Allele-Specific Chromosome 3p Deletions Occur at an Early Stage in the Pathogenesis of Lung Carcinoma

Hung, Jaclyn Y.; Kishimoto, Yosuke; Sugio, Kenji; Virmani, Arvind K.; McIntire, Donald D.; Minna, John D.; Gazdar, Adi F.

doi:10.1001/jama.1995.03520310056030

Cited by 253 publications

(101 citation statements)

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“…We and others have documented this phenomenon (allele speci®c mutations, ASM) previously both in the respiratory epithelium of smokers and in patients with lung cancer (Hung et al, 1995;Kishimoto et al, 1995;Sundaresan et al, 1992;Wistuba et al, 1995). The mechanism by which this phenomenon occurs is unknown.…”

Section: Discussionmentioning

confidence: 68%

“…Previous studies of di erent bronchial lesions from the same individual patient demonstrated that at any one locus, loss of parental alleles was not random, and that there was a strong tendency for the identical allele to be lost in all non-neoplastic and neoplastic foci examined (Hung et al, 1995;Kishimoto et al, 1995;Sundaresan et al, 1992;Wistuba et al, 1995) (Figure 1). We refer to this phenomenon as allele speci®c mutations (ASM) (Hung et al, 1995;Kishimoto et al, 1995;Sundaresan et al, 1992;Wistuba et al, 1995).…”

Section: Allele Speci®c Mutations (Asm)mentioning

confidence: 88%

“…The mechanism by which this phenomenon occurs is unknown. We have proposed two possibilities for ASM (Hung et al, 1995): (a) a single cell or small clone of cells develops loss at a speci®c parental allele of one or more polymorphic loci, migrates widely throughout the respiratory epithelium of lung and gives rise to multiple foci of abnormal epithelium; or (b) in individuals, one of any pair of alleles has a greater tendency to be lost, perhaps as a result of some form of genomic imprinting or the presence of fragile sites. The ®nding of a single point mutation in the TP53 gene widely dispersed in the respiratory epithelium of a smoker (Franklin et al, 1997) would favor the clonal theory.…”

Section: Discussionmentioning

confidence: 99%

“…We refer to this phenomenon as allele speci®c mutations (ASM) (Hung et al, 1995;Kishimoto et al, 1995;Sundaresan et al, 1992;Wistuba et al, 1995). We determined the frequencies of ASM in the 69 foci demonstrating one or more sites of allelic loss in all 12 patients.…”

Section: Allele Speci®c Mutations (Asm)mentioning

confidence: 99%

“…However, relatively little is known about the sequence of molecular events preceding the development of invasive lung carcinoma. Allelic losses at chromosomal regions 3p, 9p and 17p occur relatively early during the multistage development of invasive lung cancer (Chung et al, 1996;Hung et al, 1995;Kishimoto et al, 1995;Sundaresan et al, 1992;Thiberville et al, 1995). In addition, the occurrence of aneuploidy and microsatellite alterations (MA) is evidence of more generalized genomic instability in lung cancer and its preneoplastic lesions (Mao et al, 1994;Miozzo et al, 1996).…”

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: Discussionmentioning

confidence: 68%

Section: Allele Speci®c Mutations (Asm)mentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Allele Speci®c Mutations (Asm)mentioning

confidence: 99%

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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Tumors Arising After Organ Transplantation

Gazdar¹

1997

JAMA

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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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Allele-Specific Chromosome 3p Deletions Occur at an Early Stage in the Pathogenesis of Lung Carcinoma

Cited by 253 publications

References 25 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

Tumors Arising After Organ Transplantation

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

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