Zöchbauer-Müller S, Fong K M, Maitra A, Lam S, Geradts J, Ashfaq R, Virmani A K, Milchgrub S, Gazdar A F, Minna J D
Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Cancer Res. 2001 May 1;61(9):3581-5.
Allele loss and loss of expression of fragile histidine triad (FHIT), a putative tumor suppressor gene located in chromosome region 3p14.2, are frequent in several types of cancers. Tumor-acquired methylation of promoter region CpG islands is one method for silencing tumor suppressor genes. We investigated 5' CpG island methylation of the FHIT gene in 107 primary non-small cell lung cancer (NSCLC) samples and corresponding nonmalignant lung tissues, 39 primary breast carcinomas, as well as in 49 lung and 22 breast cancer cell lines by a methylation-specific PCR assay. In addition, we analyzed brushes from the bronchial epithelium of 35 heavy smokers without cancer. FHIT methylation was detected in 37% of primary NSCLCs, 31% of primary breast cancers, and 65% of lung and 86% of breast cancer cell lines. The frequency of methylation in small cell and NSCLC cell lines were identical. Methylation was found in 9% of the corresponding nonmalignant lung tissues and in 17% of bronchial brushes from heavy cigarette smokers. FHIT methylation was significantly correlated with loss of FHIT mRNA expression by Northern blot analysis in lung cancer cell lines and with loss of Fhit expression in NSCLC and breast tumors by immunostaining. We conclude that methylation of FHIT is a frequent event in NSCLC and breast cancers and is an important mechanism for loss of expression of this gene. Methylation of FHIT commences during lung cancer pathogenesis and may represent a marker for risk assessment.
脆性组氨酸三联体（FHIT）是一个位于染色体3p14.2区域的假定肿瘤抑制基因，其等位基因缺失和表达缺失在多种癌症中很常见。肿瘤获得性启动子区域CpG岛甲基化是使肿瘤抑制基因沉默的一种方法。我们通过甲基化特异性PCR分析，研究了107例原发性非小细胞肺癌（NSCLC）样本及相应的非恶性肺组织、39例原发性乳腺癌以及49株肺癌细胞系和22株乳腺癌细胞系中FHIT基因的5' CpG岛甲基化情况。此外，我们还分析了35名无癌症的重度吸烟者支气管上皮的刷检样本。在37%的原发性NSCLC、31%的原发性乳腺癌、65%的肺癌细胞系和8\6%的乳腺癌细胞系中检测到FHIT甲基化。小细胞肺癌和NSCLC细胞系中的甲基化频率相同。在9%的相应非恶性肺组织和17%的重度吸烟者支气管刷检样本中发现甲基化。通过Northern印迹分析，FHIT甲基化与肺癌细胞系中FHIT mRNA表达缺失显著相关，通过免疫染色与NSCLC和乳腺肿瘤中Fhit表达缺失显著相关。我们得出结论，FHIT甲基化在NSCLC和乳腺癌中是常见事件，是该基因表达缺失的重要机制。FHIT甲基化在肺癌发病过程中开始，可能代表一种风险评估标志物。
