title: Genotype-phenotype comparison of German MLH1 and MSH2 mutation carriers clinically affected with Lynch syndrome: a report by the German HNPCC Consortium.
abstract: 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.
authors.affiliation: University Hospital, Heinrich-Heine-University, Institute of Human Genetics and Department of Surgery, Düsseldorf, Germany. goecke@uni-duesseldorf.de
authors.forename: Timm
authors.initials: T
authors.lastname: Goecke
authors.forename: Karsten
authors.initials: K
authors.lastname: Schulmann
authors.forename: Christoph
authors.initials: C
authors.lastname: Engel
authors.forename: Elke
authors.initials: E
authors.lastname: Holinski-Feder
authors.forename: Constanze
authors.initials: C
authors.lastname: Pagenstecher
authors.forename: Hans K
authors.initials: HK
authors.lastname: Schackert
authors.forename: Matthias
authors.initials: M
authors.lastname: Kloor
authors.forename: Erdmute
authors.initials: E
authors.lastname: Kunstmann
authors.forename: Holger
authors.initials: H
authors.lastname: Vogelsang
authors.forename: Gisela
authors.initials: G
authors.lastname: Keller
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Dietmaier
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Mangold
authors.forename: Nicolaus
authors.initials: N
authors.lastname: Friedrichs
authors.forename: Peter
authors.initials: P
authors.lastname: Propping
authors.forename: Stefan
authors.initials: S
authors.lastname: Krüger
authors.forename: Johannes
authors.initials: J
authors.lastname: Gebert
authors.forename: Wolff
authors.initials: W
authors.lastname: Schmiegel
authors.forename: Josef
authors.initials: J
authors.lastname: Rueschoff
authors.forename: Markus
authors.initials: M
authors.lastname: Loeffler
authors.forename: Gabriela
authors.initials: G
authors.lastname: Moeslein
mesh_terms: 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*
chemical_list: 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