ALLELE-SPECIFIC LOSS IN CHROMOSOME 9P LOCI IN PRENEOPLASTIC LESIONS ACCOMPANYING NON-SMALL-CELL LUNG CANCERS
ALLELE-SPECIFIC LOSS IN CHROMOSOME 9P LOCI IN PRENEOPLASTIC LESIONS ACCOMPANYING NON-SMALL-CELL LUNG CANCERS
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DOI：
10.1093/jnci/87.16.1224
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发表时间：
1995-08-16
影响因子：
10.3
通讯作者：
GAZDAR, AF
中科院分区：
文献类型：
--
作者：
KISHIMOTO, Y;SUGIO, K;GAZDAR, AF
背景：癌变是一个多步骤的过程，可能开始作为染色体改变的结果。在肺癌中观察到9号染色体短臂（9 p）的缺失。此外，形态学上可识别的癌前病变，通常是多个，先于浸润性癌的发生。目的：我们检测了非小细胞肺癌（NSCLC）患者肺内癌前病变和肿瘤灶中9 p位点的缺失和杂合性丢失（洛）。方法：选择7例存档、石蜡包埋、手术切除的NSCLC标本。它们主要来自腺癌患者，包含多个癌前病变，包括增生、化生、异型增生和原位癌（CIS）。五十三个组织学鉴定的癌前病变和恶性病变存在于支气管，细支气管和肺泡精确显微解剖染色组织切片与显微操作。间质淋巴细胞用于确定组成杂合性。采用聚合酶链反应技术检测干扰素α（IFNA）和D9 S171位点的二核苷酸重复序列（微卫星标记）多态性，分析标本的洛缺失。结果：所有7例患者的一个或两个微卫星标记组成杂合。7例浸润性原发癌中有5例在一个或两个9 p位点上有洛丢失（双重信息病例）。这5例中有4例在癌前病变中也发现了洛缺失。在双重信息的情况下，洛检测到5（38%）的13个病灶的增生，4（80%）的5个病灶的异型增生，3（100%）的CIS病变。洛缺失在呼吸道所有区域的癌前病变中检测到，包括支气管、细支气管和肺泡，涉及五种不同的细胞类型。相同的等位基因在癌前病变和相应的肿瘤中丢失（12个病变中有12个，17个比较中有17个），我们称这种现象为“等位基因特异性突变”。采用累积二项检验的统计分析表明，这些发现偶然发生的概率分别为2.4 × 10（-4）和7.6 × 10（-6）。与先前发表的相同组织标本中其他染色体异常的数据相比，3 p和9 p位点的洛似乎发生在增生阶段的早期，但ras基因点突变相对较晚，在CIS阶段。结论：9 p位点的洛缺失发生于肺癌发病的最早期，并累及呼吸道的各个部位。非小细胞肺癌的洛缺失不是随机的，而是针对个体中的特定等位基因。研究癌前病变可能有助于确定风险评估和化学预防的中间标志物。
Background: Carcinogenesis is a multistep process, which may begin as a consequence of chromosomal changes. Deletions in the short arm of chromosome 9 (9p) have been observed in lung carcinomas. In addition, morphologically recognizable preneoplastic lesions, frequently multiple in number, precede onset of invasive carcinomas. Purpose: We tested for deletions and loss of heterozygosity (LOH) at 9p loci in preneoplastic and neoplastic foci in lungs of patients with non-small-cell lung carcinomas (NSCLCs). Methods: Seven archival, paraffin-embedded, surgically resected NSCLC specimens were selected. They were predominantly from patients with adenocarcinomas and contained multiple preneoplastic lesions, including hyperplasia, metaplasia, dysplasia, and carcinoma in situ (CIS). Fifty-three histologically identified preneoplastic and malignant lesions present in bronchi, bronchioles, and alveoli were precisely microdissected from stained tissue sections with a micromanipulator. Stromal lymphocytes were used to determine constitutional heterozygosity. The specimens were analyzed for LOH using polymerase chain reaction-based assays for polymorphism in dinucleotide repeats (microsatellite markers) in interferon alfa (IFNA) and D9S171 loci on 9p. Results: All seven cases were constitutionally heterozygous for one or both microsatellite markers. Five of seven cases had LOH at one or both 9p loci in the invasive primary cancers (doubly informative cases). Four of these five cases also revealed LOH in preneoplastic foci. In the doubly informative cases, LOH was detected in five (38%) of 13 foci of hyperplasia, four (80%) of five foci of dysplasia, and three (100%) of three CIS lesions. LOH was detected in preneoplastic lesions from all regions of the respiratory tract, including bronchi, bronchioles, and alveoli, and involved five different cell types. The identical allele was lost from both the preneoplastic lesions and the corresponding tumors (12 of 12 lesions, 17 of 17 comparisons), a phenomenon we have referred to as ''allele-specific mutation.'' Statistical analyses employing a cumulative binomial test demonstrated that the probabilities of such findings occurring by chance are 2.4 x 10(-4) and 7.6 x 10(-6), respectively. From comparisons with the previously published data on other chromosomal abnormalities in the same tissue specimens, it appears that LOH at 3p and 9p loci occurred early in the hyperplasia stage, but the ras gene point mutations were relatively late, at the CIS stage. Conclusions: LOH at 9p loci occurs at the earliest stage in the pathogenesis of lung cancer and involves all regions of the respiratory tract. LOH in NSCLC is not random but targets a specific allele in individuals. Studying preneoplastic lesions may help identify intermediate markers for risk assessment and chemoprevention.