title: Performance characteristics of screening strategies for Lynch syndrome in unselected women with newly diagnosed endometrial cancer who have undergone universal germline mutation testing.
abstract: BACKGROUND
  Immunohistochemistry (IHC) for mismatch repair protein expression, microsatellite instability (MSI) testing, tumor morphology, and family history were compared to determine which screening strategy is superior in identifying Lynch syndrome (LS) in unselected women with newly diagnosed endometrial cancer (EC) who have undergone universal germline mutation testing.
  
  
  METHODS
  A prospective cohort study was performed that recruited women with newly diagnosed EC. Participants completed a family history assessment with molecular characterization of EC with IHC and MSI testing and EC assessment for LS-associated morphologic features and underwent universal germline mutation testing for mutations in the mismatch repair pathway. The sensitivity, specificity, and positive and negative predictive values were compared between the screening strategies.
  
  
  RESULTS
  A total of 118 (65%) of 182 consecutive women with EC participated. Of these, 34 women (29%) had tumors that were IHC deficient and 27 women (23%; N = 117) had tumors that were positive for MSI. Twenty women (17%) met IHC criteria and 16 women (15.2%, N = 105) met family history criteria based on Ontario Ministry of Health Criteria for the genetic assessment for LS. Seven women (5.9%) had a germline mutation: 4 had MLH1 (mutL homolog 1), 2 had MSH6 (mutS homolog 6), and 1 had MSH2 (mutS homolog 2). IHC in women aged <60 years had the best performance characteristics, with a sensitivity of 100%, a specificity of 86.1%, a positive predictive value of 58.3%, and a negative predictive value of 100%. Family history and tumor morphology both had the lowest sensitivity at 71.4%. Overall tumor morphology had the poorest performance, with a specificity of 42.1%.
  
  
  CONCLUSIONS
  The mutation rate of 5.9% was higher than expected in this unselected cohort of women with EC. The superior screening strategy to identify women presenting with EC is universal IHC screening in women aged <60 years.
authors: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Princess Margaret Hospital/University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors: Sarah E
authors: SE
authors: Ferguson
authors: Melyssa
authors: M
authors: Aronson
authors: Aaron
authors: A
authors: Pollett
authors: Lua R
authors: LR
authors: Eiriksson
authors: Amit M
authors: AM
authors: Oza
authors: Steven
authors: S
authors: Gallinger
authors: Jordan
authors: J
authors: Lerner-Ellis
authors: Zahra
authors: Z
authors: Alvandi
authors: Marcus Q
authors: MQ
authors: Bernardini
authors: Helen J
authors: HJ
authors: MacKay
authors: Golnessa
authors: G
authors: Mojtahedi
authors: Alicia A
authors: AA
authors: Tone
authors: Christine
authors: C
authors: Massey
authors: Blaise A
authors: BA
authors: Clarke
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000150:complications / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics; D004252:DNA Mutational Analysis; D055088:Early Detection of Cancer / Q000379:methods*; D016889:Endometrial Neoplasms / Q000150:complications / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics; D005260:Female; D005820:Genetic Testing / Q000379:methods*; D018095:Germ-Line Mutation; D006801:Humans; D008875:Middle Aged; D011237:Predictive Value of Tests
keywords: Lynch syndrome; endometrial cancer; germline mutation testing; immunohistochemistry; mismatch repair