Burke L, Khan M A, Freedman A N, Gemma A, Rusin M, Guinee D G, Bennett W P, Caporaso N E, Fleming M V, Travis W D, Colby T V, Trastek V, Pairolero P C, Tazelaar H D, Midthun D E, Liotta L A, Harris C C
National Cancer Institute, Bethesda, Maryland 20892, USA.
Cancer Res. 1998 Jun 15;58(12):2533-6.
The fragile histidine triad (FHIT) gene at chromosome 3p14.2 is a candidate tumor suppressor gene linked to cancers of the lung, breast, colon, pancreas, and head and neck. Reports of frequent allelic deletion and abnormal transcripts in primary lung tumors plus recent evidence that it is targeted by tobacco smoke carcinogens suggest that it plays an important role in lung carcinogenesis. Non-small cell lung carcinoma still maintains a poor 5-year survival rate with the stage of disease at presentation as a major determinant of prognosis. We examined for allelic deletion at the FHIT locus in a series of 106 non-small cell lung carcinomas for which a full clinical, epidemiological, and 5-year survival profile was available. We found an allelic deletion frequency of 38% at one or two intragenic microsatellites. Allelic deletion of FHIT was related to tumor histology with 4 of 20 adenocarcinomas (20%) displaying loss of heterozygosity (LOH) compared with 12 of 22 (55%) nonadenocarcinomas (P = 0.03). We found that 63% of tumors with LOH of FHIT also had p53 missense mutations whereas only 26% with LOH had wild type p53 negative sequence (P = 0.02). We also found a significant trend toward poorer survival in patients with LOH of at least one locus of the FHIT gene (log rank, P = 0.01). This survival correlation is independent of tumor stage, size, histological subtype, degree of differentiation, and p53 mutation status. Our data support the hypothesis that the loss of the FHIT contributes to the molecular pathogenesis of human lung cancer and is an indicator of poor prognosis.
位于染色体3p14.2的脆性组氨酸三联体（FHIT）基因是一种候选肿瘤抑制基因，与肺癌、乳腺癌、结肠癌、胰腺癌以及头颈癌相关。原发性肺癌中频繁出现等位基因缺失和异常转录本的报道，以及最近关于它是烟草烟雾致癌物作用靶点的证据表明，该基因在肺癌发生过程中发挥重要作用。非小细胞肺癌的5年生存率仍然很低，疾病呈现时的阶段是预后的主要决定因素。我们检测了106例非小细胞肺癌患者FHIT基因座的等位基因缺失情况，这些患者均有完整的临床、流行病学及5年生存资料。我们发现一个或两个基因内微卫星处的等位基因缺失频率为38%。FHIT等位基因缺失与肿瘤组织学相关，20例腺癌中有4例（20%）显示杂合性缺失（LOH），相比之下，22例非腺癌中有12例（55%）出现LOH（P = 0.03）。我们发现，FHIT基因发生LOH的肿瘤中，63%同时存在p53错义突变，而发生LOH的肿瘤中只有26%的p53基因序列为野生型阴性（P = 0.02）。我们还发现，FHIT基因至少一个位点发生LOH的患者生存率有显著降低的趋势（对数秩检验，P = 0.01）。这种生存相关性与肿瘤分期、大小、组织学亚型、分化程度及p53突变状态无关。我们的数据支持这样的假说，即FHIT基因缺失促成了人类肺癌的分子发病机制，并且是预后不良的一个指标。
