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Analysis of 108 patients with endometrial carcinoma using the PROMISE classification and additional genetic analyses for MMR-D.
Gynecol Oncol. 2020 04; 157(1):245-251.GO

Abstract

OBJECTIVES

To apply the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) to a consecutive series of endometrial cancer (EC) patients diagnosed at a tertiary referral center and assign EC specimens to one of four molecular subgroups using immunohistochemistry (IHC) for p53/mismatch repair protein expression and sequencing for Polymerase Epsilon Exonuclease Domain Mutations (POLE-EDM). Mismatch Repair Deficient (MMR-D) cases were more thoroughly investigated to identify underlying somatic or germline genetic defects.

METHODS

Hundred-and eight consecutive endometrial cancer patients, diagnosed between March 2017 and April 2019, were subjected to immunohistochemical and molecular analysis, according to ProMisE. IHC for p53 and the mismatch repair proteins (MLH1, PMS2, MSH6 and PMS2) was performed. All patients were also tested for POLE-EDM by Sanger sequencing. In addition, tumor and corresponding normal tissue of cases with abnormal MMR IHC were tested by PCR for microsatellite instability (MSI) (MSI analysis system, Promega). Hypermethylation of MLH1 promotor was tested with (methylation specific) multiplex ligation dependent probe amplification. MMR-D cases were subjected to germline mutation analysis of the mismatch repair genes, using next generation sequencing on MiSeq (Illumina) with the BRCA Hereditary Cancer MASTR Plus, (Multiplicom/Agilent), RNA mutation analysis and MLPA.

RESULTS

FIGO classification was stage IA (n = 54), IB (n = 22) II(n = 8), III(n = 18) and IV(n = 6). Of the 33 patients with MMR-D on IHC (31%), 26 showed MLH1 promotor hypermethylation as the probable cause of MMR-D. The remaining 7 patients without MLH1 promotor hypermethylation were referred for germline analysis of Lynch syndrome. Six patients carried a pathogenic germline mutation in one of the mismatch repair genes: MSH6(n = 3), PMS2(n = 1), MLH1(n = 1) and MSH2 (n = 1). Pathogenic POLE-EDM were identified in 7 (6%) patients. Multiple molecular features (POLE-EDM + MMR-D or POLE-EDM + p53 abnormal) were observed in 4 patients (4%). A high concordance between MMR-D and microsatellite instability was observed in our cohort. In cases of a genetic defect in the MMR genes, we do note a large proportion of cases exhibiting microsatellite instability. On the contrary a hypermutation state, as seen in POLE EDM, does not result in accompanied phenotypic changes in MSI status.

CONCLUSION

The ProMisE classification proved to be an efficient and easily implementable system. Future research should elucidate the precise biological and prognostic meaning of the cases with multiple molecular markers.

Authors+Show Affiliations

Department of Gynaecology and Obstetrics, Division of Gynaecological Oncology, University Hospitals Leuven, Leuven Cancer Institute, KU Leuven, Leuven, Belgium.Department of Pathology, University Hospitals Leuven, KU Leuven, Leuven, Belgium.Department of Gynaecology and Obstetrics, Division of Gynaecological Oncology, University Hospitals Leuven, Leuven Cancer Institute, KU Leuven, Leuven, Belgium.Department of Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium.Department of Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium.Department of Gynaecology and Obstetrics, Division of Gynaecological Oncology, University Hospitals Leuven, Leuven Cancer Institute, KU Leuven, Leuven, Belgium.Department of Gynaecology and Obstetrics, Division of Gynaecological Oncology, University Hospitals Leuven, Leuven Cancer Institute, KU Leuven, Leuven, Belgium.Department of Gynaecology and Obstetrics, Division of Gynaecological Oncology, University Hospitals Leuven, Leuven Cancer Institute, KU Leuven, Leuven, Belgium.Department of Pathology, University Hospitals Leuven, KU Leuven, Leuven, Belgium.KU Leuven, Biostatistics and Statistical Bioinformatics Centre, Kapucijnenvoer 35 blok d - bus 700, 3000 Leuven, Belgium.Department of Gynaecology and Obstetrics, Division of Gynaecological Oncology, University Hospitals Leuven, Leuven Cancer Institute, KU Leuven, Leuven, Belgium. Electronic address: Ignace.vergote@uzleuven.be.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31980219

Citation

Timmerman, S, et al. "Analysis of 108 Patients With Endometrial Carcinoma Using the PROMISE Classification and Additional Genetic Analyses for MMR-D." Gynecologic Oncology, vol. 157, no. 1, 2020, pp. 245-251.
Timmerman S, Van Rompuy AS, Van Gorp T, et al. Analysis of 108 patients with endometrial carcinoma using the PROMISE classification and additional genetic analyses for MMR-D. Gynecol Oncol. 2020;157(1):245-251.
Timmerman, S., Van Rompuy, A. S., Van Gorp, T., Vanden Bempt, I., Brems, H., Van Nieuwenhuysen, E., Han, S. N., Neven, P., Victoor, J., Laenen, A., & Vergote, I. (2020). Analysis of 108 patients with endometrial carcinoma using the PROMISE classification and additional genetic analyses for MMR-D. Gynecologic Oncology, 157(1), 245-251. https://doi.org/10.1016/j.ygyno.2020.01.019
Timmerman S, et al. Analysis of 108 Patients With Endometrial Carcinoma Using the PROMISE Classification and Additional Genetic Analyses for MMR-D. Gynecol Oncol. 2020;157(1):245-251. PubMed PMID: 31980219.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Analysis of 108 patients with endometrial carcinoma using the PROMISE classification and additional genetic analyses for MMR-D. AU - Timmerman,S, AU - Van Rompuy,A S, AU - Van Gorp,T, AU - Vanden Bempt,I, AU - Brems,H, AU - Van Nieuwenhuysen,E, AU - Han,S N, AU - Neven,P, AU - Victoor,J, AU - Laenen,A, AU - Vergote,I, Y1 - 2020/01/21/ PY - 2019/10/29/received PY - 2020/01/06/revised PY - 2020/01/11/accepted PY - 2020/1/26/pubmed PY - 2020/10/7/medline PY - 2020/1/26/entrez KW - Endometrial cancer KW - Microsatellite instability KW - Molecular classification KW - ProMisE SP - 245 EP - 251 JF - Gynecologic oncology JO - Gynecol Oncol VL - 157 IS - 1 N2 - OBJECTIVES: To apply the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) to a consecutive series of endometrial cancer (EC) patients diagnosed at a tertiary referral center and assign EC specimens to one of four molecular subgroups using immunohistochemistry (IHC) for p53/mismatch repair protein expression and sequencing for Polymerase Epsilon Exonuclease Domain Mutations (POLE-EDM). Mismatch Repair Deficient (MMR-D) cases were more thoroughly investigated to identify underlying somatic or germline genetic defects. METHODS: Hundred-and eight consecutive endometrial cancer patients, diagnosed between March 2017 and April 2019, were subjected to immunohistochemical and molecular analysis, according to ProMisE. IHC for p53 and the mismatch repair proteins (MLH1, PMS2, MSH6 and PMS2) was performed. All patients were also tested for POLE-EDM by Sanger sequencing. In addition, tumor and corresponding normal tissue of cases with abnormal MMR IHC were tested by PCR for microsatellite instability (MSI) (MSI analysis system, Promega). Hypermethylation of MLH1 promotor was tested with (methylation specific) multiplex ligation dependent probe amplification. MMR-D cases were subjected to germline mutation analysis of the mismatch repair genes, using next generation sequencing on MiSeq (Illumina) with the BRCA Hereditary Cancer MASTR Plus, (Multiplicom/Agilent), RNA mutation analysis and MLPA. RESULTS: FIGO classification was stage IA (n = 54), IB (n = 22) II(n = 8), III(n = 18) and IV(n = 6). Of the 33 patients with MMR-D on IHC (31%), 26 showed MLH1 promotor hypermethylation as the probable cause of MMR-D. The remaining 7 patients without MLH1 promotor hypermethylation were referred for germline analysis of Lynch syndrome. Six patients carried a pathogenic germline mutation in one of the mismatch repair genes: MSH6(n = 3), PMS2(n = 1), MLH1(n = 1) and MSH2 (n = 1). Pathogenic POLE-EDM were identified in 7 (6%) patients. Multiple molecular features (POLE-EDM + MMR-D or POLE-EDM + p53 abnormal) were observed in 4 patients (4%). A high concordance between MMR-D and microsatellite instability was observed in our cohort. In cases of a genetic defect in the MMR genes, we do note a large proportion of cases exhibiting microsatellite instability. On the contrary a hypermutation state, as seen in POLE EDM, does not result in accompanied phenotypic changes in MSI status. CONCLUSION: The ProMisE classification proved to be an efficient and easily implementable system. Future research should elucidate the precise biological and prognostic meaning of the cases with multiple molecular markers. SN - 1095-6859 UR - https://www.unboundmedicine.com/medline/citation/31980219/Analysis_of_108_patients_with_endometrial_carcinoma_using_the_PROMISE_classification_and_additional_genetic_analyses_for_MMR_D_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0090-8258(20)30061-5 DB - PRIME DP - Unbound Medicine ER -