay, R. Michael

AU - Thibodeau, Stephen N

AU - Puisieux, Alain

PY - 2003/2

Y1 - 2003/2

N2 - DNA mismatch repair (MMR) is the process by which incorrectly paired DNA nucleotides are recognized and repaired. A germline mutation in one of the genes involved in the process may be responsible for a dominantly inherited cancer syndrome, hereditary nonpolyposis colon cancer. Cancer progression in predisposed individuals results from the somatic inactivation of the normal copy of the MMR gene, leading to a mutator phenotype affecting preferentially repeat sequences (microsatellite instability, MSI). Recently, we identified children with a constitutional deficiency of MMR activity attributable to a mutation in the hMLHl gene. These children exhibited a constitutional genetic instability associated with clinical features of de novo neurofibromatosis type 1 (NF1) and early onset of extracolonic cancer. Based on these observations, we hypothesized that somatic NF1 gene mutation was a frequent and possibly early event in MMR-deficient cells. To test this hypothesis, we screened for NF1 mutations in cancer cells. Genetic alterations were identified in five out of ten tumor cell lines with MSI, whereas five MMR-proficient tumor cell lines expressed a wild-type NF1 gene. Somatic NF1 mutations were also detected in two primary tumors exhibiting an MSI phenotype. Finally, a 35-bp deletion in the murine Nf1 coding region was identified in mlh1 -/- mouse embryonic fibroblasts. These observations demonstrate that the NF1 gene is a mutational target of MMR deficiency and suggest that its inactivation is an important step of the malignant progression of MMR-deficient cells.

AB - DNA mismatch repair (MMR) is the process by which incorrectly paired DNA nucleotides are recognized and repaired. A germline mutation in one of the genes involved in the process may be responsible for a dominantly inherited cancer syndrome, hereditary nonpolyposis colon cancer. Cancer progression in predisposed individuals results from the somatic inactivation of the normal copy of the MMR gene, leading to a mutator phenotype affecting preferentially repeat sequences (microsatellite instability, MSI). Recently, we identified children with a constitutional deficiency of MMR activity attributable to a mutation in the hMLHl gene. These children exhibited a constitutional genetic instability associated with clinical features of de novo neurofibromatosis type 1 (NF1) and early onset of extracolonic cancer. Based on these observations, we hypothesized that somatic NF1 gene mutation was a frequent and possibly early event in MMR-deficient cells. To test this hypothesis, we screened for NF1 mutations in cancer cells. Genetic alterations were identified in five out of ten tumor cell lines with MSI, whereas five MMR-proficient tumor cell lines expressed a wild-type NF1 gene. Somatic NF1 mutations were also detected in two primary tumors exhibiting an MSI phenotype. Finally, a 35-bp deletion in the murine Nf1 coding region was identified in mlh1 -/- mouse embryonic fibroblasts. These observations demonstrate that the NF1 gene is a mutational target of MMR deficiency and suggest that its inactivation is an important step of the malignant progression of MMR-deficient cells.

UR - http://www.scopus.com/inward/record.url?scp=0037315934&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037315934&partnerID=8YFLogxK

M3 - Article

VL - 112

SP - 117

EP - 123

JO - Human Genetics

JF - Human Genetics

SN - 0340-6717

IS - 2

ER -