title: A novel MSH2 germline mutation in homozygous state in two brothers with colorectal cancers diagnosed at the age of 11 and 12 years.
abstract: Hereditary non-polyposis colorectal cancer (HNPCC) syndrome is caused by heterozygous germline mutations in DNA mismatch repair genes (MMR), (MSH2, MLH1, MSH6, and PMS2) and it is inherited in an autosomal dominant pattern with high penetrance. Several patients have been reported carrying bi-allelic MMR gene mutations and whose phenotype resembled a syndrome with childhood malignancies including hematological malignancies, brain, and colorectal tumors. This phenotype is similar to the tumor spectrum of MMR knockout mice. Herein we describe two brothers of healthy consanguineous parents from Pakistan, who had developed two and three colorectal cancers at the ages of 11 and 12 years, respectively, and less than 30 polyps. Tumor specimens were microsatellite instable (MSI-H), and expression of MSH2 and MSH6 was lost. Mutation analyses of DNA samples from both patients revealed a novel homozygous c.2006-5T > A mutation in intron 12 of the MSH2 gene. This phenotype of the brothers is unusual as they neither develop hematological malignancies nor brain tumors at an older age of presentation than other patients with homozygous MSH2 mutations. The milder phenotype may be due to the expression of low amounts of MSH2 protein with reduced activity.
authors.affiliation: Department of General Surgery, University of Göttingen, Göttingen, Germany. dramueller@aol.com
authors.forename: Annegret
authors.initials: A
authors.lastname: Müller
authors.forename: Hans K
authors.initials: HK
authors.lastname: Schackert
authors.forename: Bettina
authors.initials: B
authors.lastname: Lange
authors.forename: Josef
authors.initials: J
authors.lastname: Rüschoff
authors.forename: Laslow
authors.initials: L
authors.lastname: Füzesi
authors.forename: Joerg
authors.initials: J
authors.lastname: Willert
authors.forename: Peter
authors.initials: P
authors.lastname: Burfeind
authors.forename: Parantu
authors.initials: P
authors.lastname: Shah
authors.forename: Heinz
authors.initials: H
authors.lastname: Becker
authors.forename: Joerg Thomas
authors.initials: JT
authors.lastname: Epplen
authors.forename: Susanne
authors.initials: S
authors.lastname: Stemmler
mesh_terms: D002648:Child; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D018095:Germ-Line Mutation; D006720:Homozygote; D006801:Humans; D007150:Immunohistochemistry; D051718:MutS Homolog 2 Protein / Q000032:analysis / Q000235:genetics*; D035781:Siblings
chemical_list: C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein