Joel Del Bel Pádua, Carolline Fontes Alves Mariano, Alexandre Todorovic Fabro, Fermino Sanches Lizarte Neto, Rogério Lenotti Zuliani, Cláudia Tarcila Gomes Sares, José Sebastião Dos Santos, Ajith Kumar Sankarankutty, Daniela Pretti da Cunha Tirapelli, Vanessa da Silva Silveira, Greice Andreotti de Molfetta, Wilson Araújo da Silva Júnior, Mariângela Ottoboni Brunaldi
{"title":"胃腺癌中 RAD51、ATM、ATR、BRCA1 和 BRCA2 基因的 mRNA 表达和甲基化。","authors":"Joel Del Bel Pádua, Carolline Fontes Alves Mariano, Alexandre Todorovic Fabro, Fermino Sanches Lizarte Neto, Rogério Lenotti Zuliani, Cláudia Tarcila Gomes Sares, José Sebastião Dos Santos, Ajith Kumar Sankarankutty, Daniela Pretti da Cunha Tirapelli, Vanessa da Silva Silveira, Greice Andreotti de Molfetta, Wilson Araújo da Silva Júnior, Mariângela Ottoboni Brunaldi","doi":"10.1177/11772719231225206","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Immunohistochemical prognostic significance of the homologous recombination-related proteins RAD51, ATM, BRCA1, and BRCA2 is known in gastric adenocarcinoma, one of the deadliest cancers.</p><p><strong>Objective and design: </strong>This retrospective cohort study aimed to evaluate mRNA expression and promoter methylation of some homologous recombination-related genes in this neoplasm.</p><p><strong>Methods: </strong>We evaluated mRNA expression and methylation of <i>RAD51</i>, <i>ATM</i>, <i>ATR</i>, <i>BRCA1</i>, and <i>BRCA2</i> in tumor and non-tumor frozen samples from gastrectomy specimens by RT-qPCR and MS-HRM, correlating our results with previous immunohistochemistry data and prognostic features.</p><p><strong>Results: </strong><i>RAD51</i>, <i>ATR</i>, <i>BRCA1</i>, <i>BRCA2</i>, and <i>ATM</i> mRNA expression was detected in 93.75% (45/48), 93.75% (45/48), 91.67% (44/48), 83.33% (40/48), and 89.58% (43/48) of the tumors; partial or complete methylation, in 94.87% (37/39), 0 (0/42), 97.56% (40/41), 100% (41/41), and 0 (0/40), respectively. Most gene pairs showed significant weak to moderate positive correlations of tumoral mRNA expression with each other: <i>RAD51</i> with <i>ATR</i> (<i>P</i> = .027), <i>BRCA1</i> (<i>P</i> < .001), and <i>BRCA2</i> (<i>P</i> < .001); <i>ATR</i> with <i>BRCA1</i> (<i>P</i> = .007), and <i>ATM</i> (<i>P</i> = .001); <i>BRCA1</i> with <i>BRCA2</i> (<i>P</i> = 0.001). <i>BRCA1</i> mRNA was reduced in tumors compared with non-neoplastic mucosa (0.345 vs 1.272, <i>P</i> = .015) and, excluding neoadjuvant therapy cases, in T3 to T4 tumors compared with T2 (0.414 vs 0.954, <i>P</i> = .035). Greater tumoral <i>RAD51</i> mRNA levels correlated with perineural invasion (1.822 vs 0.725, <i>P</i> = .010) and death (1.664 vs 0.929, <i>P</i> = .036), but not with survival time. There was an inverse association between nuclear immunohistochemical positivity for ATR and its mRNA levels (0.487 vs 0.907, <i>P</i> = .032), and no significant correlation for the other markers.</p><p><strong>Conclusions: </strong>Our results suggest <i>RAD51</i>, <i>BRCA1</i>, and <i>BRCA2</i> methylation as a frequent epigenetic mechanism in gastric cancer, support the hypothesis that reduced <i>BRCA1</i> expression participates in disease progression, and show an association between <i>RAD51</i> mRNA and perineural invasion and mortality that may be considered unexpected, considering the former immunohistochemical studies. The lack of correlation between immunohistochemistry and mRNA, and even the inverse association, for <i>ATR</i>, can be seen as indicative of action of post-transcriptional or post-translational regulatory mechanisms, to be better investigated.</p>","PeriodicalId":47060,"journal":{"name":"Biomarker Insights","volume":null,"pages":null},"PeriodicalIF":3.4000,"publicationDate":"2024-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10826385/pdf/","citationCount":"0","resultStr":"{\"title\":\"mRNA Expression and Methylation of the <i>RAD51</i>, <i>ATM</i>, <i>ATR</i>, <i>BRCA1</i>, and <i>BRCA2</i> Genes in Gastric Adenocarcinoma.\",\"authors\":\"Joel Del Bel Pádua, Carolline Fontes Alves Mariano, Alexandre Todorovic Fabro, Fermino Sanches Lizarte Neto, Rogério Lenotti Zuliani, Cláudia Tarcila Gomes Sares, José Sebastião Dos Santos, Ajith Kumar Sankarankutty, Daniela Pretti da Cunha Tirapelli, Vanessa da Silva Silveira, Greice Andreotti de Molfetta, Wilson Araújo da Silva Júnior, Mariângela Ottoboni Brunaldi\",\"doi\":\"10.1177/11772719231225206\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Immunohistochemical prognostic significance of the homologous recombination-related proteins RAD51, ATM, BRCA1, and BRCA2 is known in gastric adenocarcinoma, one of the deadliest cancers.</p><p><strong>Objective and design: </strong>This retrospective cohort study aimed to evaluate mRNA expression and promoter methylation of some homologous recombination-related genes in this neoplasm.</p><p><strong>Methods: </strong>We evaluated mRNA expression and methylation of <i>RAD51</i>, <i>ATM</i>, <i>ATR</i>, <i>BRCA1</i>, and <i>BRCA2</i> in tumor and non-tumor frozen samples from gastrectomy specimens by RT-qPCR and MS-HRM, correlating our results with previous immunohistochemistry data and prognostic features.</p><p><strong>Results: </strong><i>RAD51</i>, <i>ATR</i>, <i>BRCA1</i>, <i>BRCA2</i>, and <i>ATM</i> mRNA expression was detected in 93.75% (45/48), 93.75% (45/48), 91.67% (44/48), 83.33% (40/48), and 89.58% (43/48) of the tumors; partial or complete methylation, in 94.87% (37/39), 0 (0/42), 97.56% (40/41), 100% (41/41), and 0 (0/40), respectively. Most gene pairs showed significant weak to moderate positive correlations of tumoral mRNA expression with each other: <i>RAD51</i> with <i>ATR</i> (<i>P</i> = .027), <i>BRCA1</i> (<i>P</i> < .001), and <i>BRCA2</i> (<i>P</i> < .001); <i>ATR</i> with <i>BRCA1</i> (<i>P</i> = .007), and <i>ATM</i> (<i>P</i> = .001); <i>BRCA1</i> with <i>BRCA2</i> (<i>P</i> = 0.001). <i>BRCA1</i> mRNA was reduced in tumors compared with non-neoplastic mucosa (0.345 vs 1.272, <i>P</i> = .015) and, excluding neoadjuvant therapy cases, in T3 to T4 tumors compared with T2 (0.414 vs 0.954, <i>P</i> = .035). Greater tumoral <i>RAD51</i> mRNA levels correlated with perineural invasion (1.822 vs 0.725, <i>P</i> = .010) and death (1.664 vs 0.929, <i>P</i> = .036), but not with survival time. There was an inverse association between nuclear immunohistochemical positivity for ATR and its mRNA levels (0.487 vs 0.907, <i>P</i> = .032), and no significant correlation for the other markers.</p><p><strong>Conclusions: </strong>Our results suggest <i>RAD51</i>, <i>BRCA1</i>, and <i>BRCA2</i> methylation as a frequent epigenetic mechanism in gastric cancer, support the hypothesis that reduced <i>BRCA1</i> expression participates in disease progression, and show an association between <i>RAD51</i> mRNA and perineural invasion and mortality that may be considered unexpected, considering the former immunohistochemical studies. The lack of correlation between immunohistochemistry and mRNA, and even the inverse association, for <i>ATR</i>, can be seen as indicative of action of post-transcriptional or post-translational regulatory mechanisms, to be better investigated.</p>\",\"PeriodicalId\":47060,\"journal\":{\"name\":\"Biomarker Insights\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.4000,\"publicationDate\":\"2024-01-29\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10826385/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Biomarker Insights\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1177/11772719231225206\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q2\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biomarker Insights","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1177/11772719231225206","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/1/1 0:00:00","PubModel":"eCollection","JCR":"Q2","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
mRNA Expression and Methylation of the RAD51, ATM, ATR, BRCA1, and BRCA2 Genes in Gastric Adenocarcinoma.
Background: Immunohistochemical prognostic significance of the homologous recombination-related proteins RAD51, ATM, BRCA1, and BRCA2 is known in gastric adenocarcinoma, one of the deadliest cancers.
Objective and design: This retrospective cohort study aimed to evaluate mRNA expression and promoter methylation of some homologous recombination-related genes in this neoplasm.
Methods: We evaluated mRNA expression and methylation of RAD51, ATM, ATR, BRCA1, and BRCA2 in tumor and non-tumor frozen samples from gastrectomy specimens by RT-qPCR and MS-HRM, correlating our results with previous immunohistochemistry data and prognostic features.
Results: RAD51, ATR, BRCA1, BRCA2, and ATM mRNA expression was detected in 93.75% (45/48), 93.75% (45/48), 91.67% (44/48), 83.33% (40/48), and 89.58% (43/48) of the tumors; partial or complete methylation, in 94.87% (37/39), 0 (0/42), 97.56% (40/41), 100% (41/41), and 0 (0/40), respectively. Most gene pairs showed significant weak to moderate positive correlations of tumoral mRNA expression with each other: RAD51 with ATR (P = .027), BRCA1 (P < .001), and BRCA2 (P < .001); ATR with BRCA1 (P = .007), and ATM (P = .001); BRCA1 with BRCA2 (P = 0.001). BRCA1 mRNA was reduced in tumors compared with non-neoplastic mucosa (0.345 vs 1.272, P = .015) and, excluding neoadjuvant therapy cases, in T3 to T4 tumors compared with T2 (0.414 vs 0.954, P = .035). Greater tumoral RAD51 mRNA levels correlated with perineural invasion (1.822 vs 0.725, P = .010) and death (1.664 vs 0.929, P = .036), but not with survival time. There was an inverse association between nuclear immunohistochemical positivity for ATR and its mRNA levels (0.487 vs 0.907, P = .032), and no significant correlation for the other markers.
Conclusions: Our results suggest RAD51, BRCA1, and BRCA2 methylation as a frequent epigenetic mechanism in gastric cancer, support the hypothesis that reduced BRCA1 expression participates in disease progression, and show an association between RAD51 mRNA and perineural invasion and mortality that may be considered unexpected, considering the former immunohistochemical studies. The lack of correlation between immunohistochemistry and mRNA, and even the inverse association, for ATR, can be seen as indicative of action of post-transcriptional or post-translational regulatory mechanisms, to be better investigated.
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