A novel MSH2 germline mutation in homozygous state in two brothers with colorectal cancers diagnosed at the age of 11 and 12 years.
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.
Müller
Annegret
A
Department of General Surgery, University of Göttingen, Göttingen, Germany. dramueller@aol.com
Schackert
Hans K
HK
Lange
Bettina
B
Rüschoff
Josef
J
Füzesi
Laslow
L
Willert
Joerg
J
Burfeind
Peter
P
Shah
Parantu
P
Becker
Heinz
H
Epplen
Joerg Thomas
JT
Stemmler
Susanne
S
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
C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein