A homozygous mutation in MSH6 causes Turcot syndrome

Madhuri R. Hegde, Belinda Chong, Maria E. Blazo, Lip Hon E Chin, Patricia A. Ward, Murali M. Chintagumpala, John Y. Kim, Sharon E. Plon, Carolyn (Sue) Richards

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Abstract

Heterozygous mutations in one of the DNA mismatch repair genes cause hereditary nonpolyposis colorectal cancer (MIM114500). Turcot syndrome (MIM276300) has been described as the association of central nervous system malignant tumors and familial colorectal cancer and has been reported to be both a dominant and recessive disorder. Homozygous and compound heterozygous mutations in APC, MLH1, MSH2, and PMS2 genes have been reported in five families. Here we describe a nonconsanguineous Pakistani family, including a son with lymphoma and colorectal cancer diagnosed at ages 5 and 8, respectively, and an 8-year-old daughter with glioblastoma multiforme. Both children had features of neurofibromatosis type 1 including atypical café au lait spots and axillary freckling without a family history consistent with neurofibromatosis type 1, familial adenomatous polyposis, or hereditary nonpolyposis colorectal cancer. Mutational analysis was done for MLH1, MSH2, and MSH6 using denaturing high-performance liquid chromatography and sequencing of a blood sample from the daughter. A novel homozygous single base insertion mutation was identified (3634insT) resulting in a premature stop at codon 1,223 in exon 7 of the MSH6 gene. Both parents were found to be heterozygous for the 3634insT mutation. Microsatellite instability testing showed instability in the glioblastoma sample. We report here the first identification of a homozygous mutation in MSH6 in a family with childhood-onset brain tumor, lymphoma, colorectal cancer, and neurofibromatosis type 1 phenotype. Our findings support a role for MSH6 in Turcot syndrome and are consistent with an autosomal recessive mode of inheritance.

Original languageEnglish (US)
Pages (from-to)4689-4693
Number of pages5
JournalClinical Cancer Research
Volume11
Issue number13
DOIs
StatePublished - Jul 1 2005

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Neurofibromatosis 1
Nuclear Family
Hereditary Nonpolyposis Colorectal Neoplasms
Colorectal Neoplasms
Mutation
Glioblastoma
Lymphoma
Genes
Central Nervous System Neoplasms
Microsatellite Instability
Adenomatous Polyposis Coli
DNA Mismatch Repair
Nonsense Codon
Insertional Mutagenesis
Brain Neoplasms
Exons
Parents
High Pressure Liquid Chromatography
Phenotype
Turcot syndrome

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Hegde, M. R., Chong, B., Blazo, M. E., Chin, L. H. E., Ward, P. A., Chintagumpala, M. M., ... Richards, C. S. (2005). A homozygous mutation in MSH6 causes Turcot syndrome. Clinical Cancer Research, 11(13), 4689-4693. https://doi.org/10.1158/1078-0432.CCR-04-2025

A homozygous mutation in MSH6 causes Turcot syndrome. / Hegde, Madhuri R.; Chong, Belinda; Blazo, Maria E.; Chin, Lip Hon E; Ward, Patricia A.; Chintagumpala, Murali M.; Kim, John Y.; Plon, Sharon E.; Richards, Carolyn (Sue).

In: Clinical Cancer Research, Vol. 11, No. 13, 01.07.2005, p. 4689-4693.

Research output: Contribution to journalArticle

Hegde, MR, Chong, B, Blazo, ME, Chin, LHE, Ward, PA, Chintagumpala, MM, Kim, JY, Plon, SE & Richards, CS 2005, 'A homozygous mutation in MSH6 causes Turcot syndrome', Clinical Cancer Research, vol. 11, no. 13, pp. 4689-4693. https://doi.org/10.1158/1078-0432.CCR-04-2025
Hegde MR, Chong B, Blazo ME, Chin LHE, Ward PA, Chintagumpala MM et al. A homozygous mutation in MSH6 causes Turcot syndrome. Clinical Cancer Research. 2005 Jul 1;11(13):4689-4693. https://doi.org/10.1158/1078-0432.CCR-04-2025
Hegde, Madhuri R. ; Chong, Belinda ; Blazo, Maria E. ; Chin, Lip Hon E ; Ward, Patricia A. ; Chintagumpala, Murali M. ; Kim, John Y. ; Plon, Sharon E. ; Richards, Carolyn (Sue). / A homozygous mutation in MSH6 causes Turcot syndrome. In: Clinical Cancer Research. 2005 ; Vol. 11, No. 13. pp. 4689-4693.
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