Carlotta Ceccon, Chiara Borga, Valentina Angerilli, Francesca Bergamo, Giada Munari, Marianna Sabbadin, Jessica Gasparello, Francesca Schiavi, Stefania Zovato, Marco Scarpa, Emanuele Damiano Luca Urso, Angelo Paolo Dei Tos, Claudio Luchini, Federica Grillo, Sara Lonardi, Paola Parente, Matteo Fassan
{"title":"在结直肠癌中，MLH1基因启动子甲基化状态与CpG甲基化表型（CIMP）部分重叠。","authors":"Carlotta Ceccon, Chiara Borga, Valentina Angerilli, Francesca Bergamo, Giada Munari, Marianna Sabbadin, Jessica Gasparello, Francesca Schiavi, Stefania Zovato, Marco Scarpa, Emanuele Damiano Luca Urso, Angelo Paolo Dei Tos, Claudio Luchini, Federica Grillo, Sara Lonardi, Paola Parente, Matteo Fassan","doi":"10.1016/j.prp.2024.155786","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>RAS/BRAF mutations, mismatch DNA repair complex deficiency (MMRd)/microsatellite instability (MSI), and CpG methylator phenotype (CIMP) are key molecular actors in colorectal carcinogenesis. To date, conflicting evidence about the correlations between these molecular features has been reported.</p><p><strong>Materials and methods: </strong>A retrospectively selected cohort of 123 CRCs was divided into 3 groups based on the molecular characteristics: MMR proficient (MMRp)/BRAF p.V600E mutated (BRAF<sup>mut</sup>), MMRd/BRAF<sup>mut</sup>, and MMRd/BRAF wild type (BRAF<sup>wt</sup>). MLH1 promoter (pMLH1) methylation status was assessed by pyrosequencing. For 82 samples the CIMP phenotype was evaluated using the EpiTect® MethyLight kit.</p><p><strong>Results: </strong>The MMRd/BRAF<sup>mut</sup> group showed a higher pMLH1 methylation rate compared to both the MMRd/BRAF<sup>wt</sup> and the MMRp/BRAF<sup>mut</sup> groups. Overall, the two MMRd groups had a higher methylation rate compared to the MMRp cases independently from the mutational status of BRAF (p-value <0.0001). The MMRd/BRAF<sup>mut</sup> group was characterized by a 90.0 % of CIMP high (CIMP-H) tumors of which 97.2 % were pMLH1 methylated. Instead, the MMRd/BRAF<sup>wt</sup> group presented 50.0 % of CIMP-H adenocarcinomas.</p><p><strong>Conclusions: </strong>Our study demonstrates that pMLH1 hypermethylation, MMRd, BRAF<sup>mut</sup> and CIMP phenotype do not completely overlap in CRC. These findings further refine the knowledge on the molecular landscape of CRC and may have critical implications also for the clinical management of the disease.</p>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"266 ","pages":"155786"},"PeriodicalIF":2.9000,"publicationDate":"2024-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"MLH1 gene promoter methylation status partially overlaps with CpG methylator phenotype (CIMP) in colorectal adenocarcinoma.\",\"authors\":\"Carlotta Ceccon, Chiara Borga, Valentina Angerilli, Francesca Bergamo, Giada Munari, Marianna Sabbadin, Jessica Gasparello, Francesca Schiavi, Stefania Zovato, Marco Scarpa, Emanuele Damiano Luca Urso, Angelo Paolo Dei Tos, Claudio Luchini, Federica Grillo, Sara Lonardi, Paola Parente, Matteo Fassan\",\"doi\":\"10.1016/j.prp.2024.155786\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>RAS/BRAF mutations, mismatch DNA repair complex deficiency (MMRd)/microsatellite instability (MSI), and CpG methylator phenotype (CIMP) are key molecular actors in colorectal carcinogenesis. To date, conflicting evidence about the correlations between these molecular features has been reported.</p><p><strong>Materials and methods: </strong>A retrospectively selected cohort of 123 CRCs was divided into 3 groups based on the molecular characteristics: MMR proficient (MMRp)/BRAF p.V600E mutated (BRAF<sup>mut</sup>), MMRd/BRAF<sup>mut</sup>, and MMRd/BRAF wild type (BRAF<sup>wt</sup>). MLH1 promoter (pMLH1) methylation status was assessed by pyrosequencing. For 82 samples the CIMP phenotype was evaluated using the EpiTect® MethyLight kit.</p><p><strong>Results: </strong>The MMRd/BRAF<sup>mut</sup> group showed a higher pMLH1 methylation rate compared to both the MMRd/BRAF<sup>wt</sup> and the MMRp/BRAF<sup>mut</sup> groups. Overall, the two MMRd groups had a higher methylation rate compared to the MMRp cases independently from the mutational status of BRAF (p-value <0.0001). The MMRd/BRAF<sup>mut</sup> group was characterized by a 90.0 % of CIMP high (CIMP-H) tumors of which 97.2 % were pMLH1 methylated. Instead, the MMRd/BRAF<sup>wt</sup> group presented 50.0 % of CIMP-H adenocarcinomas.</p><p><strong>Conclusions: </strong>Our study demonstrates that pMLH1 hypermethylation, MMRd, BRAF<sup>mut</sup> and CIMP phenotype do not completely overlap in CRC. These findings further refine the knowledge on the molecular landscape of CRC and may have critical implications also for the clinical management of the disease.</p>\",\"PeriodicalId\":19916,\"journal\":{\"name\":\"Pathology, research and practice\",\"volume\":\"266 \",\"pages\":\"155786\"},\"PeriodicalIF\":2.9000,\"publicationDate\":\"2024-12-21\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Pathology, research and practice\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.prp.2024.155786\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"PATHOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Pathology, research and practice","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.prp.2024.155786","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"PATHOLOGY","Score":null,"Total":0}
MLH1 gene promoter methylation status partially overlaps with CpG methylator phenotype (CIMP) in colorectal adenocarcinoma.
Background: RAS/BRAF mutations, mismatch DNA repair complex deficiency (MMRd)/microsatellite instability (MSI), and CpG methylator phenotype (CIMP) are key molecular actors in colorectal carcinogenesis. To date, conflicting evidence about the correlations between these molecular features has been reported.
Materials and methods: A retrospectively selected cohort of 123 CRCs was divided into 3 groups based on the molecular characteristics: MMR proficient (MMRp)/BRAF p.V600E mutated (BRAFmut), MMRd/BRAFmut, and MMRd/BRAF wild type (BRAFwt). MLH1 promoter (pMLH1) methylation status was assessed by pyrosequencing. For 82 samples the CIMP phenotype was evaluated using the EpiTect® MethyLight kit.
Results: The MMRd/BRAFmut group showed a higher pMLH1 methylation rate compared to both the MMRd/BRAFwt and the MMRp/BRAFmut groups. Overall, the two MMRd groups had a higher methylation rate compared to the MMRp cases independently from the mutational status of BRAF (p-value <0.0001). The MMRd/BRAFmut group was characterized by a 90.0 % of CIMP high (CIMP-H) tumors of which 97.2 % were pMLH1 methylated. Instead, the MMRd/BRAFwt group presented 50.0 % of CIMP-H adenocarcinomas.
Conclusions: Our study demonstrates that pMLH1 hypermethylation, MMRd, BRAFmut and CIMP phenotype do not completely overlap in CRC. These findings further refine the knowledge on the molecular landscape of CRC and may have critical implications also for the clinical management of the disease.
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Pathology, Research and Practice provides accessible coverage of the most recent developments across the entire field of pathology: Reviews focus on recent progress in pathology, while Comments look at interesting current problems and at hypotheses for future developments in pathology. Original Papers present novel findings on all aspects of general, anatomic and molecular pathology. Rapid Communications inform readers on preliminary findings that may be relevant for further studies and need to be communicated quickly. Teaching Cases look at new aspects or special diagnostic problems of diseases and at case reports relevant for the pathologist''s practice.
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