Sequential molecular abnormalities are involved in the multistage development of squamous cell lung carcinoma

Abstract

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 RB, and 17p13 TP53) frequently deleted in lung cancer, using 31 polymorphic microsatellite markers, including 24 that spanned the entire 3p arm. Our major ®ndings 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 speci®c 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 ®ndings indicate that multiple, sequentially occurring allele speci®c molecular changes commence in widely dispersed, apparently clonally independent foci, early in the multistage pathogenesis of squamous cell carcinomas of the lung.

Microscopic analysis of chromium accumulation in the bronchi and lung of chromate workers

“…13 Sozzi et al 29 reported that MSI was found not only in lung carcinoma (32%) but also in normal epithelia (36%). Wistuba et al 30 reported a progressive increase in LOH frequency according to increasing severity of histopathologic changes in squamous cell carcinoma. Others have also pointed out that the incidence of aberrant promoter methylation of the p16 tumor suppressor gene gradually increased with malignant progression in preneoplastic lesions of human squamous cell carcinoma.…”

The association between atypical adenomatous hyperplasia and primary lung cancer

“…The finding of multiple AAH lesions in patients with multiple lung cancers, together with the report of AAH in a patient with multiple synchronous lung cancers in Li-Fraumeni syndrome (Nadav et al, 1998) and multiple AAH lesions associated with tumours which have deletions in the tuberous sclerosis complex (TSC-1) region on 9 q (Suzuki et al, 1998b), raises interesting questions about possible underlying genetic abnormalities in this disease. The idea that multiple AAH may represent a form of 'field cancerization' in the lung periphery is also an attractive one, similar to the widespread genotypic changes which parallel the multifocal phenotypic changes seen in the bronchial epithelium in many tobacco smokers (Wistuba et al, 1999). Niho et al (1999) have demonstrated monoclonality in AAH with clonal heterogeneity between multiple AAH lesions from the same patient.…”

Histological types and significance of bronchial epithelial dysplasia

“…Experimentation has revealed that bronchial and alveolar epithelial cells undergo multiple morphological and molecular changes before the overt expression of lung cancer. [3][4][5][6][7][8][9][10] However, only squamous dysplasia of bronchial epithelium and atypical adenomatous hyperplasia (AAH) have been extensively investigated [11][12][13][14][15][16][17] and listed as precursors of so-called central squamous cell carcinoma (SCC) or adenocarcinoma in the World Health Organization (WHO) histological classification of lung and pleural tumors. 18 The origin and development of central (ie bronchogenic) non-SCC and peripheral SCC are still poorly understood as yet.…”