This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hegde, M. R. Articles by Richards, C. S. Search for Related Content PubMed PubMed Citation Articles by Hegde, M. R. Articles by Richards, C. S.

A Homozygous Mutation in MSH6 Causes Turcot Syndrome

Authors' Affiliations: ¹ Diagnostic Sequencing Laboratory, Department of Molecular and Human Genetics and ² Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas

Requests for reprints: Madhuri Hegde, Medical Genetics Laboratories, Baylor College of Medicine, NAB 2015, One Baylor Plaza, Department Of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030. Phone: 713-798-7576; Fax: 713-798-8937; E-mail: mhegde{at}bcm.tmc.edu.

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.

This article has been cited by other articles:

				H. Feitsma, R. V. Kuiper, J. Korving, I. J. Nijman, and E. Cuppen Zebrafish with Mutations in Mismatch Repair Genes Develop Neurofibromas and Other Tumors Cancer Res., July 1, 2008; 68(13): 5059 - 5066. [Abstract] [Full Text] [PDF]

				D. P. Cahill, K. K. Levine, R. A. Betensky, P. J. Codd, C. A. Romany, L. B. Reavie, T. T. Batchelor, P. A. Futreal, M. R. Stratton, W. T. Curry, et al. Loss of the Mismatch Repair Protein MSH6 in Human Glioblastomas Is Associated with Tumor Progression during Temozolomide Treatment Clin. Cancer Res., April 1, 2007; 13(7): 2038 - 2045. [Abstract] [Full Text] [PDF]

				R. D. Kennedy and A. D. D'Andrea DNA Repair Pathways in Clinical Practice: Lessons From Pediatric Cancer Susceptibility Syndromes J. Clin. Oncol., August 10, 2006; 24(23): 3799 - 3808. [Abstract] [Full Text] [PDF]

				C. Hunter, R. Smith, D. P. Cahill, P. Stephens, C. Stevens, J. Teague, C. Greenman, S. Edkins, G. Bignell, H. Davies, et al. A Hypermutation Phenotype and Somatic MSH6 Mutations in Recurrent Human Malignant Gliomas after Alkylator Chemotherapy. Cancer Res., April 15, 2006; 66(8): 3987 - 3991. [Abstract] [Full Text] [PDF]