Genotype-phenotype comparison of German MLH1 and MSH2 mutation carriers clinically affected with Lynch syndrome: a report by the German HNPCC Consortium.
OBJECTIVE
Lynch syndrome is linked to germline mutations in mismatch repair genes. We analyzed the genotype-phenotype correlations in the largest cohort so far reported.


METHODS
Following standard algorithms, we identified 281 of 574 unrelated families with deleterious germline mutations in MLH1 (n = 124) or MSH2 (n = 157). A total of 988 patients with 1,381 cancers were included in this analysis.


RESULTS
We identified 181 and 259 individuals with proven or obligatory and 254 and 294 with assumed MLH1 and MSH2 mutations, respectively. Age at diagnosis was younger both in regard to first cancer (40 v 43 years; P < .009) and to first colorectal cancer (CRC; 41 v 44 years; P = .004) in MLH1 (n = 435) versus MSH2 (n = 553) mutation carriers. In both groups, rectal cancers were remarkably frequent, and the time span between first and second CRC was smaller if the first primary occurred left sided. Gastric cancer was the third most frequent malignancy occurring without a similarly affected relative in most cases. All prostate cancers occurred in MSH2 mutation carriers.


CONCLUSIONS
The proportion of rectal cancers and shorter time span to metachronous cancers indicates the need for a defined treatment strategy for primary rectal cancers in hereditary nonpolyposis colorectal cancer patients. Male MLH1 mutation carriers require earlier colonoscopy beginning at age 20 years. We propose regular gastric surveillance starting at age 35 years, regardless of the familial occurrence of this cancer. The association of prostate cancer with MSH2 mutations should be taken into consideration both for clinical and genetic counseling practice.
Goecke
Timm
T
University Hospital, Heinrich-Heine-University, Institute of Human Genetics and Department of Surgery, Düsseldorf, Germany. goecke@uni-duesseldorf.de
Schulmann
Karsten
K
Engel
Christoph
C
Holinski-Feder
Elke
E
Pagenstecher
Constanze
C
Schackert
Hans K
HK
Kloor
Matthias
M
Kunstmann
Erdmute
E
Vogelsang
Holger
H
Keller
Gisela
G
Dietmaier
Wolfgang
W
Mangold
Elisabeth
E
Friedrichs
Nicolaus
N
Propping
Peter
P
Krüger
Stefan
S
Gebert
Johannes
J
Schmiegel
Wolff
W
Rueschoff
Josef
J
Loeffler
Markus
M
Moeslein
Gabriela
G
D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000367:Age Factors; D002352:Carrier Proteins / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D005260:Female; D005838:Genotype; D018095:Germ-Line Mutation; D005858:Germany; D006579:Heterozygote; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D018895:Microsatellite Repeats; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D009154:Mutation; D016609:Neoplasms, Second Primary / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics*; D010641:Phenotype; D012004:Rectal Neoplasms / Q000235:genetics; D044465:White People / Q000235:genetics*
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein