Alexandre How-Kit

Kai Ye

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Editorial: Microsatellite andmicrosatellite instabilityAlexandre How-Kit1* and Kai Ye2,3,4,5,6*1Laboratory for Genomics, Foundation Jean Dausset—CEPH, Paris, France, 2MOE Key Lab for IntelligentNetworks and Networks Security, Faculty of Electronic and Information Engineering, Xi’an JiaotongUniversity, Xi’an, China, 3School of Automation Science and Engineering, Faculty of Electronic andInformation Engineering, Xi’an Jiaotong University, Xi’an, China, 4Genome Institute, The First AffiliatedHospital of Xi’an Jiaotong University, Xi’an, China, 5The School of Life Science and Technology, Xi’anJiaotong University, Xi’an, China, 6Faculty of Science, Leiden University, Leiden, NetherlandsKEYWORDSmicrosatellite instability, polymerase slippage, cancer, immunotherapy, HSP110 HT17,biomarker, next-generation sequencing – NGSEditorial on the Research TopicMicrosatellite and microsatellite instabilityMicrosatellite instability (MSI) is a genome-wide genetic alteration initially discovered incolorectal cancers (CRC) in 1993, where about 15% of tumors presented this phenotype thatbears relevant information for diagnostics, prognostics and prediction of therapeutic response(Boland and Goel, 2010). MSI is characterized by the accumulation of mutations–insertions ordeletions of a few nucleotides–in microsatellites, introduced during replication by polymeraseslippage (Boland and Goel, 2010). MSI is caused by the loss of function of one of the DNAmismatch repair system (MMR) proteins (mostly in MLH1, MSH2, PMS2 and MSH6) due tosomatic and/or inherited inactivating (epi)mutations of their gene (Boland andGoel, 2010).Withthe advent of next-generation sequencing (NGS) in the era of genomics, several pan-cancerinvestigations on publicly available whole genome/exome sequencing (WGS/WES) cancer datahighlighted the presence of MSI in most solid cancer types at variable frequencies (<1%–~30%)with tumor-specific MSI signatures (Hause et al., 2016; Cortes-Ciriano et al., 2017).Concomitantly, the development and availability of immune checkpoint blockade therapies(ICI) for cancer patients allowed the identification of MSI as a major predictor of treatmentresponse, first in CRC (Le et al., 2015) and soon after in all solid cancers (Le et al., 2017). This ledthe FDA to approve the use of MSI status as a universal biomarker for the administration ofimmune checkpoint inhibitors in advanced solid cancers, regardless of the type of cancers.Due to the considerable clinical implication of MSI for cancer patient’s management, thestudy of MSI in cancer was marked by a renewed interest in the biomedical community, eitherfor basic researches, development of new approaches for MSI detection, or assessment of itsclinical significance in various cancer types and sub-types. In this Research Topic dedicated to‘Microsallite and Microsatellite Instability’, Aska et al., presented a fundamental study ofgenome-wide single-cell mononucleotide microsatellites of MMR-proficient and MMR-deficient thymic T cells in mouse model, aiming to decipher the mutationnal dynamics ofMSI in vivo. By comparing WES data fromMlh1−/− andMlh1+/+ T cells, their analyses revealedseveral specific genomic features of MSI in MMRD cells, distinguishing deletion and insertiondynamics (Aska et al.). They notably showed that deletions far outnumbered insertions as inMSItumors and also preferentially affected long A/Tmononucelotide microsatellites of 10–14 nt andlater-replicating genes (Aska et al.). Moreover, their results indicated that longer-than-averageand transcriptionnally active genes were areas of fragility more prone to MSI, which couldOPEN ACCESSEDITED AND REVIEWED BYHoney V. Reddi,Medical College of Wisconsin,United States*CORRESPONDENCEAlexandre How-Kit,alexandre.how-kit@fjd-ceph.orgKai Ye,kaiye@xjtu.edu.cnRECEIVED 18 March 2023ACCEPTED 25 May 2023PUBLISHED 30 May 2023CITATIONHow-Kit A and Ye K (2023), Editorial:Microsatellite andmicrosatellite instability.Front. Genet. 14:1189212.doi: 10.3389/fgene.2023.1189212COPYRIGHT© 2023 How-Kit and Ye. This is an open-access article distributed under the termsof the Creative Commons AttributionLicense (CC BY). The use, distribution orreproduction in other forums ispermitted, provided the original author(s)and the copyright owner(s) are creditedand that the original publication in thisjournal is cited, in accordance withaccepted academic practice. No use,distribution or reproduction is permittedwhich does not comply with these terms.Frontiers in Genetics frontiersin.org01TYPE EditorialPUBLISHED 30 May 2023DOI 10.3389/fgene.2023.1189212potentially explain why some microsatellites are more unstable thanothers depending on the cancer type.In the second article of this Research Topic, Han et al., proposed anoverall and updated review that summerized the clinical, genomic andtumor immunobiology of sporadic and familial MSI cancers with aparticular attention to metastatic or recurrent disease. They notablyfocused in three cancer types with high frequencies of MSI,i.e., colorectal, gastric and endometrial cancer and emphatised in thedifferences of MSI cancers compared to their microsatellite stable(MSS) counterparts (Han et al.). Treatment options and results ofclinical trials were discussed, including notably patients response to ICIand resistance mechansims, and they suggested several perspectivesabout the possible evolution of MSI cancer treaments including multi-combined therapies.In a third study, Liu et al., indentifyed a fatty-acid metabolism-related (FAM) gene signature from colon adenocarcinoma TCGARNA-seq data and developed a FAM risk-score associated with abetter prognostic value (AUC = 0.734) than otherclinicopathological parameters. In addition, they showed that thehigh-risk group of CRC patients was enriched inMSI (high and low)phenotypes compared to the low-risk group and sugested that theirrisk score might also be a predicator of chemotherapy orimmunotherapy (Liu et al.). Although further validations areneeded for this FAM risk score, identifying new predicators ofICI is still highly valuable as neither MSI, TMB nor PD-L1expression alone can fully predict response to ICI and theyshould be combined with other biomarkers to improve predictionperformances in the different cancer types and sub-types.The gold-standard approach for MSI detection in cancer stillremains to date PCR and capillary electrophoresis fragment analysisof a panel of five microsatellites, which can be either the pentaplex orthe first recommended NCI/Bethesda panel. The NCI/Bethesdapanel was proposed for MSI CRC and Lynch syndrome diagnosisbut presented several limitations and Research Topic, notably due touse of three highly polymorphic di-nucleotide microsatellites (Umaret al., 2004; Baudrin et al., 2018). Several groups proposed alternativemarkers for improved MSI detection, including HT17, a quasi-monomorphic mononucleotide microsatellite located in theHSP110gene that showed improved sensitivity for similar specificity in CRCcompared to the pentaplex panel (Buhard et al., 2016), while the sizeof HT17 deletions could also be a predictor of 5-FU–basedchemotherapy response in CRC patients (Collura et al., 2014).Tachon et al., performed a comprehensive evaluation of HT17 asa diagnostic and prognostic biomarker in a cohort of 381 MSI CRCpatients, including 280 stage II and III patients of whom 37%received adjuvant chemotherapy mostly based (80.6%) on 5-FUassociated with oxaliplatin. Interestingly, their results confirmedHT17 as a good marker for MSI detection achieving 95.5%sensitivity, even allowing the detection of false-positive MSIsamples by the pentaplex panel. However, neitherHSP110 expression nor deletion size correlated with time torecurrence in patients with stage II and III CRC having receivedor not an adjuvant chemotherapy (Tachon et al.), highlighting theimportance of validation studies on independent cohorts.In conclusion, this Research Topic on ‘Microsatellite andMicrosatellite Instability’ covers different aspects of basic,translational and clinical research on MSI, including itsimportance in oncology for cancer patients’ management. Wethank the contributing authors and hope that their papers will beappreciated by their readers and that the interest for microsatellitesand MSI will continue to grow within the biomedical community.Author contributionsAH-K and KY drafted, edited and revised the manuscript andapproved the final version. All authors contributed to the article andapproved the submitted version.Conflict of interestThe authors declare that the research was conducted in theabsence of any commercial or financial relationships that could beconstrued as a potential conflict of interest.Publisher’s noteAll claims expressed in this article are solely those of the authorsand do not necessarily represent those of their affiliated organizations,or those of the publisher, the editors and the reviewers. Any productthat may be evaluated in this article, or claim that may be made by itsmanufacturer, is not guaranteed or endorsed by the publisher.ReferencesBaudrin, L. G., Deleuze, J. F., and How-Kit, A. (2018). Molecular and computationalmethods for the detection of microsatellite instability in cancer. Front. Oncol. 8, 621.doi:10.3389/fonc.2018.00621Boland, C. R., and Goel, A. (2010). Microsatellite instability in colorectal cancer.Gastroenterology 138, 2073–2087. doi:10.1053/j.gastro.2009.12.064Buhard, O., Lagrange, A., Guilloux, A., Colas, C., Chouchene, M., Wanherdrick, K., et al.(2016). HSP110 T17 simplifies and improves the microsatellite instability testing in patientswith colorectal cancer. J. Med. Genet. 53, 377–384. doi:10.1136/jmedgenet-2015-103518Collura, A., Lagrange, A., Svrcek, M., Marisa, L., Buhard, O., Guilloux, A., et al. (2014).Patients with colorectal tumors with microsatellite instability and large deletions inHSP110 T17 have improved response to 5-fluorouracil-based chemotherapy.Gastroenterology 146, 401–411. doi:10.1053/j.gastro.2013.10.054Cortes-Ciriano, I., Lee, S., Park, W. Y., Kim, T. M., and Park, P. J. (2017). A molecularportrait of microsatellite instability across multiple cancers. Nat. Commun. 8, 15180.doi:10.1038/ncomms15180Hause, R. J., Pritchard, C. C., Shendure, J., and Salipante, S. J. (2016). Classificationand characterization of microsatellite instability across 18 cancer types. Nat. Med. 22,1342–1350. doi:10.1038/nm.4191Le, D. T., Durham, J. N., Smith, K. N., Wang, H., Bartlett, B. R., Aulakh, L. K.,et al. (2017). Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 357, 409–413. doi:10.1126/science.aan6733Le, D. T., Uram, J. N., Wang, H., Bartlett, B. R., Kemberling, H., Eyring, A. D., et al.(2015). PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372,2509–2520. doi:10.1056/NEJMoa1500596Umar, A., Boland, C. R., Terdiman, J. P., Syngal, S., De La Chapelle, A., Ruschoff,J., et al. (2004). Revised Bethesda Guidelines for hereditary nonpolyposis colorectalcancer (Lynch syndrome) and microsatellite instability. J. Natl. Cancer Inst. 96,261–268. doi:10.1093/jnci/djh034Frontiers in Genetics frontiersin.org02How-Kit and Ye 10.3389/fgene.2023.1189212

Editorial: Microsatellite and microsatellite instability

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Editorial: Microsatellite and microsatellite instability

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