Sahnane Nora, Rivera Daniela, Libera Laura, Carnevali Ileana, Banelli Barbara, Facchi Sofia, Gismondi Viviana, Paudice Michele, Cirmena Gabriella, Vellone Valerio G, Sessa Fausto, Varesco Liliana, Tibiletti Maria G
Unit of Pathology, Ospedale di Circolo, Azienda Socio Sanitaria Territoriale (ASST) Sette Laghi Hospital, Varese, Italy; Research Center for Familial and Hereditary Tumors, Department of Medicine and Surgery, University of Insubria, Varese, Italy.
Hereditary Cancer Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale Policlinico San Martino, Genoa, Italy.
J Mol Diagn. 2023 Apr;25(4):217-226. doi: 10.1016/j.jmoldx.2023.01.003. Epub 2023 Feb 3.
Epithelial ovarian cancers (EOCs) harboring germline or somatic pathogenic variants in BRCA1 and BRCA2 genes show sensitivity to poly(ADP-ribose) polymerase inhibition. It has been suggested that BRCA1 promoter methylation is perhaps a better determinant of therapy response, because of its intrinsic dynamic feature, with respect to genomic scars or gene mutation. Conflicting evidence was reported so far, and the lack of a validated assay to measure promoter methylation was considered a main confounding factor in data interpretation. To contribute to the validation process of a pyrosequencing assay for BRCA1 promoter methylation, 109 EOCs from two Italian centers were reciprocally blindly investigated. By comparing two different pyrosequencing assays, addressing a partially overlapping region of BRCA1 promoter, an almost complete concordance of results was obtained. Moreover, the clinical relevance of this approach was also supported by the finding of BRCA1 transcript down-regulation in BRCA1-methylated EOCs. These findings could lead to the development of a simple and cheap pyrosequencing assay for diagnostics, easily applicable to formalin-fixed, paraffin-embedded tissues. This technique may be implemented in routine clinical practice in the near future to identify EOCs sensitive to poly(ADP-ribose) polymerase inhibitor therapy, thus increasing the subset of women affected by EOCs who could benefit from such treatment.
携带BRCA1和BRCA2基因种系或体细胞致病变体的上皮性卵巢癌（EOC）对聚（ADP-核糖）聚合酶抑制敏感。有人提出，BRCA1启动子甲基化可能是治疗反应更好的决定因素，因为相对于基因组疤痕或基因突变，它具有内在的动态特征。到目前为止，已有相互矛盾的证据报道，并且缺乏用于测量启动子甲基化的经过验证的检测方法被认为是数据解释中的一个主要混杂因素。为了有助于BRCA1启动子甲基化焦磷酸测序检测的验证过程，对来自两个意大利中心的109例EOC进行了相互盲法研究。通过比较两种针对BRCA1启动子部分重叠区域的不同焦磷酸测序检测方法，结果几乎完全一致。此外，BRCA1甲基化的EOC中BRCA1转录本下调这一发现也支持了该方法的临床相关性。这些发现可能会促成一种简单且廉价的用于诊断的焦磷酸测序检测方法的开发，该方法易于应用于福尔马林固定、石蜡包埋的组织。这项技术可能在不久的将来应用于常规临床实践，以识别对聚（ADP-核糖）聚合酶抑制剂治疗敏感的EOC，从而增加可能从这种治疗中受益的EOC女性患者的比例。
