Pádua Joel Del Bel, Mariano Carolline Fontes Alves, Fabro Alexandre Todorovic, Lizarte Neto Fermino Sanches, Zuliani Rogério Lenotti, Sares Cláudia Tarcila Gomes, Dos Santos José Sebastião, Sankarankutty Ajith Kumar, Tirapelli Daniela Pretti da Cunha, Silveira Vanessa da Silva, de Molfetta Greice Andreotti, Júnior Wilson Araújo da Silva, Brunaldi Mariângela Ottoboni
Department of Pathology and Forensic Medicine, Ribeirão Preto Medical School, Universidade de São Paulo (USP), Ribeirão Preto, SP, Brazil.
Department of Surgery and Anatomy, Ribeirão Preto Medical School, USP, Ribeirão Preto, SP, Brazil.
Biomark Insights. 2024 Jan 29;19:11772719231225206. doi: 10.1177/11772719231225206. eCollection 2024.
Immunohistochemical prognostic significance of the homologous recombination-related proteins RAD51, ATM, BRCA1, and BRCA2 is known in gastric adenocarcinoma, one of the deadliest cancers.
This retrospective cohort study aimed to evaluate mRNA expression and promoter methylation of some homologous recombination-related genes in this neoplasm.
We evaluated mRNA expression and methylation of , , , , and 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.
, , , , and 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: with ( = .027), ( < .001), and ( < .001); with ( = .007), and ( = .001); with ( = 0.001). mRNA was reduced in tumors compared with non-neoplastic mucosa (0.345 vs 1.272, = .015) and, excluding neoadjuvant therapy cases, in T3 to T4 tumors compared with T2 (0.414 vs 0.954, = .035). Greater tumoral mRNA levels correlated with perineural invasion (1.822 vs 0.725, = .010) and death (1.664 vs 0.929, = .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, = .032), and no significant correlation for the other markers.
Our results suggest , , and methylation as a frequent epigenetic mechanism in gastric cancer, support the hypothesis that reduced expression participates in disease progression, and show an association between 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 , can be seen as indicative of action of post-transcriptional or post-translational regulatory mechanisms, to be better investigated.
同源重组相关蛋白RAD51、ATM、BRCA1和BRCA2的免疫组化预后意义在胃癌（最致命的癌症之一）中是已知的。
这项回顾性队列研究旨在评估该肿瘤中一些同源重组相关基因的mRNA表达和启动子甲基化情况。
我们通过RT-qPCR和MS-HRM评估了胃癌切除标本中肿瘤和非肿瘤冷冻样本中、、、和的mRNA表达和甲基化情况，并将我们的结果与先前的免疫组化数据和预后特征相关联。
在93.75%（45/48）、93.75%（45/48）、91.67%（44/48）、83.33%（40/48）和89.58%（43/48）的肿瘤中检测到、、、和的mRNA表达；部分或完全甲基化分别为94.87%（37/39）、0（0/42）、97.56%（40/41）、100%（41/41）和0（0/40）。大多数基因对显示肿瘤mRNA表达之间存在显著的弱至中度正相关：与（=0.027）、（<0.001）和（<0.001）；与（=0.007）和（=0.001）；与（=0.001）。与非肿瘤黏膜相比，肿瘤中的mRNA减少（0.345对1.272，=0.015），并且排除新辅助治疗病例后，与T2期肿瘤相比，T3至T4期肿瘤中的mRNA减少（0.414对0.954，=0.035）。更高的肿瘤mRNA水平与神经周围浸润（1.822对0.725，=0.010）和死亡（1.664对0.929，=0.036）相关，但与生存时间无关。ATR核免疫组化阳性与其mRNA水平之间存在负相关（0.487对0.907，=0.032），而其他标志物无显著相关性。
我们的结果表明、和甲基化是胃癌中常见的表观遗传机制，支持表达降低参与疾病进展的假设，并显示mRNA与神经周围浸润和死亡率之间的关联，考虑到先前的免疫组化研究，这可能被认为是出乎意料的。、免疫组化与mRNA之间缺乏相关性，甚至存在负相关，可以被视为转录后或翻译后调控机制作用的指标，有待进一步深入研究。
