The natural history of a combined defect in MSH6 and MUTYH in a HNPCC family.
In the inherited syndromes, MUTYH-associated polyposis (MAP) and hereditary nonpolyposis colorectal cancer (HNPCC), somatic mutations occur due to loss of the caretaker function that base-repair (BER) and mismatch repair (MMR) genes have, respectively. Recently, we identified a large branch from a MSH6 HNPCC family in which 19 family members are heterozygous or compound heterozygous for MUTYH germ line mutations. MSH6/MUTYH heterozygote mutation carriers display a predominant HNPCC molecular tumour phenotype, with microsatellite instability and underrepresentation of G>T transversions. A single unique patient is carrier of the MSH6 germline mutation and is compound heterozygote for MUTYH. Unexpectedly, this patient has an extremely mild clinical phenotype with sofar only few adenomas at age 56. Four out of five adenomas show characteristic G>T transversions in APC and/or KRAS2, as seen in MUTYH associated polyposis. No second hit of MSH6 is apparent in any of the adenomas, due to retained MSH6 nuclear expression and a lack of microsatellite instability. Although this concerns only one case, we argue that the chance to find an additional one is extremely small and currently a mouse model with this genotype combination is not available. Moreover, the patients brother who is also compound heterozygous for MUTYH but lacks the MSH6 germline mutation presented with a full blown polyposis coli. In conclusion, these data would support the notion that abrogation of both MSH6 DNA mismatch repair and base repair might be mutually exclusive in humans.
van Puijenbroek
Marjo
M
Department of Pathology, Leiden University Medical Center, Building L1Q, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
Nielsen
Maartje
M
Reinards
Tjitske H C M
TH
Weiss
Marjan M
MM
Wagner
Anja
A
Hendriks
Yvonne M C
YM
Vasen
Hans F A
HF
Tops
Carli M J
CM
Wijnen
Juul
J
van Wezel
Tom
T
Hes
Frederik J
FJ
Morreau
Hans
H
D000328:Adult; D000368:Aged; D020137:Base Pair Mismatch / Q000235:genetics; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics* / Q000473:pathology; D045647:DNA Glycosylases / Q000235:genetics*; D053843:DNA Mismatch Repair; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D018095:Germ-Line Mutation / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D016609:Neoplasms, Second Primary / Q000235:genetics*; D009426:Netherlands; D010375:Pedigree; D019683:Penetrance
D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; D045647:DNA Glycosylases