Institute of Human Genetics, University Hospital Schleswig-Holstein, Campus Kiel/Christian-Albrechts, University Kiel, D-24105 Kiel, Germany.
Int J Oncol. 2011 Aug;39(2):505-14. doi: 10.3892/ijo.2011.1039. Epub 2011 May 11.
Fanconi anemia (FA) associated genes [FANCA, -B, -C, FANCD1(BRCA2), -D2, -E, -F, -G, -I, -L, -M, FANCN (PALB2), FANCJ(BRIP1) and FA-linked BRCA1] encode proteins of DNA damage response pathways mutated in FA patients. FA is characterized by congenital malformations, chromosomal instability and high cancer susceptibility. FA patients have a 500-700 times higher risk of head and neck squamous cell carcinoma (HNSCC) compared to the non-FA population. As DNA methylation comprises one of the known gene inactivation mechanisms in cancer we have investigated the methylation status of 13 FA and one FA-linked gene in order to assess the role of FA in sporadic laryngeal squamous cell carcinoma (LSCC) tumor samples. Thirteen laryngeal squamous carcinoma cell lines (UT-SCC) and 64 primary laryngeal carcinoma cases were analyzed by bisulfite pyrosequencing. DNA from buccal swabs of 10 healthy volunteers was used as a control group. Promoter regions of FANCA, BRCA1 and BRCA2 displayed recurrent alterations in the methylation levels in cancer samples as compared to buccal swabs controls. For FANCA, hypomethylation was observed in 11/13 cell lines (p<0.0003) and all 64 primary larynx samples (p<0.001) compared to buccal swabs. For BRCA1, 4/13 cell lines (p=0.04) and 3/58 primary laryngeal cases (p=0.22) showed hypomethylation. In BRCA2, all 13 cell lines (p<0.0001) 4/63 primary LSCC (p<0.01) showed hypermethylation as compared to controls. In conclusion, we show recurrent alterations of DNA methylation levels in three Fanconi anemia genes which might contribute to the pathogenesis of LSCC.
范可尼贫血（FA）相关基因[FANCA、-B、-C、FANCD1（BRCA2）、-D2、-E、-F、-G、-I、-L、-M、FANCN（PALB2）、FANCJ（BRIP1）和 FA 相关的 BRCA1]编码 DNA 损伤反应途径中的蛋白质，这些蛋白质在 FA 患者中发生突变。FA 的特征是先天畸形、染色体不稳定和高癌症易感性。与非 FA 人群相比，FA 患者患头颈部鳞状细胞癌（HNSCC）的风险高出 500-700 倍。由于 DNA 甲基化是癌症中已知的基因失活机制之一，我们研究了 13 个 FA 和 1 个 FA 相关基因的甲基化状态，以评估 FA 在散发性喉鳞状细胞癌（LSCC）肿瘤样本中的作用。通过亚硫酸氢盐焦磷酸测序分析了 13 个喉鳞状细胞癌细胞系（UT-SCC）和 64 例原发性喉癌病例。10 名健康志愿者的口腔拭子 DNA 用作对照组。与口腔拭子对照组相比，在癌症样本中观察到 FANCA、BRCA1 和 BRCA2 的启动子区域的甲基化水平发生了反复改变。对于 FANCA，与口腔拭子相比，13 个细胞系中的 11 个（p<0.0003）和所有 64 个原发性喉样本（p<0.001）中观察到低甲基化。对于 BRCA1，13 个细胞系中的 4 个（p=0.04）和 58 个原发性喉癌病例中的 3 个（p=0.22）显示低甲基化。在 BRCA2 中，与对照组相比，所有 13 个细胞系（p<0.0001）和 63 个原发性 LSCC 中的 4 个（p<0.01）显示高甲基化。总之，我们显示了三个范可尼贫血基因中 DNA 甲基化水平的反复改变，这可能有助于 LSCC 的发病机制。
