title: Molecular analysis of familial endometrial carcinoma: a manifestation of hereditary nonpolyposis colorectal cancer or a separate syndrome?
abstract: OBJECTIVE
  Familial clustering of endometrial carcinoma (EC) may occur as part of hereditary nonpolyposis colorectal cancer (HNPCC), a multiorgan cancer syndrome with mismatch repair (MMR) deficiency. Clustering of EC alone, termed as familial site-specific EC, may constitute a separate entity. Because its genetic basis is unknown, our purpose was to characterize such families molecularly.
  
  
  METHODS
  Twenty-three families with site-specific EC were identified among 519 consecutive patients diagnosed with EC during 1986 to 1997. Tumor tissues were examined for MMR protein expression by immunohistochemical (IHC) analysis, and MMR genes pinpointed by IHC changes were screened for germline mutations by exon-by-exon sequencing, multiplex ligation-dependent probe amplification, and direct tests for mutations common in the population.
  
  
  RESULTS
  Among 33 ECs from 23 families, MLH1 protein was lost in seven tumors (21%), MSH2 together with MSH6 was lost in four tumors (12%), and MSH6 alone was lost in five tumors (15%). A truncating germline mutation in MSH6 (3261insC) was identified in one family and a likely pathogenic missense mutation in MSH2 (D603N) was identified in another family. Among the original 519 patients, nine (all with colon cancer in the family) were diagnosed with HNPCC at the outset-six with MLH1 and three with MSH2 mutations.
  
  
  CONCLUSIONS
  Our study gives a minimum overall frequency of 2.1% (11 of 519) for germline MMR defects ascertained through EC in the index patients. The fact that only two of 23 families with site-specific EC (8.7%) had germline mutations in MMR genes suggests another as yet unknown etiology in most families with site-specific EC.
authors.affiliation: Department of Medical Genetics, University of Helsinki, Helsinki, Finland.
authors.forename: Miina
authors.initials: M
authors.lastname: Ollikainen
authors.forename: Wael M
authors.initials: WM
authors.lastname: Abdel-Rahman
authors.forename: Anu-Liisa
authors.initials: AL
authors.lastname: Moisio
authors.forename: Annette
authors.initials: A
authors.lastname: Lindroos
authors.forename: Reetta
authors.initials: R
authors.lastname: Kariola
authors.forename: Irma
authors.initials: I
authors.lastname: Järvelä
authors.forename: Minna
authors.initials: M
authors.lastname: Pöyhönen
authors.forename: Ralf
authors.initials: R
authors.lastname: Butzow
authors.forename: Päivi
authors.initials: P
authors.lastname: Peltomäki
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002352:Carrier Proteins; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D016889:Endometrial Neoplasms / Q000235:genetics*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity / Q000235:genetics; D008745:Methylation; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D000074081:MutS Homolog 3 Protein; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D013577:Syndrome
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; C078444:MSH3 protein, human; D000074081:MutS Homolog 3 Protein; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein