Mismatch-repair deficiency, microsatellite instability, and lynch syndrome in ovarian cancer: A systematic review and meta-analysis

Cristina Mitric; Lina Salman; Lusine Abrahamyan; Soyoun Rachel Kim; Petros Pechlivanoglou; Kelvin K W Chan; Lilian T Gien; Sarah E Ferguson

doi:10.1016/j.ygyno.2022.12.008

Mismatch-repair deficiency, microsatellite instability, and lynch syndrome in ovarian cancer: A systematic review and meta-analysis

Gynecol Oncol. 2023 Mar:170:133-142. doi: 10.1016/j.ygyno.2022.12.008. Epub 2023 Jan 20.

Authors

Cristina Mitric¹, Lina Salman¹, Lusine Abrahamyan², Soyoun Rachel Kim³, Petros Pechlivanoglou⁴, Kelvin K W Chan⁵, Lilian T Gien⁶, Sarah E Ferguson⁷

Affiliations

¹ Division of Gynecologic Oncology, University Health Network and Sinai Health System, Toronto, Canada; Department of Obstetrics and Gynecology, University of Toronto, Toronto, Canada; Division of Gynecologic Oncology, Sunnybrook Health Sciences Centre, Toronto, Canada.
² Institute of Health Policy, Management and Evaluation (IHPME), University of Toronto, Toronto, Canada; Toronto General Hospital Research Institute, University Health Network, Toronto, Canada.
³ Division of Gynecologic Oncology, University Health Network and Sinai Health System, Toronto, Canada; Department of Obstetrics and Gynecology, University of Toronto, Toronto, Canada.
⁴ Institute of Health Policy, Management and Evaluation (IHPME), University of Toronto, Toronto, Canada.
⁵ Division of Medical Oncology, Sunnybrook Health Sciences Centre, Toronto, Canada; Department of Medicine, University of Toronto, Canada.
⁶ Department of Obstetrics and Gynecology, University of Toronto, Toronto, Canada; Division of Gynecologic Oncology, Sunnybrook Health Sciences Centre, Toronto, Canada; Institute of Health Policy, Management and Evaluation (IHPME), University of Toronto, Toronto, Canada.
⁷ Division of Gynecologic Oncology, University Health Network and Sinai Health System, Toronto, Canada; Department of Obstetrics and Gynecology, University of Toronto, Toronto, Canada. Electronic address: sarah.ferguson@uhn.ca.

PMID: 36682091
DOI: 10.1016/j.ygyno.2022.12.008

Abstract

Objective: Investigating for mismatch repair protein deficiency (MMRd), microsatellite instability (MSI), and Lynch syndrome (LS) is widely accepted in endometrial cancer, but knowledge is limited on its value in epithelial ovarian cancer (EOC). The primary objective was to evaluate the prevalence of mismatch repair protein deficiency (MMRd), microsatellite instability (MSI)-high, and Lynch syndrome (LS) in epithelial ovarian cancer (EOC), as well as the diagnostic accuracy of LS screening tests. The secondary objective was to determine the prevalence of MMRd, MSI-high, and LS in synchronous ovarian endometrial cancer and in histological subtypes.

Methods: We systematically searched the MEDLINE, Epub Ahead of Print, MEDLINE In-Process and Other Non-Indexed Citations, Cochrane Central Register of Controlled Trials, and Embase databases. We included studies analysing MMR, MSI, and/or LS by sequencing.

Results: A total of 55 studies were included. The prevalence of MMRd, MSI-high, and LS in EOC was 6% (95% confidence interval (CI) 5-8%), 13% (95% CI 12-15%), and 2% (95% CI 1-3%) respectively. Hypermethylation was present in 76% of patients with MLH1 deficiency (95% CI 64-84%). The MMRd prevalence was highest in endometrioid (12%) followed by non-serous non-mucinous (9%) and lowest in serous (1%) histological subtypes. MSI-high prevalence was highest in endometrioid (12%) and non-serous non-mucinous (12%) and lowest in serous (9%) histological subtypes. Synchronous and endometrioid EOC had the highest prevalence of LS pathogenic variants at 7% and 3% respectively, with serous having lowest prevalence (1%). Synchronous ovarian and endometrial cancers had highest rates of MMRd (28%) and MSI-high (28%). Sensitivity was highest for IHC (91.1%) and IHC with MSI (92.8%), while specificity was highest for IHC with methylation (92.3%).

Conclusion: MMRd and germline LS testing should be considered for non-serous non-mucinous EOC, particularly for endometrioid.

Precis: The rates of mismatch repair deficiency, microsatellite instability high, and mismatch repair germline mutations are highest in endometrioid subtype and non-serous non-mucinous ovarian cancer. The rates are lowest in serous histologic subtype.

Keywords: DNA mismatch repair; Immunohistochemistry; Lynch syndrome; Microsatellite repeats; Ovarian neoplasms.

Publication types

Meta-Analysis
Systematic Review
Review

MeSH terms

Carcinoma, Endometrioid* / pathology
Carcinoma, Ovarian Epithelial
Colorectal Neoplasms, Hereditary Nonpolyposis* / genetics
DNA Mismatch Repair
Endometrial Neoplasms* / pathology
Female
Humans
Microsatellite Instability
MutL Protein Homolog 1 / genetics
Ovarian Neoplasms* / pathology
Protein Deficiency*

Substances

MutL Protein Homolog 1

Supplementary concepts

Turcot syndrome