Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China.
Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, People's Republic of China.
J Cancer Res Clin Oncol. 2023 Sep;149(11):8557-8571. doi: 10.1007/s00432-023-04745-8. Epub 2023 Apr 25.
Aberrant methylation of Ras association domain family 1, isoform A (RASSF1A), and short-stature homeobox gene 2 (SHOX2) promoters has been validated as a pair of valuable biomarkers for diagnosing early lung adenocarcinomas (LUADs). Epidermal growth factor receptor (EGFR) is the key driver mutation in lung carcinogenesis. This study aimed to investigate the aberrant promoter methylation of RASSF1A and SHOX2, and the genetic mutation of EGFR in 258 specimens of early LUADs.
We retrospectively selected 258 paraffin-embedded samples of pulmonary nodules measuring 2 cm or less in diameter and evaluated the diagnostic performance of individual biomarker assays and multiple panels between noninvasive (group 1) and invasive lesions (groups 2A and 2B). Then, we investigated the interaction between genetic and epigenetic alterations.
The degree of RASSF1A and SHOX2 promoter methylation and EGFR mutation was significantly higher in invasive lesions than in noninvasive lesions. The three biomarkers distinguished between noninvasive and invasive lesions with reliable sensitivity and specificity: 60.9% sensitivity [95% confidence interval (CI) 52.41-68.78] and 80.0% specificity (95% CI 72.14-86.07). The novel panel biomarkers could further discriminate among three invasive pathological subtypes (area under the curve value > 0.6). The distribution of RASSF1A methylation and EGFR mutation was considerably exclusive in early LUAD (P = 0.002).
DNA methylation of RASSF1A and SHOX2 is a pair of promising biomarkers, which may be used in combination with other driver alterations, such as EGFR mutation, to support the differential diagnosis of LUADs, especially for stage I.
Ras 相关结构域家族 1 异构体 A（RASSF1A）和矮小同源盒基因 2（SHOX2）启动子的异常甲基化已被验证为诊断早期肺腺癌（LUAD）的一对有价值的生物标志物。表皮生长因子受体（EGFR）是肺癌发生的关键驱动突变。本研究旨在探讨 258 例早期 LUAD 中 RASSF1A 和 SHOX2 启动子的异常甲基化和 EGFR 基因突变。
我们回顾性选择了 258 例直径 2cm 或以下的肺结节石蜡包埋样本，并评估了单个生物标志物检测和多个检测面板在非侵袭性病变（第 1 组）和侵袭性病变（第 2A 组和第 2B 组）之间的诊断性能。然后，我们研究了遗传和表观遗传改变之间的相互作用。
与非侵袭性病变相比，侵袭性病变中 RASSF1A 和 SHOX2 启动子甲基化和 EGFR 突变程度更高。三个生物标志物具有可靠的灵敏度和特异性，可区分非侵袭性和侵袭性病变：60.9%的灵敏度（95%置信区间[CI] 52.41-68.78）和 80.0%的特异性（95%CI 72.14-86.07）。新的面板生物标志物可以进一步区分三种侵袭性病理亚型（曲线下面积值>0.6）。RASSF1A 甲基化和 EGFR 突变的分布在早期 LUAD 中差异显著（P=0.002）。
RASSF1A 和 SHOX2 的 DNA 甲基化是一对很有前途的生物标志物，可能与其他驱动突变（如 EGFR 突变）结合使用，以支持 LUAD 的鉴别诊断，尤其是对 I 期 LUAD。
