title: Increased risk for hereditary nonpolyposis colorectal cancer-associated synchronous and metachronous malignancies in patients with microsatellite instability-positive endometrial carcinoma lacking MLH1 promoter methylation.
abstract: OBJECTIVE
  The aim of this study was to evaluate number and types of synchronous and metachronous malignancies in patients with endometrial carcinoma with and without microsatellite instability (MSI).
  
  
  METHODS
  From a series of 413 endometrial cancer patients, we identified 94 patients with MSI-positive (MSI+) cancers and grouped them by tumor MLH1 promoter methylation status. These 94 patients were matched by year of surgery to 94 patients with MSI-negative (MSI-) endometrial cancers from the same series. Medical records were reviewed for clinicopathologic information including rates and types of synchronous and metachronous malignancies. Hereditary nonpolyposis colorectal cancer (HNPCC)-associated second and third cancers were analyzed for MSI and MSH2, MSH6, and MLH1 expression for comparison with the corresponding endometrial cancers.
  
  
  RESULTS
  The MSI+ and MSI- cohorts were similar with regard to age, race, grade, and histology. Twenty-eight MSI+ endometrial cancers (29.8%) were MLH1 unmethylated. Rates of synchronous and metachronous cancers were also similar in the MSI+ and MSI- groups at 20 and 23%, respectively. However, patients with MSI+ MLH1 unmethylated endometrial cancers had an excess of HNPCC-associated second and third cancers compared with those with MSI+ MLH1 methylated and MSI- endometrial cancers (18% versus 4.5%, P = 0.034, and 2.1%, P = 0.002). Six of seven second tumors from 5 patients with MSI+ MLH1 unmethylated endometrial cancers showed concordant MSI and mismatch repair protein expression status.
  
  
  CONCLUSIONS
  Our observation that patients with MSI-positive MLH1 unmethylated endometrial carcinoma are at increased risk for HNPCC-associated synchronous and metachronous malignancies suggests inherited cancer susceptibility. These patients and their families may warrant more intense cancer surveillance.
authors.affiliation: Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Buttin
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Powell
authors.forename: David G
authors.initials: DG
authors.lastname: Mutch
authors.forename: Janet S
authors.initials: JS
authors.lastname: Rader
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Herzog
authors.forename: Randall K
authors.initials: RK
authors.lastname: Gibb
authors.forename: Phyllis
authors.initials: P
authors.lastname: Huettner
authors.forename: Tina Bocker
authors.initials: TB
authors.lastname: Edmonston
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Goodfellow
mesh_terms: D017668:Age of Onset; D000368:Aged; D015331:Cohort Studies; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D004247:DNA / Q000378:metabolism; D019175:DNA Methylation; D016889:Endometrial Neoplasms / Q000150:complications / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D018895:Microsatellite Repeats; D008875:Middle Aged; D008954:Models, Biological; D016609:Neoplasms, Second Primary / Q000235:genetics*; D011401:Promoter Regions, Genetic; D012306:Risk; D013629:Tamoxifen / Q000627:therapeutic use
chemical_list: D013629:Tamoxifen; D004247:DNA