Molecular Damage in the Bronchial Epithelium of Current and Former Smokers

Wistuba, Ignacio I.; Lam, Stephen; Behrens, Carmen; Virmani, Arvind K.; Fong, Kwun M.; LeRiche, Jean; Samet, Jonathan M.; Srivastava, Sudhir; Minna, John D.; Gazdar, Adi F.

doi:10.1093/jnci/89.18.1366

Cited by 421 publications

(295 citation statements)

References 32 publications

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“…Our current ®ndings con®rm and greatly extend the previous observations of ours and others that mutations accumulate early in the multistage pathogenesis in smoking damaged epithelium (Mao et al, 1997;Wistuba et al, 1997a). We limited the present study to the pathogenesis of squamous carcinoma arising in the setting of smoking damaged respiratory epithelium because the sequence of histologic changes in this cancer is well established.…”

Section: Discussionsupporting

confidence: 80%

“…Unlike allelic losses, the frequency of MAs did not increase with more advanced histologic changes. We have previously reported similar ®ndings in smoking damaged epithelium (Wistuba et al, 1997a). Of interest, MAs, when present in nonmalignant foci, were always of a di erent size than those present in the corresponding invasive tumors.…”

Section: Discussionsupporting

confidence: 67%

“…, Upper allele lost; , Lower allele lost (Wistuba et al, 1997a). In the latter study,¯uorescence bronchoscopy was used to select biopsy sites (from areas of abnormal¯uorescence), possibly accounting for the higher mutational frequency.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, we and others (Mao et al, 1997;Wistuba et al, 1997a) have reported a very high incidence of molecular abnormalities (LOH and MAs) in the normal and abnormal bronchial mucosa of former and current smokers. While 80% of current and former smokers had evidence of clones of cells exhibiting allele loss in their bronchial mucosa, never smoker subjects had no or only rare changes (Wistuba et al, 1997a).…”

Section: Introductionmentioning

confidence: 89%

“…While 80% of current and former smokers had evidence of clones of cells exhibiting allele loss in their bronchial mucosa, never smoker subjects had no or only rare changes (Wistuba et al, 1997a). Given this background and to further understand the molecular pathways involved in the pathogenesis of lung cancers, we studied the sequence of molecular abnormalities involved in the pathogenesis of the multistep development of squamous cell lung carcinoma.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 1999

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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.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionsupporting

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

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

et al. 1999

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Comparison of Molecular Changes in Lung Cancers in HIV-Positive and HIV-Indeterminate Subjects

Wistuba

Behrens

Milchgrub

et al. 1998

JAMA

112

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Context.-Human immunodeficiency virus (HIV) infection has been associated with an increasing incidence of malignancy, and HIV-infected persons have an increased incidence of primary lung carcinoma compared with the general population.Objective.-To investigate the molecular changes present in HIV-associated lung tumors and compare them with those present in lung carcinomas arising in HIV-indeterminate subjects ("sporadic tumors").Design.-Convenience sample. Subjects.-Archival tissues from 11 HIV-positive persons and from 35 persons of indeterminate HIV status. Setting.-University-based medical centers and affiliated hospitals. Main Outcome Measures.-Analysis of frequency of loss of heterozygosity (LOH) and microsatellite alteration (MA) using polymerase chain reaction and 16 polymorphic microsatellite markers at 8 chromosomal regions frequently deleted in lung cancer. Presence of HIV and human papillomavirus (HPV) sequences.Results.-The overall frequency of LOH at all chromosomal regions tested and the frequencies at most of the individual regions were similar in the 2 groups. Frequency of MA present in the HIV-associated tumors (0.18) was 6-fold higher than in sporadic tumors (0.03) (PϽ.001). At least 1 MA was present in 10 (91%) of 11 HIV-associated tumors vs 17 (48%) of 35 sporadic tumors (P=.02). Molecular changes were independent of tumor stage and gender. HIV and HPV sequences were not detected in the HIV-associated lung carcinomas.Conclusions.-Microsatellite alterations, which reflect widespread genomic instability, occur at greatly increased frequency in HIV-associated lung carcinomas. Although the mechanism underlying the development of increased MAs is unknown, it may play a crucial role in the development of many HIV-associated tumors.

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Molecular epidemiology of human cancer risk: gene-environment interactions andp53 mutation spectrum in human lung cancer

et al. 1999

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Molecular Damage in the Bronchial Epithelium of Current and Former Smokers

Abstract: Genetic changes similar to those found in lung cancers can be detected in the nonmalignant bronchial epithelium of current and former smokers and may persist for many years after smoking cessation.

Cited by 421 publications

References 32 publications

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

Comparison of Molecular Changes in Lung Cancers in HIV-Positive and HIV-Indeterminate Subjects

Molecular epidemiology of human cancer risk: gene-environment interactions andp53 mutation spectrum in human lung cancer

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