Adele Wong1, Chik Hong Kuick1, Wai Loong Wong2, Jill M Tham3, Sorsiah Mansor1, Eva Loh1, Sudhanshi Jain1, Nadkarni N Vikas4, Sze Huey Tan5, Sock Hoai Chan6, Shao Tzu Li6, Sung Hock Chew1, Wanjin Hong3, Joanne Ngeow7. 1. Department of Pathology and Laboratory Medicine, KK Women's and Children's Hospital, Singapore, 100 Bukit Timah Road, Singapore 229899, Singapore. 2. Department of Gynaecological Oncology, KK Women's and Children's Hospital, Singapore, 100 Bukit Timah Road, Singapore 229899, Singapore. 3. Protein Trafficking and Cancer Cell Biology, Institute of Molecular and Cell Biology, 61 Biopolis Drive, Singapore 138673, Singapore. 4. Centre for Quantitative Medicine, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore. 5. Division of Clinical Trials and Epidemiological Sciences, National Cancer Centre Singapore, 11 Hospital Drive, Singapore 169610, Singapore. 6. Cancer Genetics Service, Division of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Drive, Singapore 169610, Singapore. 7. 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.
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. CONCLUSION: 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.
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 POLD1patients, 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. CONCLUSION: 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: Carlos Parra-Herran; Jordan Lerner-Ellis; Bin Xu; Sam Khalouei; Dina Bassiouny; Matthew Cesari; Nadia Ismiil; Sharon Nofech-Mozes Journal: Mod Pathol Date: 2017-08-04 Impact factor: 7.842
Authors: Sara Imboden; Denis Nastic; Mehran Ghaderi; Filippa Rydberg; Tilman T Rau; Michael D Mueller; Elisabeth Epstein; Joseph W Carlson Journal: PLoS One Date: 2019-03-27 Impact factor: 3.240