title: Mutation spectrum of POLE and POLD1 mutations in South East Asian women presenting with grade 3 endometrioid endometrial carcinomas.
abstract: OBJECTIVE
  Somatic POLE mutations have been found in a subset of endometrioid ECs particularly in FIGO grade 3 tumors while POLD1 mutations are reportedly rare in ECs. While it has been suggested that POLE mutation confers good prognosis, the data remains conflicting. Our study aims to determine the mutation spectrum of somatic and germline POLE and POLD1 gene mutations in South East Asian (SEA) women with FIGO grade 3 endometrioid ECs.
  
  
  METHODS
  Forty-seven patients diagnosed with FIGO grade 3 endometrioid EC, diagnosed between 2009 and 2013 were included. Next generation sequencing (NGS) using formalin fixed embedded (FFPE) tissue was utilized to sequence tumor and matched normal tissue. Tumors were also assessed for other clinicopathologic and microsatellite status phenotype. Survival curves for pathogenic somatic POLE mutated and wild-type tumors were estimated by Kaplan-Meier method.
  
  
  RESULTS
  Pathogenic POLE (somatic or germline) and POLD1 (germline) mutations were detected in 29.7% (14/47) and 4.3% (2/47) patients, respectively. Three pathogenic germline mutations; one POLE and two POLD1 mutations were novel. Pathogenic germline and somatic POLE and POLD1 mutations were associated with 100% recurrence free survival. In contrast, among the wild-type POLE and POLD1 patients, 25% (8/32) had recurrence with 15.6% (5/32) subsequently dying of the disease. Somatic POLE-mutated tumors were more commonly associated with microsatellite stable (MSS) ECs (83% vs 49%; p=0.04) and peritumoral lymphocytic infiltration (75% vs 42%; p=0.05). All tumors with tumoral infiltrating lymphocytes exhibited peritumoral lymphocytic infiltrate but not vice versa.
  
  
  CONCLUSIONS
  Mutations in POLE and POLD1 in SEA women with grade 3 endometrioid ECs are associated with improved recurrence free survival. Notably, germline mutations in either POLE/POLD1 were seen in 8.5% of patients who will require appropriate genetic counseling regarding risk of developing colorectal carcinoma and on the need for additional surveillance for colonic changes. MSS and peritumoral lymphocytic infiltration may be useful histological features for distinguishing POLE mutated grade 3 endometrioid ECs.
authors.affiliation: Department of Pathology and Laboratory Medicine, KK Women's and Children's Hospital, Singapore, 100 Bukit Timah Road, Singapore 229899, Singapore.
authors.forename: Adele
authors.initials: A
authors.lastname: Wong
authors.affiliation: Department of Pathology and Laboratory Medicine, KK Women's and Children's Hospital, Singapore, 100 Bukit Timah Road, Singapore 229899, Singapore.
authors.forename: Chik Hong
authors.initials: CH
authors.lastname: Kuick
authors.affiliation: Department of Gynaecological Oncology, KK Women's and Children's Hospital, Singapore, 100 Bukit Timah Road, Singapore 229899, Singapore.
authors.forename: Wai Loong
authors.initials: WL
authors.lastname: Wong
authors.affiliation: Protein Trafficking and Cancer Cell Biology, Institute of Molecular and Cell Biology, 61 Biopolis Drive, Singapore 138673, Singapore.
authors.forename: Jill M
authors.initials: JM
authors.lastname: Tham
authors.affiliation: Department of Pathology and Laboratory Medicine, KK Women's and Children's Hospital, Singapore, 100 Bukit Timah Road, Singapore 229899, Singapore.
authors.forename: Sorsiah
authors.initials: S
authors.lastname: Mansor
authors.affiliation: Department of Pathology and Laboratory Medicine, KK Women's and Children's Hospital, Singapore, 100 Bukit Timah Road, Singapore 229899, Singapore.
authors.forename: Eva
authors.initials: E
authors.lastname: Loh
authors.affiliation: Department of Pathology and Laboratory Medicine, KK Women's and Children's Hospital, Singapore, 100 Bukit Timah Road, Singapore 229899, Singapore.
authors.forename: Sudhanshi
authors.initials: S
authors.lastname: Jain
authors.affiliation: Centre for Quantitative Medicine, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore.
authors.forename: Nadkarni N
authors.initials: NN
authors.lastname: Vikas
authors.affiliation: Division of Clinical Trials and Epidemiological Sciences, National Cancer Centre Singapore, 11 Hospital Drive, Singapore 169610, Singapore.
authors.forename: Sze Huey
authors.initials: SH
authors.lastname: Tan
authors.affiliation: Cancer Genetics Service, Division of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Drive, Singapore 169610, Singapore.
authors.forename: Sock Hoai
authors.initials: SH
authors.lastname: Chan
authors.affiliation: Cancer Genetics Service, Division of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Drive, Singapore 169610, Singapore.
authors.forename: Shao Tzu
authors.initials: ST
authors.lastname: Li
authors.affiliation: Department of Pathology and Laboratory Medicine, KK Women's and Children's Hospital, Singapore, 100 Bukit Timah Road, Singapore 229899, Singapore.
authors.forename: Sung Hock
authors.initials: SH
authors.lastname: Chew
authors.affiliation: Protein Trafficking and Cancer Cell Biology, Institute of Molecular and Cell Biology, 61 Biopolis Drive, Singapore 138673, Singapore.
authors.forename: Wanjin
authors.initials: W
authors.lastname: Hong
authors.affiliation: Cancer Genetics Service, Division of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Drive, Singapore 169610, Singapore; Oncology Academic Clinical Program, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore. Electronic address: Joanne.Ngeow.Yuen.Yie@singhealth.com.sg.
authors.forename: Joanne
authors.initials: J
authors.lastname: Ngeow
mesh_terms: D018269:Carcinoma, Endometrioid / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D004257:DNA Polymerase II / Q000235:genetics*; D004258:DNA Polymerase III / Q000235:genetics*; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D005260:Female; D006801:Humans; D009154:Mutation; D060787:Neoplasm Grading; D000075223:Poly-ADP-Ribose Binding Proteins
chemical_list: D000075223:Poly-ADP-Ribose Binding Proteins; C434055:POLD1 protein, human; D004257:DNA Polymerase II; D004258:DNA Polymerase III; C119525:POLE protein, human
keywords: Asian; Endometrial cancer; Germline; POLD1; POLE