Journal of Oncology
Volume 2020 (2020), Article ID 1807929, 17 pages
https://doi.org/10.1155/2020/1807929

Review Article

Epidemiology of Microsatellite Instability High (MSI-H) and Deficient Mismatch Repair (dMMR) in Solid Tumors: A Structured Literature Review

Maria Lorenzi,¹ Mayur Amonkar,² Jacky Zhang,¹ Shivani Mehta,¹ and Kai-Li Liaw²

¹Precision Xtract, Oakland, CA, USA
²Merck & Co, Inc., North Wales, PA, USA

Correspondence should be addressed to Maria Lorenzi; maria.lorenzi@precisionxtract.com

Received 9 October 2019; Revised 23 January 2020; Accepted 28 January 2020; Published 9 March 2020

Academic Editor: Giandomenico Roviello

Copyright © 2020 Maria Lorenzi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

Background. Given limited data on the epidemiology of MSI-H and dMMR across solid tumors (except colorectal cancer (CRC)), the current study was designed to estimate their prevalence. Materials and Methods. A structured literature review identified English language publications that used immunohistochemistry (IHC) or polymerase chain replication (PCR) techniques. Publications were selected for all tumors except CRC using MEDLINE, EMBASE, and Cochrane databases and key congresses; CRC and pan-tumor genomic publications were selected through a targeted review. Meta-analysis was performed to estimate pooled prevalence of MSI-H/dMMR across all solid tumors and for selected tumor types. Where possible, prevalence within tumor types was estimated by disease stages. Results. Of 1,176 citations retrieved, 103 and 48 publications reported prevalence of MSI-H and dMMR, respectively. Five pan-tumor genomic studies supplemented the evidence base. Tumor types with at least 5 publications included gastric (n = 39), ovarian (n = 23), colorectal (n = 20), endometrial (n = 53), esophageal (n = 6), and renal cancer (n = 8). Overall MSI-H prevalence (with 95% CI) across 25 tumors was based on 90 papers (28,213 patients) and estimated at 14% (10%–19%). MSI-H prevalence among Stage 1/2 cancers was estimated at 15% (8%–23%); Stages 3 and 4 prevalence was estimated at 9% (3%–17%) and 3% (1%–7%), respectively. Overall, dMMR prevalence across 13 tumor types (based on 54 papers and 20,383 patients) was estimated at 16% (11%–22%). Endometrial cancer had the highest pooled MSI-H and dMMR prevalence (26% and 25% all stages, respectively). Conclusions. This is the first comprehensive attempt to report pooled prevalence estimates of MSI-H/dMMR across solid tumors based on published data. Prevalence determined by IHC and PCR was generally comparable, with some variations by cancer type. Late-stage prevalence was lower than that in earlier stages.

1. Introduction

DNA mismatch repair (MMR) is a process that plays a key role in maintaining genomic stability by recognizing and repairing base-base mismatches and insertion/deletion of DNA generated during replication and recombination. Defects in MMR are associated with genome-wide instability and the progressive accumulation of mutations, especially regions of simple repetitive DNA sequences known as microsatellites, resulting in MSI. MSI-high (MSI-H) is a hypermutable phenotype that allows mutations to be accumulated rapidly, resulting in tumor development via the selection of cancer-promoting mutations in pathways that are responsible for maintaining functional DNA repair, apoptosis, and cell growth.

To test for MSI-H and dMMR statuses in solid tumors, polymerase chain reaction (PCR) and immunohistochemistry (IHC) methods have been widely accepted as respective testing platforms for these biomarkers. The PCR method uses a panel of microsatellite markers to detect size shifts in different loci. The IHC method uses a more direct test to determine the presence of MMR proteins. A tumor is typically classified as MSI-H if shifts are detected in at least 2 of 5 loci using the PCR method and dMMR if at least one MMR protein is absent using the IHC method. The use of NCI (BAT-25, BAT-26, D2S123, D5S346, and D17S250) [1] and Promega (BAT-25, BAT-26, NR-21, NR-24, and MONO-27) [2] panels in PCR and the use of MLH1, MSH2, MSH6, and PMS2 proteins in IHC are considered the gold standard approaches [3, 4, 5].

Among patients diagnosed with metastatic cancer and MSI-H or dMMR, prognosis is generally poor [6]. Recently, evidence has mounted on the benefits of immunotherapy, especially with checkpoint inhibitors such as pembrolizumab on MSI-H/dMMR tumors [7, 8, 9]. Historically, most patients with a solid tumor diagnosis were not tested for MSI; a better understanding of MSI-H and dMMR prevalence can help estimate the size of the potential target population. To provide reliable estimates of MSI-H and dMMR prevalence, a comprehensive structured literature review was conducted to gather relevant and recent evidence on the epidemiology of MSI-H and dMMR across multiple tumors. When sufficient data were available, meta-analysis was performed to estimate the prevalence of MSI-H and dMMR tumors overall, across individual tumor types, and by stage of disease.

2. Methods

Study eligibility criteria outlined in Table 1 guided study identification and selection for the literature review.

Table 1: Eligibility criteria.

Criteria
Description

Population
Patients with solid tumors

Outcomes
(i) Assessment of prevalence of MSI-H (using NCI marker panel: BAT25, BAT26, D2S123, D5S346, and D17S250) or Promega marker panel: BAT25, BAT26, NR21, NR24, and MONO27) and/or dMMR (by immunohistochemistry for all four MMR proteins: MLH1, MSH2, MSH6, and PMS2) overall, by tumor type, by histology subtype, by stage, by treatment, by region, by country, and by gender

(a) Proportion of MSI as defined in study (e.g., MSI-H, MSI-L, and MSI-S)

(b) Proportion of dMMR and pMMR as defined in study

(ii) Survival rates by MSI-H/dMMR status overall, by stage and by tumor type

(a) Overall survival (OS) and progression-free survival (PFS)

(1) Hazard ratios along with 95% confidence interval (CI)

(2) Median (in months) and 95% CI

(iii) Objective response rate (ORR), defined as complete response (CR) or partial response (PR)

(iv) Disease control rate, defined as CR, PR, or stable disease

Study design
(i) Prospective and retrospective cohort studies

(ii) Randomized controlled trials

(iii) Case-control studies

(iv) Cross-sectional studies

(v) Controlled and uncontrolled longitudinal studies (cohorts or case series)

Language
Only studies published in English will be included

Time
No time limit

Abbreviations: dMMR, deficient mismatch repair; MLH1, MutL homolog 1; MSH2, MutS protein homolog 2; MSH6, MutS homolog 6; MSI-H, microsatellite instability high; MSI-L, microsatellite instability low; MSI-S/MSS, microsatellite stable; NCI, National Cancer Institute; pMMR, proficient mismatch repair; PMS2, postmeiotic segregation increased 2.

2.1. Literature Review

Relevant studies were identified by searching the following through the Ovid platform: Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica database (Embase), and Cochrane Central Register of Controlled Trials. Predefined search strategies were executed on October 26th, 2017. Study design filters recommended by the Scottish Intercollegiate Guidelines Network (SIGN) were used. Population terms were adapted from published research [9]; no intervention or comparator terms were used.

Systematic reviews, meta-analyses, and key narrative reviews of interest were identified via hand searching. Targeted hand searches were conducted to identify colorectal cancer (CRC) studies and pan-tumor genomic studies reporting MSI-H/dMMR prevalence. Studies for all solid tumors except CRC were selected through database searches; CRC and pan-tumor genomic studies were selected through a targeted review. One reviewer reviewed all abstracts and proceedings identified through database searches and the targeted review according to the selection criteria. Studies identified as potentially eligible during abstract screening were screened in full-text by the same reviewer. The full-text studies identified at this stage were included for data extraction. The process of study identification and selection are summarized with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagrams [10].

One reviewer extracted data on study characteristics, interventions, patient characteristics, and outcomes from included studies. The second reviewer independently extracted data from a random 10% of the publications, reconciled the data, and determined the error rate and missing data rate of data extraction by the first reviewer. The error rate (number of cells with incorrect data/number of cells with text) was 2.9%, and the missing data rate (number of cells with missing data/number of blank cells) was 1.2% (an error rate greater than 5% would have triggered extraction of a further 10% of publications by the second reviewer). All errors discovered through this process were corrected. Potential publication biases were checked through funnel plots. Data were stored and managed in a Microsoft Excel workbook.

Only studies that used PCR or IHC methods were included in this review. To increase validity of the meta-analysis, only studies that used NCI (BAT-25, BAT-26, D2S123, D5S346, and D17S250) or Promega (BAT-25, BAT-26, NR-21, NR-24, and MONO-27) panels in PCR and MLH1, MSH2, MSH6, and PMS2 proteins in IHC were included in the meta-analysis. The only exceptions were pan-tumor genomic studies, which used large-scale sequencing techniques to test for the presence of only the MLH1 gene. These genomic studies were included in sensitivity analyses to detect their potential effect on the meta-analysis.

Prevalence of MSI-H and/or dMMR was extracted overall, by tumor type, histology, stage, and country.

2.2. Meta-Analysis

Reported proportions were transformed according to the Freeman–Tukey variant of the arcsine square root (double arcsine) transformed proportion [11]. The pooled proportion was calculated by back-transforming the weighted mean of the transformed proportions, using the DerSimonian–Laird random effects model [12].

Meta-analysis was conducted using the metafor package version 1.9-9 in R 3.4.0. Weighting of each tumor type was based on cancer-specific prevalence estimates provided by the GLOBOCAN 2012 database from the World Health Organization [13]. For rare tumor types, when data were unavailable on the GLOBOCAN database, other databases and peer-reviewed publications were referenced [14–18]. Each tumor type was assigned a weight based on its general prevalence; in cases where two or more studies were included for a given tumor type, weight was split proportionally between studies based on the sample size.

3. Results

The study selection process for identification of studies reporting MSI-H or dMMR prevalence in the structured literature review is outlined in Figure 1. Overall, 1,176 publications were assessed for eligibility; a total of 156 full-text publications were included based on the structured and targeted literature review.

Figure 1: PRISMA study flow diagram of included studies for the structured literature review.

3.1. Feasibility Assessment of Meta-Analysis

References for included studies can be found in Tables 2–4. Of the 156 included full-text publications, 103 studies reported prevalence of any MSI status, which included MSI-H, MSI-L (microsatellite instability-low), and MSS (microsatellite stable). Forty-eight studies reported prevalence of dMMR according to the eligibility criteria. Five large pan-tumor genomic studies reported MSI-H status across multiple solid tumors.

Table 2: References—MSI studies.

Author
Year
Title
Journal
Tumor type

Abraham
2002
Microsatellite instability in intraductal papillary neoplasms of the biliary tract
Nature
Pancreatic

Adduri
2014
P53 nuclear stabilization is associated with FHIT loss and younger age of onset in squamous cell carcinoma of oral tongue
BMC Clinical Pathology
Oral cavity

Akbari
2017
Correlation between germline mutations in MMR genes and microsatellite instability in ovarian cancer specimens
Familial Cancer
Ovarian

Alldinger
2007
Microsatellite instability in Ewing tumor is not associated with loss of mismatch repair protein expression
Journal of Cancer Research and Clinical Oncology
Ewing sarcoma

Altavilla
2010
Microsatellite instability and hMLH1 and hMSH2 expression in renal tumors
Oncology Reports
Renal

Amaki-Takao
2016
Colorectal cancer with BRAF D594G mutation is not associated with microsatellite instability or poor prognosis
Oncology (Switzerland)
Colorectal

An
2005
Prognostic significance of CpG island methylator phenotype and microsatellite instability in gastric carcinoma
Clinical Cancer Research
Gastric

An
2012
Microsatellite instability in sporadic gastric cancer: its prognostic role and guidance for 5-fu based chemotherapy after r0 resection
International Journal of Cancer
Gastric

Aparicio
2013
Small bowel adenocarcinoma phenotyping, a clinicobiological prognostic study
British Journal of Cancer
Small bowel

Aysal
2012
Ovarian endometrioid adenocarcinoma: incidence and clinical significance of the morphologic and immunohistochemical markers of mismatch repair protein defects and tumor microsatellite instability
The American Journal of Surgical Pathology
Ovarian

Bacani
2005
Tumor microsatellite instability in early onset gastric cancer
Journal of Molecular Diagnostics
Gastric

Bae
2015
Usefulness of immunohistochemistry for microsatellite instability screening in gastric cancer
Gut and Liver
Gastric

Basil
2000
Clinical significance of microsatellite instability in endometrial carcinoma
Cancer
Endometrial

Bataille
2003
Alterations in p53 predict response to preoperative high dose chemotherapy in patients with gastric cancer
Journal of Clinical Pathology-Molecular Pathology
Gastric

Billingsley
2015
Polymerase e (pole) mutations in endometrial cancer: clinical outcomes and implications for Lynch syndrome testing
Cancer
Endometrial

Black
2006
Clinicopathologic significance of defective DNA mismatch repair in endometrial carcinoma
Journal of Clinical Oncology
Endometrial

Buller
2001
p53 mutations and microsatellite instability in ovarian cancer: Yin and Yang
American Journal of Obstetrics & Gynecology
Ovarian

Buttin
2006
Increased risk for abnormalities on perioperative colon screening in patients with microsatellite instability-positive endometrial carcinoma
International Journal of Gynecological Cancer
Endometrial

Cai
2004
Microsatellite instability and alteration of the expression of hMLH1 and hMSH2 in ovarian clear cell carcinoma
Human Pathology
Ovarian

Catasus
2004
Molecular genetic alterations in endometrioid carcinomas of the ovary: similar frequency of beta-catenin abnormalities but lower rate of microsatellite instability and PTEN alterations than in uterine endometrioid carcinomas
Human Pathology
Ovarian

Cesinaro
2007
Mismatch repair proteins expression and microsatellite instability in skin lesions with sebaceous differentiation: a study in different clinical subgroups with and without extracutaneous cancer
The American Journal of Dermatopathology
Sebaceous

Chiaravalli
2001
Immunohistochemical pattern of hMSH2/hMLH1 in familial and sporadic colorectal, gastric, endometrial and ovarian carcinomas with instability in microsatellite sequences
Virchows Archiv
Gastric, endometrial, ovarian, and colorectal

Choe
2005
High frequency of microsatellite instability in intestinal-type gastric cancer in Korean patients
The Korean Journal of Internal Medicine
Gastric

Choi
2015
Correlation between microsatellite instability-high phenotype and occult lymph node metastasis in gastric carcinoma
APMIS
Gastric

Chong
2013
The genomic landscape of oesophagogastric junctional adenocarcinoma
Journal of Pathology
Oesophagogastric junctional

Choy
2004
Microsatellite instability and MLH1 promoter methylation in human retinoblastoma
Investigative Ophthalmology and Visual science
Retinoblastoma

Cook
2013
Endometrial cancer and a family history of cancer
Gynecologic Oncology
Endometrial and other unspecified tumors

Cullinane
2004
Microsatellite instability is a rare finding in tumors of patients with both primary renal and rectal neoplasms
Cancer Genetics & Cytogenetics
Rectal and renal

Dewdney
2012
Uterine serous carcinoma: increased familial risk for Lynch-associated malignancies
Cancer Prevention Research
Endometrial

Evans
2004
Microsatellite instability in esophageal adenocarcinoma
Cancer Letters
Esophageal

Fu
2012
Cpg island methylator phenotype-positive tumors in the absence of mlh1 methylation constitute a distinct subset of duodenal adenocarcinomas and are associated with poor prognosis
Clinical Cancer Research
Small bowel

Garcia
2006
Mismatch repair protein expression and microsatellite instability: a comparison of clear cell sarcoma of soft parts and metastatic melanoma
Modern Pathology
Clear Cell Sarcoma and Melanoma

Gargano
2007
Aberrant methylation within RUNX3 CpG island associated with the nuclear and mitochondrial microsatellite instability in sporadic gastric cancers. Results of a GOIM (gruppo oncologico dell’italia meridionale) prospective study
Annals of Oncology
Gastric

Geiseler
2003
Mismatch repair gene expression defects contribute to microsatellite instability in ovarian carcinoma
Cancer
Ovarian

Glavac
2003
Low microsatellite instability and high loss of heterozygosity rates indicate dominant role of the suppressor pathway in squamous cell carcinoma of head and neck and loss of heterozygosity of 11q14.3 correlates with tumor grade
Cancer Genetics & Cytogenetics
Head and neck

Goodfellow
2003
Prevalence of defective DNA mismatch repair and MSH6 mutation in an unselected series of endometrial cancers
Proceedings of the National Academy of Sciences of the United States of America
Endometrial

Gras
2001
Microsatellite instability, MLH-1 promoter hypermethylation, and frameshift mutations at coding mononucleotide repeat microsatellites in ovarian tumors
Cancer
Ovarian

Grogg
2003
Lymphocyte-rich gastric cancer: associations with Epstein-Barr virus, microsatellite instability, histology, and survival
Modern Pathology
Gastric

Gu
2009
Analysis of microsatellite instability, protein expression and methylation status of hmlh1 and hmsh2 genes in gastric carcinomas
Hepato-Gastroenterology
Gastric

Hampel
2005
Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer)
The New England Journal of Medicine
Colorectal

Hasuo
2007
Assessment of microsatellite instability status for the prediction of metachronous recurrence after initial endoscopic submucosal dissection for early gastric cancer
British Journal of Cancer
Gastric

Hermsen
2009
Genome-wide analysis of genetic changes in intestinal-type sinonasal adenocarcinoma
Head & neck
Nasopharynx

Honecker
2009
Microsatellite instability, mismatch repair deficiency, and BRAF mutation in treatment-resistant germ cell tumors
Journal of Clinical Oncology
Testis

Hong
2012
The differential impact of microsatellite instability as a marker of prognosis and tumour response between colon cancer and rectal cancer
European Journal of Cancer
Colorectal

Huang
2010
Comparative features of colorectal and gastric cancers with microsatellite instability in Chinese patients
Journal of Zhejiang University Science
Gastric and colorectal

Jahng
2012
Endoscopic and clinicopathologic characteristics of early gastric cancer with high microsatellite instability
World Journal of Gastroenterology
Gastric

Jensen
2008
Microsatellite instability and mismatch repair protein defects in ovarian epithelial neoplasms in patients 50 years of age and younger
American Journal of surgical Pathology
Ovarian

Jung
2016a
Prognostic impact of microsatellite instability in colorectal cancer presenting with mucinous, signet-ring, and poorly differentiated cells
Annals of Coloproctology
Colorectal

Jung
2016b
Observational study: familial relevance and oncological significance of revised bethesda guidelines in colorectal patients that have undergone curative resection
Medicine (United States)
Colorectal

Kanopiene
2014
Impact of microsatellite instability on survival of endometrial cancer patients
Medicina
Endometrial

Karpińska-Kaczmarczyk
2016
Expression of mismatch repair proteins in early and advanced gastric cancer in Poland
Medical Science Monitor
Gastric

Kawaguchi
2009
Analysis of candidate target genes for mononucleotide repeat mutation in microsatellite instability-high (MSI-H) endometrial cancer
International Journal of Oncology
Endometrial

Kawanaka
2016
Effects of Helicobacter pylori eradication on the development of metachronous gastric cancer after endoscopic treatment: analysis of molecular alterations by a randomised controlled trial
British Journal of Cancer
Gastric

Kim
1999
Accumulated frameshift mutations at coding nucleotide repeats during the progression of gastric carcinoma with microsatellite instability
Laboratory Investigation
Gastric

Kim
2013a
Microsatellite instability status in gastric cancer: a reappraisal of its clinical significance and relationship with mucin phenotypes
Korean Journal of Pathology
Gastric

Kim
2013b
Differential clinicopathologic features in microsatellite-unstable gastric cancers with and without MLH1 methylation
Human Pathology
Gastric

Kim
2016a
Clinicopathologic features of gastric cancer with synchronous and metachronous colorectal cancer in Korea: are microsatellite instability and p53 overexpression useful markers for predicting colorectal cancer in gastric cancer patients?
Gastric Cancer
Gastric and colorectal

Kim
2016b
Microsatellite instability of gastric and colorectal cancers as a predictor of synchronous gastric or colorectal neoplasms
Gut and Liver
Gastric and colorectal

Koopman
2009
Deficient mismatch repair system in patients with sporadic advanced colorectal cancer
British Journal of Cancer
Colorectal

Kubo
2005
Frequent microsatellite instability in primary esophageal carcinoma associated with extraesophageal primary carcinoma
International Journal of Cancer
Esophageal

Kumagai
2015
Mucinous phenotype and cd10 expression of primary adenocarcinoma of the small intestine
World Journal of Gastroenterology
Small bowel

Leenen
2012
Prospective evaluation of molecular screening for Lynch syndrome in patients with endometrial cancer ≤70 years
Gynecologic Oncology
Endometrial

Leite
2011
MSI phenotype and MMR alterations in familial and sporadic gastric cancer
International Journal of Cancer
Gastric

Liu
2004
Microsatellite instability and expression of hMLH1 and hMSH2 proteins in ovarian endometrioid cancer
Modern Pathology
Ovarian

Lu
2007
Prospective determination of prevalence of Lynch syndrome in young women with endometrial cancer
Journal of Clinical Oncology
Endometrial

Martinez
2005
Low-level microsatellite instability phenotype in sporadic glioblastoma multiforme
Journal of Cancer Research and Clinical Oncology
Brain

Mathiak
2017
Clinicopathologic characteristics of microsatellite instable gastric carcinomas revisited: urgent need for standardization
Applied Immunohistochemistry and Molecular Morphology
Gastric

Matsumoto
2007
Microsatellite instability and clinicopathological features in esophageal squamous cell cancer
Oncology Reports
Esophageal

McCleary
2016
Prognostic utility of molecular factors by age at diagnosis of colorectal cancer
Clinical Cancer Research
Colorectal

McConechy
2015
Detection of DNA mismatch repair (mmr) deficiencies by immunohistochemistry can effectively diagnose the microsatellite instability (msi) phenotype in endometrial carcinomas
Gynecologic Oncology
Endometrial

McCourt
2007
Body mass index: relationship to clinical, pathologic and features of microsatellite instability in endometrial cancer
Gynecologic Oncology
Endometrial

Moy
2015
Microsatellite instability in gallbladder carcinoma
Virchows Archiv
Gallbladder

Nagahashi
2008
Genetic changes of p53, Kras, and microsatellite instability in gallbladder carcinoma in high-incidence areas of Japan and Hungary
World Journal of Gastroenterology
Gallbladder

Okuda
2005
The profile of hMLH1 methylation and microsatellite instability in colorectal and non-small cell lung cancer
International Journal of Molecular Medicine
Colorectal, NSCLC

Rajan
2014
DNA mismatch repair defects and microsatellite instability status in periocular sebaceous carcinoma
American Journal of Ophthalmology
Sebaceous

Roa
2005
Microsatellite instability in preneoplastic and neoplastic lesions of the gallbladder
Journal of Gastroenterology
Gallbladder

Rodriguez-Hernandez
2013
Integrated analysis of mismatch repair system in malignant astrocytomas
PLoS One (electronic resource)
Brain

Rubio
2016
Analysis of Lynch syndrome mismatch repair genes in women with endometrial cancer
Oncology
Endometrial

Rubio-Del-Campo
2008
Implications of mismatch repair genes hmlh1 and hmsh2 in patients with sporadic renal cell carcinoma
BJU international
Renal

Ruemmele
2009
Histopathologic features and microsatellite instability of cancers of the papilla of vater and their precursor lesions
The American Journal of Survival Pathology
Pancreatic

Saetta
2004
Mononucleotide markers of microsatellite instability in carcinomas of the urinary bladder
European Journal of Surgical Oncology
Bladder

Schneider
2000
Microsatellite instability, prognosis and metastasis in gastric cancers from a low-risk population
International Journal of Cancer
Gastric

Seo
2009
Clinicopathologic characteristics and outcomes of gastric cancers with the MSI-H phenotype
Journal of Surgical Oncology
Gastric

Seo
2015
Clinicopathologic and molecular features associated with patient age in gastric cancer
World Journal of Gastroenterology
Gastric

Shibata
2006
RAB32 hypermethylation and microsatellite instability in gastric and endometrial adenocarcinomas
International Journal of Cancer
Gastric and endometrial

Shilpa
2014
Microsatellite instability, promoter methylation and protein expression of the DNA mismatch repair genes in epithelial ovarian cancer
Genomics
Ovarian

Shirai
2006
Interleukin-8 gene polymorphism associated with susceptibility to non-cardia gastric carcinoma with microsatellite instability
Journal of Gastroenterology and Hepatology (Australia)
Gastric

Singer
2004
Different types of microsatellite instability in ovarian carcinoma
International Journal of Cancer
Ovarian

Skenderi
2017
Warthin-like papillary renal cell carcinoma: Clinicopathologic, morphologic, immunohistochemical and molecular genetic analysis of 11 cases
Annals of Diagnostic Pathology
Renal

Soliman
2005
Women with synchronous primary cancers of the endometrium and ovary: do they have Lynch syndrome?
Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Endometrial and ovarian

Sood
2001
Application of the National Cancer Institute international criteria for determination of microsatellite instability in ovarian cancer
Cancer Research
Ovarian

Stello
2016
Improved risk assessment by integrating molecular and clinicopathological factors in early-stage endometrial cancer-combined analysis of the PORTEC cohorts
Clinical Cancer Research
Endometrial

Stoehr
2012
Mismatch repair proteins hMLH1 and hMSH2 are differently expressed in the three main subtypes of sporadic renal cell carcinoma
Pathobiology
Renal

Suemori
2015
Intratumoral cd8+ lymphocyte infiltration as a prognostic factor and its relationship with cyclooxygenase 2 expression and microsatellite instability in endometrial cancer
International Journal of Gynecological Cancer
Endometrial

Sugai
2017
Genetic differences stratified by PCR-based microsatellite analysis in gastric intramucosal neoplasia
Gastric Cancer
Gastric

Tanaka
2006
Effect of eradication of Helicobacter pylori on genetic instabilities in gastric intestinal metaplasia
Alimentary Pharmacology and Therapeutics Symposium Series
Gastric

Tay
2003
A combined comparative genomic hybridization and expression microarray analysis of gastric cancer reveals novel molecular subtypes
Cancer Research
Gastric

Vladimirova
2008
Low level of microsatellite instability in paediatric malignant astrocytomas
Neuropathology and Applied Neurobiology
Brain

Wen
2012
DNA mismatch repair deficiency in breast carcinoma a pilot study of triple-negative and non-triple-negative tumors
The American Journal of Survival Pathology
Breast

Wong
2003
The role of microsatellite instability in cervical intraepithelial neoplasia and squamous cell carcinoma of the cervix
Gynecologic Oncology
Cervical

Yan
2016
Prediction of biological behavior and prognosis of colorectal cancer patients by tumor msi/mmr in the Chinese population
OncoTargets and Therapy
Colorectal

Yoon
2008
Clinical significance of microsatellite instability in sporadic epithelial ovarian tumors
Yonsei Medical Journal
Ovarian

Zighelboim
2007
Microsatellite instability and epigenetic inactivation of MLH1 and outcome of patients with endometrial carcinomas of the endometrioid type
Journal of Clinical Oncology
Endometrial

Table 3: References—MMR studies.

Author
Year
Title
Journal
Tumor type

Backes
2009
Prospective evaluation of DNA mismatch repair protein expression in primary endometrial cancer
Gynecologic Oncology
Endometrial

Bennett
2016
Mismatch repair protein expression in clear cell carcinoma of the ovary: incidence and morphologic associations in 109 cases
The American Journal of Surgical Pathology
Ovarian

Bhosale
2017
Can reduced field-of-view diffusion sequence help assess microsatellite instability in FIGO stage 1 endometrial cancer?
Journal of Magnetic Resonance Imaging
Endometrial

Brady
2017
Sebaceous carcinoma treated with Mohs micrographic surgery
Dermatologic Surgery
Sebaceous

Bregar
2017
Characterization of immune regulatory molecules b7-h4 and pd-l1 in low and high grade endometrial tumors
Gynecologic Oncology
Endometrial

Bruegl
2014
Evaluation of clinical criteria for the identification of Lynch syndrome among unselected patients with endometrial cancer
Cancer Prevention Research
Endometrial

Bruegl
2017
Clinical challenges associated with universal screening for Lynch syndrome-associated endometrial cancer
Cancer Prevention Research
Endometrial

Buchanan
2014
Tumor mismatch repair immunohistochemistry and DNA mlh1 methylation testing of patients with endometrial cancer diagnosed at age younger than 60 years optimizes triage for population-level germline mismatch repair gene mutation testing
Journal of Clinical Oncology
Endometrial

Carleton
2016
A detailed immunohistochemical analysis of a large series of cervical and vaginal gastric-type adenocarcinomas
The American Journal of Surgical pathology
Cervical and vaginal

Chen
2017
Immunohistochemical profiling of endometrial serous carcinoma
International Journal of Gynecological Pathology
Endometrial

Clay
2014
Risk of secondary malignancy (including breast) in patients with mismatch-repair protein deficiency
The American Journal of Surgical pathology
Endometrial

Connor
2017
Association of distinct mutational signatures with correlates of increased immune activity in pancreatic ductal adenocarcinoma
JAMA Oncology
Pancreatic

Djordjevic
2013
Relationship between PTEN, DNA mismatch repair, and tumor histotype in endometrial carcinoma: retained positive expression of PTEN preferentially identifies sporadic non-endometrioid carcinomas
Modern Pathology
Endometrial

Everett
2014
Screening for germline mismatch repair mutations following diagnosis of sebaceous neoplasm
JAMA Dermatology
Sebaceous

Gaskin
2011
The significance of DNA mismatch repair genes in the diagnosis and management of periocular sebaceous cell carcinoma and Muir-Torre syndrome
British Journal of Ophthalmology
Sebaceous

Goldberg
2017
Microcystic, elongated, and fragmented pattern invasion in ovarian endometrioid carcinoma: immunohistochemical profile and prognostic implications
International Journal of Gynecological Pathology
Ovarian

Grzankowski
2012
Clinical and pathologic features of young endometrial cancer patients with loss of mismatch repair expression
Gynecologic Oncology
Endometrial

Joehlin-Price
2014
Mismatch repair protein expression in 1049 endometrial carcinomas, associations with body mass index, and other clinicopathologic variables
Gynecologic Oncology
Endometrial

Kato
2015
DNA mismatch repair-related protein loss as a prognostic factor in endometrial cancers
Journal of Gynecologic Oncology
Endometrial

Kawazoe
2017
Clinicopathological features of programmed death ligand 1 expression with tumor-infiltrating lymphocyte, mismatch repair, and Epstein-Barr virus status in a large cohort of gastric cancer patients
Gastric Cancer
Gastric

Kobel
2017
Frequent mismatch repair protein deficiency in mixed endometrioid and clear cell carcinoma of the endometrium
International Journal of Gynecological Pathology
Endometrial

Liau
2014
Hypermethylation of the cdkn2a gene promoter is a frequent epigenetic change in periocular sebaceous carcinoma and is associated with younger patient age
Human Pathology
Sebaceous

Liu
2014
DNA mismatch repair abnormalities in acinar cell carcinoma of the pancreas frequency and clinical significance
Pancreas
Pancreatic

Milione
2016
The clinicopathologic heterogeneity of grade 3 gastroenteropancreatic neuroendocrine neoplasms: morphological differentiation and proliferation identify different prognostic categories
Neuroendocrinology
Gastroenteropancreatic

Moreira
2012
Identification of Lynch syndrome among patients with colorectal cancer
JAMA
Colorectal

Okoye
2016
Defective DNA mismatch repair influences expression of endometrial carcinoma biomarkers
International Journal of Gynecological Pathology
Endometrial

Park
2016
Epstein-Barr virus positivity, not mismatch repair-deficiency, is a favorable risk factor for lymph node metastasis in submucosa-invasive early gastric cancer
Gastric Cancer
Gastric

Pecorino
2017
Genetic screening in young women diagnosed with endometrial cancer
Journal of Gynecologic Oncology
Endometrial

Peterson
2012
Molecular characterization of endometrial cancer: a correlative study assessing microsatellite instability, mlh1 hypermethylation, DNA mismatch repair protein expression, and pten, pik3ca, kras, and braf mutation analysis
International Journal of Gynecological Pathology
Endometrial

Ramos
2017
Lymphoepithelioma-like gastric carcinoma: Clinicopathological characteristics and infection status
Journal of surgical Research
Gastric

Ring
2013
Women 50 years or younger with endometrial cancer the argument for universal mismatch repair screening and potential for targeted therapeutics
International Journal of Gynecological Cancer
Endometrial

Roberts
2013
Screening for Muir-Torre syndrome using mismatch repair protein immunohistochemistry of sebaceous neoplasms
Journal of Genetic Counseling
Sebaceous

Rosa-Rosa
2016
Molecular genetic heterogeneity in undifferentiated endometrial carcinomas
Modern Pathology
Endometrial

Ruiz
2014
Lack of association between deficient mismatch repair expression and outcome in endometrial carcinomas of the endometrioid type
Gynecologic Oncology
Endometrial

Sahnane
2015
Microsatellite unstable gastrointestinal neuroendocrine carcinomas: a new clinicopathologic entity
Endocrine-Related Cancer
Gastroenteropancreatic

Shih
2011
Clinicopathologic significance of DNA mismatch repair protein defects and endometrial cancer in women 40 years of age and younger
Gynecologic Oncology
Endometrial

Steinestel
2014
Invasion pattern and histologic features of tumor aggressiveness correlate with MMR protein expression, but are independent of activating kras and braf mutations in CRC
Virchows Archiv
Colorectal

Talhouk
2016
Molecular classification of endometrial carcinoma on diagnostic specimens is highly concordant with final hysterectomy: earlier prognostic information to guide treatment
Gynecologic Oncology
Endometrial

Talhouk
2015
A clinically applicable molecular-based classification for endometrial cancers
British Journal of Cancer
Endometrial

Talhouk
2017
Confirmation of ProMisE: a simple, genomics-based clinical classifier for endometrial cancer
Cancer
Endometrial

Therkildsen
2015
Glioblastomas, astrocytomas and oligodendrogliomas linked to Lynch syndrome
European Journal of Neurology
Brain

Thoury
2014
Evidence for different expression profiles for c-Met, EGFR, PTEN and the mTOR pathway in low and high grade endometrial carcinomas in a cohort of consecutive women. Occurrence of pik3ca and k-ras mutations and microsatellite instability
Histology and Histopathology
Endometrial

Vierkoetter
2014
Lynch syndrome in patients with clear cell and endometrioid cancers of the ovary
Gynecologic Oncology
Ovarian

Vierkoetter
2016
Loss of mismatch repair protein expression in unselected endometrial adenocarcinoma precursor lesions
International Journal of Gynecological Cancer
Endometrial

Watkins
2016
Universal screening for mismatch-repair deficiency in endometrial cancers to identify patients with Lynch syndrome and Lynch-like syndrome
International Journal of Gynecological Pathology
Endometrial

Wiegand
2014
Arid1a/baf250a as a prognostic marker for gastric carcinoma: a study of 2 cohorts
Human Pathology
Gastric

Woo
2014
The immunohistochemistry signature of mismatch repair (MMR) proteins in a multiethnic Asian cohort with endometrial carcinoma
International Journal of Gynecological Pathology
Endometrial

Zakhour
2017
Abnormal mismatch repair and other clinicopathologic predictors of poor response to progestin treatment in young women with endometrial complex atypical hyperplasia and well-differentiated endometrial adenocarcinoma: a consecutive case series
BJOG: An International Journal of Obstetrics and Gynecology
Endometrial

Table 4: References–genomic studies.

Author
Year
Title
Journal
Tumor type

Bonneville
2017
Landscape of microsatellite instability across 39 cancer types
JCO Precision Oncology
Many (genomic)

Chalmers
2017
Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden
Genome Medicine
Many (genomic)

Cortes-Ciriano
2017
A molecular portrait of microsatellite instability across multiple cancers
Nature Communications
Many (genomic)

Hause
2016
Classification and characterization of microsatellite instability across 18 cancer types
Nature Medicine
Many (genomic)

Le
2017
Mismatch-repair deficiency predicts response of solid tumors to PD-1 blockade
Science
Many (genomic)

3.2. Study Characteristics

The most common tumor types (excluding CRC) identified were endometrial (53 studies), gastric (39 studies), ovarian (23 studies), renal (9 studies), and esophageal (6 studies). Twenty CRC studies were identified from the targeted review. Overall, 54 studies were conducted in the United States, 18 in Korea, 12 in Japan, 12 in multiple countries, and 60 in other countries. Most studies provided an MSI-H cut-off between 30 and 40%, inclusive, translating into a change in loci size of greater than or equal to 2 of 5 loci tested; however, there were two prominent outliers at 9% (Glavac 2003) and 66% (Wen 2012). Fifty-four studies used all four MMR proteins to detect MMR status, 3 studies used three proteins, 6 studies used two proteins, and 3 studies did not specify number of proteins used. Included studies reported different study designs: case control, cross-sectional, prospective cohort, and retrospective cohort.

3.3. Patient Characteristics

Across studies, the mean/median age ranged from 20.7 to 74 years. Percentage of patients by ethnicity ranged as follows: Caucasian (0–94.8%), African American (0–17.2%), Asian (0–100%), and other ethnic groups (0–13.8%). In studies where disease stage was reported, percentage of patients with stage 1 disease ranged from 0 to 80.7%, stage 2 disease ranged from 4.2 to 38.6%, stage 3 disease ranged from 8 to 73.5%, and stage 4 disease ranged from 0 to 97.7%.

3.4. MSI-H and dMMR Prevalence

The number of studies with available MSI-H and dMMR data is presented in Table 5. Of the 156 included studies, MSI-H prevalence as determined by NCI or Promega markers was reported in 90 studies, and MSS prevalence was reported in 79 studies. Sixty-six studies reported dMMR prevalence; 54 of those used all 4 MMR proteins in the IHC assay. Pooled MSI-H and dMMR prevalence estimates were reported in 140 studies.

Table 5: Availability of prevalence data.

Subset
Any (with and without results)
Reported MSI-H data
Reported dMMR (any IHC)
Reported dMMR (4 MMR proteins)
Reported MSS
Reported MSI-H/dMMR

Total number of studies included
156
94
66
54
79
140

Studies in gastric cancer
39
32
6
4
23
35

Studies in endometrial cancer
53
27
28
26
16
49

Studies in ovarian cancer
23
17
8
5
13
20

Studies in colorectal cancer
20
14
8
4
6
17

Studies in esophageal cancer
6
6
0
0
3
6

Studies in renal cancer
9
7
3
1
3
8

Studies in other cancers
36
18
16
13
21
31

Abbreviations: MSI-H, microsatellite instability-high; dMMR, deficient mismatch repair; MSS, microsatellite stable.

MSI-H prevalence was available in 25 studies conducted in the United States, 17 studies conducted in Korea, and 8 studies conducted in Japan. dMMR prevalence data were available in 27 conducted in the United States and 2 studies conducted in Japan. MSI-H prevalence was reported by stages 1 (18 studies), 2 (18 studies), 3 (17 studies), 4 (16 studies), 1 or 2 (24 studies), and 3 or 4 (23 studies).

Beyond the 6 main tumor types feasible for tumor-specific meta-analyses, 19 other tumor types were included in the meta-analysis of overall MSI-H prevalence. Overall, MSI-H prevalence differed considerably across tumor types. A low prevalence of 2% (95% CI, 0%–8%) was observed in Ewing sarcoma [19], while a much higher prevalence of 35% (95% CI, 15%–57%) was reported in sebaceous tumors [20]. Small bowel [21] and cervical tumors [22] had prevalence of 12% each, which were very close to the all-tumor estimate.

3.5. Meta-Analysis Results: Random Effects

Overall meta-analysis results is presented in Figure 2. Prevalence estimates, 95% confidence intervals, and number of studies included in each analysis are shown. Meta-analysis results obtained from the random effects model in all tumor types are presented as forest plots in the Supplementary information (Appendix Figures 1–Figure 26). Funnel plots obtained from each meta-analysis are also presented in the Supplementary information (Appendix Figure 27–Figure 44).

Figure 2: Summary of meta-analysis results, all tumor types, random effects. Abbreviations: N, total number of subjects; n, number of subjects with mutation status of interest.

The weighted prevalence of MSI-H without genomic studies was estimated to be 14% (95% CI, 10%–19%) across all tumor types and stages. The prevalence was 10% (95% CI, 7%–14%) when four of the five large pan-tumor genomic studies were included (one genomic study was excluded as it did not report the total number of patients or the number of patients with MSI-H). Overall weighted dMMR prevalence was estimated to be 16% (95% CI, 11%–22%) across all tumor types and stages. This estimate remained unchanged (16% (95% CI, 12%–21%)) in the sensitivity analysis, in which two studies (Everett 2014 and Roberts 2013) that possibly screened patients based on their Lynch syndrome status were excluded. Overall, MSS prevalence was found to be 79% (95% CI, 72%–85%) across tumor types and stages. Estimated pooled MSI-H and dMMR prevalence without genomic studies was 15% (95% CI, 11%–18%) and dropped to 11% (95% CI, 8%–15%) when genomic studies were included.

Country-specific MSI-H prevalence was estimated only in the United States, Korea, and Japan, for which at least 2 publications were included. The weighted prevalence of MSI-H for the United States, Korea, and Japan was estimated at 20% (95% CI, 16%–24%), 9% (95% CI, 6%–12%), and 16% (95% CI, 9%–26%), respectively, across all cancers and stages. dMMR all-stage prevalence for the United States was estimated at 14% (95% CI, 6%–23%) and for Japan was estimated at 20% (95% CI, 0%–63%). Stages 1-2 MSI-H prevalence was 15% (8–23%), while stage 3 and stage 4 prevalence was estimated at 9% (3%–17%) and 3% (1%–7%), respectively.

Tumor-specific meta-analysis was feasible for 3 key gastrointestinal tumors (gastric, colorectal, and esophageal), 2 gynecological tumors (endometrial and ovarian), and 1 genitourinary tumor (renal) with results presented in Figures 3–5. Among the gastrointestinal tumors, gastric cancer MSI-H pooled prevalence (with 95% CI) from 32 studies (16,308 patients) was estimated at 11% (9–12%) and dMMR pooled prevalence from 4 studies (854 patients) was estimated at 8% (2–17%); Based on stages across gastrointestinal tumors, the prevalence was 13% (10%–16%; 10 studies; 3,194 patients) for stages 1-2, and the prevalence was 10% (7–13%; 10 studies; 1,319 patients) in stages 3-4 cancer. The highest MSI-H pooled prevalence was observed for the intestinal histological subtype with 13% (10–17%) based on 14 studies (2,652 patients). In CRC, MSI-H pooled prevalence from 14 studies (8,156 patients) was estimated at 13% (10–16%) and dMMR pooled prevalence from 4 studies (11,434 patients) was estimated at 10% (5–15%). For stages 1-2 CRC, the prevalence was 20% (10%–32%; 4 studies; 888 patients), and for stages 3-4, the prevalence was 9% (3–16%; 4 studies; 873 patients). Based on histology, the highest MSI-H pooled prevalence was observed for the poorly differentiated CRC subtype with 32% (25–40%) based on 6 studies (1,204 patients). Among esophageal cancers, MSI-H pooled prevalence from 3 studies (147 patients) was estimated at 4% (0–11%). For stages 3-4 esophageal cancers, the prevalence was 18% (4%–39%; 2 studies; 62 patients). Based on histology, the highest MSI-H pooled prevalence was observed for well-differentiated and poorly differentiated esophageal subtypes with 16% (3–35%) and 16% (0%–45%), respectively. dMMR analysis was not feasible for esophageal tumors. For the gynecological tumors, endometrial cancer MSI-H pooled prevalence from 27 studies (6,813 patents) was estimated at 26% (23–29%) and dMMR pooled prevalence from 26 studies (5,248 patients) was estimated at 25% (22–28%). In ovarian cancers, MSI-H pooled prevalence from 17 studies (4,150 patients) was estimated at 11% (6–18%) and dMMR pooled prevalence from 5 studies (356 patients) was estimated at 8% (6–11%). Based on histology, the highest MSI-H pooled prevalence was observed for endometrioid subtype for each tumor with 30% (25–35%) based on 6 studies (1,204 patients) for endometrial cancers and 17% (25–35%) based on 3 studies (211 patients) for ovarian cancers. Among renal tumors, MSI-H all-stage prevalence was estimated to be 1% (95% CI, 0%–2%) based on 7 studies (2,231 patients); dMMR analysis was not feasible for renal tumors.

Figure 3: Summary of meta-analysis results, gynecological tumors, random effects. Abbreviations: N, total number of subjects; n, number of subjects with mutation status of interest.

Figure 4: Summary of meta-analysis results, gastrointestinal tumors, random effects. Abbreviations: N, total number of subjects; n, number of subjects with mutation status of interest.

Figure 5: Summary of meta-analysis results, genitourinary tumors, random effects. Abbreviations: N, total number of subjects; n, number of subjects with mutation status of interest.

4. Discussion

This structured literature review and meta-analysis investigated MSI-H and dMMR prevalence across tumor types and compared prevalence estimates by tumor type, tumor stage, and country subgroups. Analysis results estimated the prevalence of MSI-H across all tumor types as 14% (95% CI, 10%–19%). dMMR prevalence was comparable at 16% (95% CI, 11%–22%).

Pooled dMMR prevalence estimates by tumor type were similar to those for MSI-H. It has been suggested that, for Lynch syndrome testing, PCR testing may be less sensitive than IHC due to the fact that mutations in MSH6 may present as MSI-L [23]. The results of this review, however, suggest that MSI-H and dMMR IHC testing results are generally comparable.

The United States had higher MSI-H prevalence than Korea and Japan, but this result is possibly biased due to the lack of weighting for country-specific tumor prevalence.

Subgroup analysis indicated that early stage diseases (stage 1 and 2) tended to have a higher MSI-H prevalence than later stages (stages 3 and 4). Numerous studies have established the value of MSI status as a prognostic factor [24–26]. Results of a meta-analysis including 7642 patients indicated that MSI (MSI-H + MSI-L) tumors corresponded with significantly improved prognosis compared to MSS CRCs (overall survival HR 0.65 (95% CI, 0.59–0.71) [27]. This may partially explain the lower MSI-H prevalence in the later stages of cancers.

Some tumor types had noticeably higher MSI-H prevalence than others. Endometrial tumors had MSI-H prevalence of 26% (95% CI, 23%–29%), whereas renal tumors only had MSI-H prevalence of 1% (95% CI, 0%–2%). This observation corroborates findings from recent genomic studies, which revealed that the frequency of MSI-H events is highly variable across tumor types [13, 28]. One study noted that MSI-H prevalence was highest in Lynch syndrome-associated tumor types (endometrial, colon, gastric, and rectal) [13] which is well-aligned with findings from the current study.

The identified evidence base included 156 articles reporting on the prevalence of MSI-H and/or dMMR published between 1999 and 2017. This review includes the most cancer types of a published review to date. Of the other two known published meta-analyses that have quantified the prevalence of MSI-H for selective tumors, the first (including publications to 2007) reported an MSI-H prevalence of 12% (95% CI, 8%–17%) in ovarian tumors [29], the second (including publications to 2009) reported an MSI-H prevalence of 10% (95% CI, 6%–14%) in ovarian tumors [30], and the third (including studies published up to 2014) reported an MSI-H prevalence of 17% (95% CI, 15%–19%) in colorectal tumors [31]. The finding from the current meta-analysis suggests MSI-H prevalence of 11% (95% CI, 6%–18%) in ovarian cancer patients and 13% (95% CI, 10%–16%) in colorectal cancer patients, which are well-aligned with findings from previous meta-analyses.

This large-scale meta-analysis of the prevalence of MSI-H and dMMR used rigorous methodology in selection of testing methods, subgroup analyses, and incorporation of pan-tumor genomic studies in sensitivity analyses. First, this meta-analysis of MSI-H and dMMR prevalence included the most number of studies (156) to date. Second, weighting techniques were used to adjust for overall tumor prevalence in order to prevent oversampling of commonly reported tumor types. Third, only studies that utilized the “gold standard” MSI-H and dMMR testing methods were included in the meta-analysis, so the results from these studies were more comparable. Fourth, the subgroup analyses, which were stratified by factors such as tumor type, country, and disease stage, indicated which factors had potential association with prevalence. Fifth, the inclusion of pan-tumor genomic studies in the sensitivity analyses offered an alternative scenario and suggested that the testing method used in large-scale genomic studies (sequencing) is significantly different from the widely accepted methods (PCR and IHC) used in other included studies.

This meta-analysis has some limitations. First, the literature review for CRC was a targeted hand search; some potentially relevant publications may not have been identified. Studies were reviewed by a single researcher, but a quality check was performed to validate the dataset. An additional limitation was the heterogeneity of included study designs included, which included case control, cross-sectional, prospective cohort, and retrospective cohort studies. However, because of scarcity of the numbers in most cancer types, studies with different designs were included to maximize the data sources. Symmetry was observed on most funnel plots, which suggest a lack of publication bias. To address heterogeneity in study designs included in the meta-analysis, data were analyzed using fixed- and random-effects models; however, this exploration did not provide evidence of any specific source of heterogeneity. Finally, given the lack of MSI/MMR publications on a few major cancer types, the “overall” prevalence estimate does not include all solid tumors.

Recent evidence [32, 33] supporting the role of MSI-H and dMMR, and associated immunogenicity as a mechanism for increased efficacy of PD-1/PD-L1 blockade in metastatic tumors with MSI-H or dMMR [8], demonstrates to the importance of increasing understanding [34] of prevalence across tumor type, stage, histology, and ethnicity.

Conflicts of Interest

M. Amonkar and K.-L. Liaw are employees of and own shares in Merck & Co, Inc. The other authors declare no conflicts of interests.

Acknowledgments

This work was financially supported by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Supplementary Materials

Meta-analysis results obtained from random effects model in all tumor types are presented as forest plots in the Supplementary information (Appendix Figures 1–Figure 26). Funnel plots obtained from each meta-analysis are also presented in the Supplementary information (Appendix Figure 27–Figure 44). (Supplementary Materials)

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