Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Feb 25:217:115233.
doi: 10.1016/j.ejca.2025.115233. Epub 2025 Jan 13.

Mismatch repair (MMR) and microsatellite instability (MSI) phenotypes across solid tumors: A comprehensive cBioPortal study on prevalence and prognostic impact

Konstantinos Venetis  1 , Chiara Frascarelli  2 , Luca Boscolo Bielo  3 , Giulia Cursano  2 , Riccardo Adorisio  1 , Mariia Ivanova  1 , Eltjona Mane  1 , Virginia Peruzzo  1 , Alberto Concardi  1 , Mariachiara Negrelli  1 , Marianna D'Ercole  1 , Francesca Maria Porta  1 , Yinxiu Zhan  4 , Antonio Marra  3 , Dario Trapani  5 , Carmen Criscitiello  5 , Giuseppe Curigliano  5 , Elena Guerini-Rocco  2 , Nicola Fusco  6
Affiliations

Mismatch repair (MMR) and microsatellite instability (MSI) phenotypes across solid tumors: A comprehensive cBioPortal study on prevalence and prognostic impact

Konstantinos Venetis et al. Eur J Cancer. .

Abstract

Mismatch repair deficiency (MMR-d) and microsatellite instability (MSI) are prognostic and predictive biomarkers in oncology. Current testing for MMR/MSI relies on immunohistochemistry (IHC) for MMR proteins and molecular assays for MSI detection. This combined diagnostic strategy, however, lacks tumor specificity and does not account for gene variants. This study provides an in-depth analysis of MMR mutations frequency, spectrum, and distribution in solid tumors. Data from 23,893 patients across 11 tumor types, using 66 publicly available studies, were analyzed. MMR-mutated (MMR-m) status was defined by alterations in MLH1, PMS2, MSH2, and/or MSH6; MSI was assessed by MSIsensor. Cases with indeterminate labelling were excluded. Survival was analyzed using the Kaplan-Meier method. Among 19,353 tumors, 949 MMR variants were identified, comprising 432 pathogenic and 517 variants of unknown significance (VUS), as defined by OncoKB. MSH6 mutations were the most frequent (n = 279, 29.4 %), followed by MSH2 (n = 198, 20.9 %), MLH1 (n = 187, 19.7 %), and PMS2 (n = 161, 16.9 %). MMR-m cases were more frequent in endometrial (EC, 20.5 %), colorectal (CRC, 8.2 %), bladder (BLCA, 8.7 %), and gastroesophageal cancers (GEC, 5.4 %). Pathogenic mutations were more common than non-pathogenic in EC, CRC, and GEC (p < 0.001, p = 0.01, p = 0.32, respectively). MMR-m status was not associated with MSI in 247 (48.9 %) cases, including 67 (13.2 %) with pathogenic mutations. The highest concordance between MMR-m and MSI was observed in CRC (65.7 %), EC (91.2 %), and GEC (69.6 %), while the lowest in pancreatic (0.2 %) and lung cancers (0.1 %). MMR-m GECs showed improved overall survival compared to MMR-wt (p = 0.009), a relationship not observed in other tumor types. This study demonstrates that the MMR spectrum is extremely hetoerogeneous in solid tumors, highliting the need for comprehensive and tumor-specific testing strategies.

Keywords: CBioPortal; Microsatellite instability (MSI); Mismatch repair (MMR); Mutations; Solid tumors.

PubMed Disclaimer

Conflict of interest statement

Declaration of Competing Interest K. V. has received honoraria for speakers' bureau participation from Merck Sharp & Dohme (MSD), Roche, and AstraZeneca. G. Cursa. from Veracyte. A. M. has received support from Menarini Group and served on the Speakers' Bureau for Roche and AstraZeneca. C. C. has participated in advisory or consultancy roles and speakers' bureau engagements for Eli Lilly, Pfizer, Novartis, Roche, AstraZeneca, MSD, Daiichi Sankyo, Gilead, and Seagen. G. Curi. has received honoraria for speaker engagements from Roche, Seattle Genetics, Novartis, Lilly, Pfizer, Foundation Medicine, NanoString, Samsung, Celltrion, BMS, and MSD; honoraria for consultancy from Roche, Seattle Genetics, and NanoString; honoraria for participation in advisory boards from Roche, Lilly, Pfizer, Foundation Medicine, Samsung, Celltrion, and Mylan; honoraria for writing engagements from Novartis and BMS; and honoraria for participation in the Ellipsis Scientific Affairs Group. He has also received institutional research funding for conducting phase I and II clinical trials from Pfizer, Roche, Novartis, Sanofi, Celgene, Servier, Orion, AstraZeneca, Seattle Genetics, AbbVie, Tesaro, BMS, Merck Serono, Merck Sharp & Dohme, Janssen-Cilag, Philogen, Bayer, Medivation, and Medimmune. E. G-R. has received advisory fees, honoraria, travel accommodations/expenses, grants, and/or non-financial support from AstraZeneca, Exact Sciences, GSK, Illumina, MSD, Novartis, Roche, and Thermo Fisher Scientific. N.F. has received honoraria for consulting, advisory roles, speakers' bureau participation, travel, and/or research grants from Merck Sharp & Dohme (MSD), Merck, Novartis, AstraZeneca, Roche, Menarini Group, Daiichi Sankyo, GlaxoSmithKline (GSK), Gilead, Sysmex, Genomic Health, Veracyte Inc., Sakura, Leica Biosystems, Lilly, Pfizer, Abbvie. These companies had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and/or in the decision to publish the results. All other authors declare no potential conflicts of interest.

LinkOut - more resources