Sequential molecular abnormalities are involved in the multistage development of squamous cell lung carcinoma
Sequential molecular abnormalities are involved in the multistage development of squamous cell lung carcinoma
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DOI：
10.1038/sj.onc.1202349
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发表时间：
1999-01-21
期刊：
影响因子：
8
通讯作者：
Gazdar, AF
中科院分区：
文献类型：
--
作者：
Wistuba, II;Behrens, C;Gazdar, AF
为了解肺鳞状细胞癌发病的分子机制，我们从12例外科手术切除的肿瘤组织中提取了94个DNA，包括组织学正常上皮(n=13)、癌前病变(n=54)、原位癌(CIS)(n=15)和浸润性肿瘤(n=12)。我们利用31个多态微卫星标记，包括24个横跨整个3p臂的微卫星标记，检测了肺癌中常见缺失的10个染色体区域(3p12、3p14.2、3p14.1-21.3、3p21、3p22-24、3p25、5q22、9p21、13q14 RE和17p13 TP53)的杂合性缺失(LOH)。我们的主要发现如下：(1)31%的组织学正常上皮和42%的轻度异常(增生/化生)标本中有一个或多个区域存在等位基因缺失的细胞克隆；(2)克隆内总的LOH频率随着组织病理学变化的加重而逐渐增加；(3)等位基因缺失的最早和最频繁的区域发生在3p21、3p22-24、3p25和9p21；(4)3p缺失的大小随着组织学变化的进展而增大；(5)在许多组织学晚期病变(异型增生和CIS)中存在TP53等位基因缺失；(6)对58个有任何分子异常的正常和非侵袭性病灶的分析表明，30个可能是独立的克隆事件，28个可能与相应的肿瘤具有相同的克隆起源：(7)当比较30个克隆性独立病变和它们的克隆性无关肿瘤的等位基因丢失时，在125个比较中有113个(90%)丢失了相同的亲本等位基因。这种现象(称为等位基因特异性突变)发生的机制尚不清楚；(8)在克隆中发现了四种等位基因丢失模式。组织学正常或轻度异常的病灶为阴性(无等位基因丢失)或早期丢失，而CIS和浸润性肿瘤的病灶均为进展型。然而，异型增生显示了等位基因丢失模式的整个谱，并且是唯一具有中间模式的组织学类别。我们的发现表明，在肺鳞状细胞癌的多阶段发病机制的早期，广泛分散的、明显的克隆性独立的病灶开始发生多个、顺序发生的等位基因特异性分子变化。
To understand the molecular pathways involved in the pathogenesis of squamous cell lung carcinoma, we obtained DNA from 94 microdissected foci from 12 archival surgically resected tumors including histologically normal epithelium (n = 13), preneoplastic lesions (n = 54), carcinoma is situ (CIS) (n = 15) and invasive tumors (n = 12). We determined loss of heterozygosity (LOH) at 10 chromosomal regions (3p12, 3p14.2, 3p14.1-21.3, 3p21, 3p22-24, 3p25, 5q22, 9p21, 13q14 RE, and 17p13 TP53) frequently deleted in lung cancer, using 31 polymorphic microsatellite markers, including 24 that spanned the entire 3p arm. Our major findings are as follows: (1) Thirty one percent of histologically normal epithelium and 42% of mildly abnormal (hyperplasia/metaplasia) specimens had clones of cells with allelic loss at one or more regions; (2) There was a progressive increase of the overall LOH frequency within clones with increasing severity of histopathological changes; (3) The earliest and most frequent regions of allelic loss occurred at 3p21, 3p22-24, 3p25 and 9p21; (4) The size of the 3p deletions increased with progressive histologic changes; (5) TP53 allelic loss was present in many histologically advanced lesions (dysplasia and CIS); (6) Analyses of 58 normal and non-invasive foci having any molecular abnormality, indicated that 30 probably arose as independent clonal events, while 28 were potentially of the same clonal origin as the corresponding tumor; (7) Nevertheless, when the allelic losses in the 30 clonally independent lesions and their clonally unrelated tumors were compared the same parental allele was lost in 113 of 125 (90%) of comparisons. The mechanism by which this phenomenon (known as allele specific mutations) occurs is unknown; (8) Four patterns of allelic loss in clones were found. Histologically normal or mildly abnormal foci had a negative pattern (no allelic loss) or early pattern of loss while all foci of CIS and invasive tumor had an advanced pattern. However dysplasias demonstrated the entire spectrum of allelic loss patterns, and were the only histologic category having the intermediate pattern. Our findings indicate that multiple, sequentially occurring allele specific molecular changes commence in widely dispersed, apparently clonally independent foci, early in the multistage pathogenesis of squamous cell carcinomas of the lung.