title: A clinically applicable molecular-based classification for endometrial cancers.
abstract: BACKGROUND
  Classification of endometrial carcinomas (ECs) by morphologic features is inconsistent, and yields limited prognostic and predictive information. A new system for classification based on the molecular categories identified in The Cancer Genome Atlas is proposed.
  
  
  METHODS
  Genomic data from the Cancer Genome Atlas (TCGA) support classification of endometrial carcinomas into four prognostically significant subgroups; we used the TCGA data set to develop surrogate assays that could replicate the TCGA classification, but without the need for the labor-intensive and cost-prohibitive genomic methodology. Combinations of the most relevant assays were carried forward and tested on a new independent cohort of 152 endometrial carcinoma cases, and molecular vs clinical risk group stratification was compared.
  
  
  RESULTS
  Replication of TCGA survival curves was achieved with statistical significance using multiple different molecular classification models (16 total tested). Internal validation supported carrying forward a classifier based on the following components: mismatch repair protein immunohistochemistry, POLE mutational analysis and p53 immunohistochemistry as a surrogate for 'copy-number' status. The proposed molecular classifier was associated with clinical outcomes, as was stage, grade, lymph-vascular space invasion, nodal involvement and adjuvant treatment. In multivariable analysis both molecular classification and clinical risk groups were associated with outcomes, but differed greatly in composition of cases within each category, with half of POLE and mismatch repair loss subgroups residing within the clinically defined 'high-risk' group. Combining the molecular classifier with clinicopathologic features or risk groups provided the highest C-index for discrimination of outcome survival curves.
  
  
  CONCLUSIONS
  Molecular classification of ECs can be achieved using clinically applicable methods on formalin-fixed paraffin-embedded samples, and provides independent prognostic information beyond established risk factors. This pragmatic molecular classification tool has potential to be used routinely in guiding treatment for individuals with endometrial carcinoma and in stratifying cases in future clinical trials.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia and BC Cancer Agency, 509-2660 Oak Street, Vancouver, British Columbia, Canada V6H 3Z6.
authors.forename: A
authors.initials: A
authors.lastname: Talhouk
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia and BC Cancer Agency, 509-2660 Oak Street, Vancouver, British Columbia, Canada V6H 3Z6.
authors.forename: M K
authors.initials: MK
authors.lastname: McConechy
authors.affiliation: Genetic Pathology Evaluation Centre, Department of Pathology and Laboratory Medicine, University of British Columbia, 509-2660 Oak Street, Vancouver, British Columbia, Canada V6H 3Z6.
authors.forename: S
authors.initials: S
authors.lastname: Leung
authors.affiliation: 1] Department of Pathology and Laboratory Medicine, University of British Columbia and BC Cancer Agency, 509-2660 Oak Street, Vancouver, British Columbia, Canada V6H 3Z6 [2] Department of Laboratory Services, Royal Victoria Regional Health Centre, 201 Georgian Drive, Barrie, Ontario, Canada L4M 6M2.
authors.forename: H H
authors.initials: HH
authors.lastname: Li-Chang
authors.affiliation: Department of Gynecology and Obstetrics, Division of Gynecologic Oncology, University of British Columbia, 2775 Laurel St. 6th Floor, Vancouver, British Columbia, Canada V5Z 1M9.
authors.forename: J S
authors.initials: JS
authors.lastname: Kwon
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia and BC Cancer Agency, 509-2660 Oak Street, Vancouver, British Columbia, Canada V6H 3Z6.
authors.forename: N
authors.initials: N
authors.lastname: Melnyk
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia and BC Cancer Agency, 509-2660 Oak Street, Vancouver, British Columbia, Canada V6H 3Z6.
authors.forename: W
authors.initials: W
authors.lastname: Yang
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia and BC Cancer Agency, 509-2660 Oak Street, Vancouver, British Columbia, Canada V6H 3Z6.
authors.forename: J
authors.initials: J
authors.lastname: Senz
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia and BC Cancer Agency, 509-2660 Oak Street, Vancouver, British Columbia, Canada V6H 3Z6.
authors.forename: N
authors.initials: N
authors.lastname: Boyd
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia and BC Cancer Agency, 509-2660 Oak Street, Vancouver, British Columbia, Canada V6H 3Z6.
authors.forename: A N
authors.initials: AN
authors.lastname: Karnezis
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia and BC Cancer Agency, 509-2660 Oak Street, Vancouver, British Columbia, Canada V6H 3Z6.
authors.forename: D G
authors.initials: DG
authors.lastname: Huntsman
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia and BC Cancer Agency, 509-2660 Oak Street, Vancouver, British Columbia, Canada V6H 3Z6.
authors.forename: C B
authors.initials: CB
authors.lastname: Gilks
authors.affiliation: Department of Gynecology and Obstetrics, Division of Gynecologic Oncology, University of British Columbia, 2775 Laurel St. 6th Floor, Vancouver, British Columbia, Canada V5Z 1M9.
authors.forename: J N
authors.initials: JN
authors.lastname: McAlpine
mesh_terms: D000368:Aged; D004257:DNA Polymerase II / Q000235:genetics; D016889:Endometrial Neoplasms / Q000145:classification* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D005260:Female; D016158:Genes, p53; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics; D000075223:Poly-ADP-Ribose Binding Proteins; D012189:Retrospective Studies
chemical_list: D000075223:Poly-ADP-Ribose Binding Proteins; D004257:DNA Polymerase II; C119525:POLE protein, human; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human