Haque Abida K, Au William, Cajas-Salazar Nohelia, Khan Shilpi, Ginzel Andrew W, Jones Dennie V, Zwischenberger Joseph B, Xie Jingwu
Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA.
Appl Immunohistochem Mol Morphol. 2004 Dec;12(4):315-22. doi: 10.1097/00129039-200412000-00005.
The expression of selected gene products involved in cell differentiation and cell growth and genetic polymorphism of detoxifying genes was examined in 105 surgically resected nonsmall cell lung cancer (NSCLC) patients, and the relationship of these factors was correlated with cigarette smoking and patient survival. Genotyping of peripheral blood lymphocytes from 87 patients was performed for CYP2E1, GSTM1, GSTT1, mEH, and MPO detoxifying genes using polymerase chain reaction. Formalin-fixed, paraffin-embedded tissue was immunostained with antibodies to p53, p27, phospho-AKT, and bcl-2 using the avidin-biotin-peroxidase method and tissue microarray technique. Tumors were assigned a positive or negative score based on more than 10% of tumor cells staining positive with the antibody. The subtypes of NSCLC included 48 adenocarcinomas, 47 squamous cell carcinomas, and 10 large cell undifferentiated carcinomas. A total of 54 tumors were pathologic stage I, 23 were stage II, and 26 were stage III. All subjects smoked (range, 10-175 pack-years; mean, 60 pack-years). The mean overall survival was 112 weeks (median, 129 weeks). Patients with p53-positive tumors had significantly fewer pack-years of smoking (52 pack-years vs 72 pack-years; P = 0.021), smoked fewer years (34 years vs 40 years; P = 0.018), and had significantly better survival compared with those with p53-negative tumors (P = 0.045). When smoking history was further analyzed, the authors found that p53 expression was associated with the number of years smoked and not the number of packs smoked per day. Patients with squamous cell carcinoma had smoked longer compared with those with adenocarcinoma (P = 0.011). Significant association was seen between the CYP2E1 wild-type allele and better survival (P = 0.016). Patients with stage I tumors had better survival compared with stages II and III (P = 0.032). No association was found between survival and tumor type; tumor differentiation; expression of phospho-AKT, p27, and bcl-2; and polymorphic metabolizing genes other than CYP2E1. The significant association of long duration of smoking (>40 years) with loss of p53 expression and poor survival suggests inactivation of the protective p53 pathway in those who had a history of more than 40 years of smoking.
在105例接受手术切除的非小细胞肺癌（NSCLC）患者中，检测了参与细胞分化和细胞生长的特定基因产物的表达以及解毒基因的遗传多态性，并将这些因素与吸烟情况和患者生存率进行关联分析。采用聚合酶链反应对87例患者外周血淋巴细胞的CYP2E1、GSTM1、GSTT1、mEH和MPO解毒基因进行基因分型。使用抗生物素蛋白-生物素-过氧化物酶法和组织芯片技术，用抗p53、p27、磷酸化AKT和bcl-2抗体对福尔马林固定、石蜡包埋的组织进行免疫染色。根据超过10%的肿瘤细胞被抗体染色呈阳性，将肿瘤分为阳性或阴性评分。NSCLC的亚型包括48例腺癌、47例鳞状细胞癌和10例大细胞未分化癌。共有54例肿瘤为病理I期，23例为II期，26例为III期。所有受试者均吸烟（范围：10 - 175包年；平均：60包年）。平均总生存期为112周（中位数：129周）。p53阳性肿瘤患者的吸烟包年数显著较少（52包年对72包年；P = 0.021），吸烟年限较短（34年对40年；P = 0.018），与p53阴性肿瘤患者相比，生存期显著更长（P = 0.045）。进一步分析吸烟史时，作者发现p53表达与吸烟年限有关，而与每日吸烟包数无关。鳞状细胞癌患者的吸烟时间比腺癌患者更长（P = 0.011）。CYP2E1野生型等位基因与更好的生存率之间存在显著关联（P = 0.016）。I期肿瘤患者的生存率优于II期和III期患者（P = 0.032）。未发现生存率与肿瘤类型、肿瘤分化、磷酸化AKT、p27和bcl-2的表达以及除CYP2E1以外的多态性代谢基因之间存在关联。吸烟时间长（>40年）与p53表达缺失及生存率差之间的显著关联表明，有超过40年吸烟史的人群中保护性p53通路失活。
