Pathology and Molecular Biology Center, National Cancer Hospital K, 30 Cau Buou Street, Thanh Tri, Hanoi, Viet Nam; Biotechnology Department, Graduate University of Science and Technology, Academy of Science and Technology, 18 Hoang Quoc Viet Street, Cau Giay, Hanoi, Viet Nam.
Pathology and Molecular Biology Center, National Cancer Hospital K, 30 Cau Buou Street, Thanh Tri, Hanoi, Viet Nam.
Pathol Res Pract. 2019 May;215(5):885-892. doi: 10.1016/j.prp.2019.01.032. Epub 2019 Jan 29.
Genetic and epigenetic alterations importantly contribute to the pathogenesis of lung cancer. In the study, we measured the frequency and distribution of molecular abnormalities of EGFR as well as the aberrant promoter methylations of BRCA1, MGMT, MLH1, and RASSF1A in Vietnamese lung adenocarcinomas. We investigated the association between genetic and epigenetic alteration, and between each abnormality with clinicopathologic parameters. Somatic EGFR mutation that was found in 49/139 (35.3%) lung adenocarcinomas showed a significant association with young age, female gender, and non-smokers. EGFR overexpression was identified in 82 tumors (59.0%) and statistical relationships with EGFR or BRCA1 methylation but not EGFR mutation. In addition, EGFR, BRCA1, MGMT, MLH1, and RASSF1A methylations were found in 33 (23.7%), 41 (29.5%), 46 (33.1%), 28 (20.1%), and 41 (29.5%) cases of a total of 139 lung adenocarcinomas, respectively. The RASSF1A methylation was found to be linked to the smoking habit. Methylations in MGMT and RASSF1A were also found to correlate with metastasis status. Furthermore, the distribution of EGFR mutation and that of BRCA1, MGMT or RASSF1A methylation were significantly exclusive in lung adenocarcinomas. The main finding of our study demonstrate that epigenetic abnormalities might play a critical role for the lung tumorigenesis in patients with smoking history and metastasis, and partly affect the predictive value of EGFR mutations through blocking expression due to promoter EGFR hypermethylation. Mutually exclusive distribution of genetic and epigenetic alterations reflects differently biological characteristics in the etiology of lung adenocarcinomas.
遗传和表观遗传改变对肺癌的发病机制有重要贡献。在这项研究中，我们测量了 EGFR 的分子异常的频率和分布，以及 BRCA1、MGMT、MLH1 和 RASSF1A 在越南肺腺癌中的异常启动子甲基化。我们研究了遗传和表观遗传改变之间的关联，以及每种异常与临床病理参数之间的关联。在 139 例肺腺癌中发现了 49 例（35.3%）的体细胞 EGFR 突变，该突变与年龄较小、女性和非吸烟者显著相关。在 82 例肿瘤中检测到 EGFR 过表达（59.0%），与 EGFR 或 BRCA1 甲基化具有统计学关系，但与 EGFR 突变无关。此外，在总共 139 例肺腺癌中，分别发现 33 例（23.7%）、41 例（29.5%）、46 例（33.1%）、28 例（20.1%）和 41 例（29.5%）存在 EGFR、BRCA1、MGMT、MLH1 和 RASSF1A 的甲基化。RASSF1A 甲基化与吸烟习惯有关。MGMT 和 RASSF1A 的甲基化也与转移状态相关。此外，EGFR 突变的分布与 BRCA1、MGMT 或 RASSF1A 甲基化的分布在肺腺癌中显著不同。我们的研究主要发现表明，表观遗传异常可能在有吸烟史和转移的患者的肺肿瘤发生中起关键作用，并通过启动子 EGFR 过度甲基化阻断表达，部分影响 EGFR 突变的预测价值。遗传和表观遗传改变的互斥分布反映了肺腺癌病因学中不同的生物学特征。
