title: Tumor mismatch repair immunohistochemistry and DNA MLH1 methylation testing of patients with endometrial cancer diagnosed at age younger than 60 years optimizes triage for population-level germline mismatch repair gene mutation testing.
abstract: OBJECTIVE
  Clinicopathologic data from a population-based endometrial cancer cohort, unselected for age or family history, were analyzed to determine the optimal scheme for identification of patients with germline mismatch repair (MMR) gene mutations.
  
  
  METHODS
  Endometrial cancers from 702 patients recruited into the Australian National Endometrial Cancer Study (ANECS) were tested for MMR protein expression using immunohistochemistry (IHC) and for MLH1 gene promoter methylation in MLH1-deficient cases. MMR mutation testing was performed on germline DNA of patients with MMR-protein deficient tumors. Prediction of germline mutation status was compared for combinations of tumor characteristics, age at diagnosis, and various clinical criteria (Amsterdam, Bethesda, Society of Gynecologic Oncology, ANECS).
  
  
  RESULTS
  Tumor MMR-protein deficiency was detected in 170 (24%) of 702 cases. Germline testing of 158 MMR-deficient cases identified 22 truncating mutations (3% of all cases) and four unclassified variants. Tumor MLH1 methylation was detected in 99 (89%) of 111 cases demonstrating MLH1/PMS2 IHC loss; all were germline MLH1 mutation negative. A combination of MMR IHC plus MLH1 methylation testing in women younger than 60 years of age at diagnosis provided the highest positive predictive value for the identification of mutation carriers at 46% versus ≤ 41% for any other criteria considered.
  
  
  CONCLUSIONS
  Population-level identification of patients with MMR mutation-positive endometrial cancer is optimized by stepwise testing for tumor MMR IHC loss in patients younger than 60 years, tumor MLH1 methylation in individuals with MLH1 IHC loss, and germline mutations in patients exhibiting loss of MSH6, MSH2, or PMS2 or loss of MLH1/PMS2 with absence of MLH1 methylation.
authors: Daniel D. Buchanan, Yen Y. Tan, Michael D. Walsh, Mark Clendenning, Alexander M. Metcalf, Kaltin Ferguson, Sven T. Arnold, Bryony A. Thompson, Felicity A. Lose, Michael T. Parsons, Rhiannon J. Walters, Sally-Ann Pearson, Joanne P. Young, Penelope M. Webb, and Amanda B. Spurdle, QIMR Berghofer Medical Research Institute, Herston; Yen Y. Tan and Andreas Obermair, University of Queensland School of Medicine, Brisbane; Margaret Cummings, University of Queensland Centre for Clinical Research, Herston, Queensland; Martin K. Oehler, Royal Adelaide Hospital, Adelaide, South Australia; Michael A. Quinn, Royal Women's Hospital, Melbourne, Victoria; Judy A. Kirk, Westmead Institute for Cancer Research, Westmead Millennium Institute, University of Sydney, Sydney, New South Wales; Colin J. Stewart, King Edward Memorial Hospital, Perth, Western Australia, Australia; and Penelope B. Blomfield, Royal Hobart Hospital, Hobart, Tasmania.
authors: Daniel D
authors: DD
authors: Buchanan
authors: Yen Y
authors: YY
authors: Tan
authors: Michael D
authors: MD
authors: Walsh
authors: Mark
authors: M
authors: Clendenning
authors: Alexander M
authors: AM
authors: Metcalf
authors: Kaltin
authors: K
authors: Ferguson
authors: Sven T
authors: ST
authors: Arnold
authors: Bryony A
authors: BA
authors: Thompson
authors: Felicity A
authors: FA
authors: Lose
authors: Michael T
authors: MT
authors: Parsons
authors: Rhiannon J
authors: RJ
authors: Walters
authors: Sally-Ann
authors: SA
authors: Pearson
authors: Margaret
authors: M
authors: Cummings
authors: Martin K
authors: MK
authors: Oehler
authors: Penelope B
authors: PB
authors: Blomfield
authors: Michael A
authors: MA
authors: Quinn
authors: Judy A
authors: JA
authors: Kirk
authors: Colin J
authors: CJ
authors: Stewart
authors: Andreas
authors: A
authors: Obermair
authors: Joanne P
authors: JP
authors: Young
authors: Penelope M
authors: PM
authors: Webb
authors: Amanda B
authors: AB
authors: Spurdle
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001315:Australia; D015331:Cohort Studies; D019175:DNA Methylation; D053843:DNA Mismatch Repair / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D055088:Early Detection of Cancer / Q000379:methods; D016889:Endometrial Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005820:Genetic Testing / Q000379:methods; D018095:Germ-Line Mutation; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D011159:Population Surveillance / Q000379:methods
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; C497172:MSH2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D045643:DNA Repair Enzymes