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February 15, 1995, Vol 273, No. 7 >
ARTICLE | February 15, 1995

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

Jaclyn Hung, PhD; Yosuke Kishimoto, MD; Kenji Sugio, MD; Arvind Virmani, PhD; Donald D. Mclntire, PhD; John D. Minna, MD; Adi F. Gazdar, MD
[+] Author Affiliations

Reprint requests to Simmons Cancer Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75235-8593 (Dr Gazdar).


JAMA. 1995;273(7):558-563. doi:10.1001/jama.1995.03520310056030
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References

Background.  —Deletions in the short arm of chromosome 3 (3p) are present in most lung carcinomas.

Objective.  —To investigate the role of these chromosome 3p deletions in the pathogenesis of non—small cell lung carcinomas.

Design.  —Seven archival, paraffin-embedded, surgically resected lung cancer specimens were studied. Fifty precisely identified malignant and preneoplastic lesions present in bronchi, bronchioles, and alveoli were microdissected from stained slides and analyzed for allele loss using polymerase chain reaction—based assays for dinucleotide repeat polymorphisms at three chromosome 3p loci (3p14,3p21.3, and 3p25).

Setting.  —University-based medical center and affiliated hospitals.

Subjects.  —Samples were analyzed from seven patients who underwent surgical resection with curative intent for non—small cell lung cancer and whose specimens included extensive multifocal areas of preneoplastic lesions (hyperplasia, metaplasia, dysplasia, or noninvasive cancer).

Results.  —Lymphocytes from all seven cases were heterozygous (ie, informative) for all three microsatellites analyzed. Six (86%) of seven invasive cancers had loss of heterozygosity at one or more chromosome 3p sites. In the accompanying preneoplastic lesions, loss of heterozygosity was detected in none of two normal bronchioles, 13 (76%) of 17 hyperplasias, six (86%) of seven dysplasias, and four (100%) of four noninvasive cancers. Loss of heterozygosity was detected throughout the respiratory tract, in bronchi, bronchioles, and alveoli. In 18 (78%) of 23 preneoplastic lesions, the specific alleles lost were identical to those lost in the corresponding carcinomas. The probability of this happening by chance is 5.3×10-3.

Conclusions.  —Deletions in the short arm of chromosome 3 occur at the earliest stage (hyperplasia) in the pathogenesis of lung cancer and involve all regions of the respiratory tract. Allele loss is highly specific, but its mechanism remains unknown. Our findings may be of considerable biologic, prognostic, and clinical significance.(JAMA. 1995;273:558-563)

REFERENCES

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Auerbach 0, Hammond EC, Garfinkel L.  Changes in bronchial epithelium in relation to cigarette smoking, 1955-1960 vs. 1970-1977. N Engl J Med . 1979;; 300:381-385.
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Saccomanno G, Archer VE, Saunders RP, Auerbach O, Klein MG.  Early indices of cancer risk among uranium miners with reference to modifying factors. Ann N Y Acad Sci . 1976;;271:377-383.
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Greenberg SD.  Carcinomas of the peripheral airways.  In: McDowell EM, ed. Lung Carcinomas . New York, NY: Churchill Livingstone Inc; 1987;: 287-309.
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Weng S, Tsuchiya E, Satoh Y, Kitagawa T, Nakagawa K, Sugano H.  Multiple atypical adenomatous hyperplasia of type II pneumonocytes and bronchiolo-alveolar carcinoma. Histopathology . 1990;;16: 101-103.
5 +
Nakanishi K.  Alveolar epithelial hyperplasia and adenocarcinoma of the lung. Arch Pathol Lab Med . 1990;;114:363-368.
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Strong MS, Incze J, Vaughan CW.  Field cancerization in the aerodigestive tract: its etiology, manifestation, and significance. J Otolaryngol . 1984;;13:1-6.
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Slaughter DP, Southwick HW, Smejkal W.  'Field cancerization' in oral stratified squamous epithelium: clinical implications of multicentric origin. Cancer . 1954;;6:963-968.
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Gazdar AF, Carbone DP. The Biology and Genetics of Lung Cancer . Austin, Tex: RG Landes Co; 1994;.
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Minna JD.  The molecular biology of lung cancer pathogenesis. Chest . 1993;;103:449S-456S.
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Hibi K, Takahashi T, Yamakawa K, et al.  Three distinct regions involved in 3p deletion in human lung cancer. Oncogene . 1992;;7:445-449.
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Brauch H, Tory K, Kotler F, et al.  Molecular mapping of deletion sites in the short arm of chromosome 3 in human lung cancer. Genes Chromosom Cancer . 1990;;1:240-246.
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Sekido Y, Bader S, Latif F, et al.  Molecular analysis of the von Hippel-Lindau disease tumor suppressor gene in human lung cancer lines. Oncogene . 1994;;9:853-859.
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Daly MC, Xiang RH, Buchhagen D, et al.  A homozygous deletion on chromosome 3 in a small cell lung cancer cell line correlates with a region of tumor suppressor activity. Oncogene . 1993;;8:1721-1729.
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Yamakawa K, Takahashi T, Horio Y, et al.  Frequent homozygous deletions in lung cancer cell lines detected by a DNA marker located at 3p21.3-p22. Oncogene . 1993;;8:327-330.
15 +
Rabbitts P, Bergh J, Douglas J, Collins F, Waters J.  A submicroscopic homozygous deletion at the D3S3 locus in a cell line isolated from a small cell lung carcinoma. Genes Chromosom Cancer . 1990;; 2:231-238.
16 +
Knudson AG.  Hereditary cancers: clues to mechanisms of carcinogenesis. Br J Cancer . 1989;; 59:661-666.
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Sundaresan V, Ganly P, Hasleton P, et al.  p53 and chromosome 3 abnormalities, characteristic of malignant lung tumours, are detectable in preinvasive lesions of the bronchus. Oncogene . 1992;;7: 1989-1997.
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Sozzi G, Miozzo M, Tagliabue E, et al.  Cytogenetic abnormalities and overexpression of receptors for growth factors in normal bronchial epithelium and tumor samples of lung cancer patients. Cancer Res . 1991;;51:400-404.
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Whetsell L, Maw G, Nadon N, Ringer DP, Schaefer FV.  Polymerase chain reaction microanalysis of tumors from stained histological slides. Oncogene . 1992;;7:2355-2361.
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Jones MH, Yamakawa K, Nakamura Y.  Isolation and characterization of 19 dinucleotide repeat polymorphisms on chromosome 3p. Hum Mol Genet . 1992;;1:131-133.
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Paabo S.  Ancient DNA: extraction, characterization, molecular cloning, and enzymatic amplification. Proc Natl Acad Sci U S A . 1989;;86:1939-1943.
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Litt M.  PCR of TG microsatellites.  In: McPherson MJ, Quirke P, Taylor GR, eds. PCR: A Practical Approach . New York, NY: Oxford University Press; 1991;:85-99.
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Litt M, Hauge X, Sharma V.  Shadow bands seen when typing polymorphic dinucleotide repeats: some causes and cures. Biotechniques . 1993;;15:280-284.
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Sarkar G, Kapelner S, Sommer SS.  Formamide can dramatically improve the specificity of PCR. Nucleic Acids Res . 1990;;18:7465.
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Siegel S. Nonparametric Statistics for the Behavioral Sciences . New York, NY: McGraw-Hill International Book Co; 1956;:36-42.
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Sugio K, Kishimoto Y, Virmani A, Hung JY, Gazdar AF.  K-ras mutations are a relatively late event in the pathogenesis of lung carcinomas. Cancer Res . 1994;;54:5811-5815.
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Whang-Peng J, Knutsen T, Gazdar A, et al.  Nonrandom structural and numerical chromosome changes in non-small-cell lung cancer. Genes Chromosom Cancer . 1991;;3:168-188.
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Kok K, Osinga J, Carritt B, et al.  Deletion of a DNA sequence at the chromosomal region 3p21 in all major types of lung cancer. Nature . 1987;;330: 578-581.
29 +
Brauch H, Johnson B, Hovis J, et al.  Molecular analysis of the short arm of chromosome 3 in smallcell and non-small cell carcinoma of the lung. N Engl J Med . 1987;;317:1109-1113.
30 +
Sato S, Nakamura Y, Tsuchiay E.  Difference of allelotype between squamous cell carcinoma and adenocarcinoma of the lung. Cancer Res . 1994;;54: 5652-5655.
31 +
Feinberg AP.  Genomic imprinting and gene activation in cancer. Nat Genet . 1993;;4:110-113.
32 +
Ferguson-Smith AC, Reik W, Surani MA.  Genomic imprinting and cancer. Cancer Surv . 1990;; 9:487-503.
33 +
Hall JG.  Genomic imprinting and its clinical implications. N Engl J Med . 1992;;326:827-829.
34 +
Suzuki H, Veda R, Takahashi T, Takahashi T.  Altered imprinting in lung cancer. Nat Genet . 1994;; 6:332-333.
35 +
O'Connell P, Pekkel V, Fuqua S, Osborne CK, Allred DC.  Molecular genetic studies of early breast cancer evolution. Breast Cancer Res Treat . 1994;; 32:5-12.
36 +
Chen B, You L, Wang Y, Stoner GD, You M.  Allele-specific activation and expression of the K-ras gene in hybrid mouse lung tumors induced by chemical carcinogens. Carcinogenesis . 1994;;15:2031-2035.
37 +
Hegi ME, Devereux TR, Dietrich WF, et al.  Allelotype analysis of mouse lung carcinomas reveals frequent allelic losses on chromosome 4 and an association between allelic imbalances on chromosome 6 and K-ras activation. Cancer Res . 1994;; 54:6257-6264.
38 +
Cheng JM, Hiemstra JL, Schneider SS, et al.  Preferential amplification of the paternal allele of the N-myc gene in human neuroblastomas. Nat Genet . 1993;;4:191-194.

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1 +
Auerbach 0, Hammond EC, Garfinkel L.  Changes in bronchial epithelium in relation to cigarette smoking, 1955-1960 vs. 1970-1977. N Engl J Med . 1979;; 300:381-385.
2 +
Saccomanno G, Archer VE, Saunders RP, Auerbach O, Klein MG.  Early indices of cancer risk among uranium miners with reference to modifying factors. Ann N Y Acad Sci . 1976;;271:377-383.
3 +
Greenberg SD.  Carcinomas of the peripheral airways.  In: McDowell EM, ed. Lung Carcinomas . New York, NY: Churchill Livingstone Inc; 1987;: 287-309.
4 +
Weng S, Tsuchiya E, Satoh Y, Kitagawa T, Nakagawa K, Sugano H.  Multiple atypical adenomatous hyperplasia of type II pneumonocytes and bronchiolo-alveolar carcinoma. Histopathology . 1990;;16: 101-103.
5 +
Nakanishi K.  Alveolar epithelial hyperplasia and adenocarcinoma of the lung. Arch Pathol Lab Med . 1990;;114:363-368.
6 +
Strong MS, Incze J, Vaughan CW.  Field cancerization in the aerodigestive tract: its etiology, manifestation, and significance. J Otolaryngol . 1984;;13:1-6.
7 +
Slaughter DP, Southwick HW, Smejkal W.  'Field cancerization' in oral stratified squamous epithelium: clinical implications of multicentric origin. Cancer . 1954;;6:963-968.
8 +
Gazdar AF, Carbone DP. The Biology and Genetics of Lung Cancer . Austin, Tex: RG Landes Co; 1994;.
9 +
Minna JD.  The molecular biology of lung cancer pathogenesis. Chest . 1993;;103:449S-456S.
10 +
Hibi K, Takahashi T, Yamakawa K, et al.  Three distinct regions involved in 3p deletion in human lung cancer. Oncogene . 1992;;7:445-449.
11 +
Brauch H, Tory K, Kotler F, et al.  Molecular mapping of deletion sites in the short arm of chromosome 3 in human lung cancer. Genes Chromosom Cancer . 1990;;1:240-246.
12 +
Sekido Y, Bader S, Latif F, et al.  Molecular analysis of the von Hippel-Lindau disease tumor suppressor gene in human lung cancer lines. Oncogene . 1994;;9:853-859.
13 +
Daly MC, Xiang RH, Buchhagen D, et al.  A homozygous deletion on chromosome 3 in a small cell lung cancer cell line correlates with a region of tumor suppressor activity. Oncogene . 1993;;8:1721-1729.
14 +
Yamakawa K, Takahashi T, Horio Y, et al.  Frequent homozygous deletions in lung cancer cell lines detected by a DNA marker located at 3p21.3-p22. Oncogene . 1993;;8:327-330.
15 +
Rabbitts P, Bergh J, Douglas J, Collins F, Waters J.  A submicroscopic homozygous deletion at the D3S3 locus in a cell line isolated from a small cell lung carcinoma. Genes Chromosom Cancer . 1990;; 2:231-238.
16 +
Knudson AG.  Hereditary cancers: clues to mechanisms of carcinogenesis. Br J Cancer . 1989;; 59:661-666.
17 +
Sundaresan V, Ganly P, Hasleton P, et al.  p53 and chromosome 3 abnormalities, characteristic of malignant lung tumours, are detectable in preinvasive lesions of the bronchus. Oncogene . 1992;;7: 1989-1997.
18 +
Sozzi G, Miozzo M, Tagliabue E, et al.  Cytogenetic abnormalities and overexpression of receptors for growth factors in normal bronchial epithelium and tumor samples of lung cancer patients. Cancer Res . 1991;;51:400-404.
19 +
Whetsell L, Maw G, Nadon N, Ringer DP, Schaefer FV.  Polymerase chain reaction microanalysis of tumors from stained histological slides. Oncogene . 1992;;7:2355-2361.
20 +
Jones MH, Yamakawa K, Nakamura Y.  Isolation and characterization of 19 dinucleotide repeat polymorphisms on chromosome 3p. Hum Mol Genet . 1992;;1:131-133.
21 +
Paabo S.  Ancient DNA: extraction, characterization, molecular cloning, and enzymatic amplification. Proc Natl Acad Sci U S A . 1989;;86:1939-1943.
22 +
Litt M.  PCR of TG microsatellites.  In: McPherson MJ, Quirke P, Taylor GR, eds. PCR: A Practical Approach . New York, NY: Oxford University Press; 1991;:85-99.
23 +
Litt M, Hauge X, Sharma V.  Shadow bands seen when typing polymorphic dinucleotide repeats: some causes and cures. Biotechniques . 1993;;15:280-284.
24 +
Sarkar G, Kapelner S, Sommer SS.  Formamide can dramatically improve the specificity of PCR. Nucleic Acids Res . 1990;;18:7465.
25 +
Siegel S. Nonparametric Statistics for the Behavioral Sciences . New York, NY: McGraw-Hill International Book Co; 1956;:36-42.
26 +
Sugio K, Kishimoto Y, Virmani A, Hung JY, Gazdar AF.  K-ras mutations are a relatively late event in the pathogenesis of lung carcinomas. Cancer Res . 1994;;54:5811-5815.
27 +
Whang-Peng J, Knutsen T, Gazdar A, et al.  Nonrandom structural and numerical chromosome changes in non-small-cell lung cancer. Genes Chromosom Cancer . 1991;;3:168-188.
28 +
Kok K, Osinga J, Carritt B, et al.  Deletion of a DNA sequence at the chromosomal region 3p21 in all major types of lung cancer. Nature . 1987;;330: 578-581.
29 +
Brauch H, Johnson B, Hovis J, et al.  Molecular analysis of the short arm of chromosome 3 in smallcell and non-small cell carcinoma of the lung. N Engl J Med . 1987;;317:1109-1113.
30 +
Sato S, Nakamura Y, Tsuchiay E.  Difference of allelotype between squamous cell carcinoma and adenocarcinoma of the lung. Cancer Res . 1994;;54: 5652-5655.
31 +
Feinberg AP.  Genomic imprinting and gene activation in cancer. Nat Genet . 1993;;4:110-113.
32 +
Ferguson-Smith AC, Reik W, Surani MA.  Genomic imprinting and cancer. Cancer Surv . 1990;; 9:487-503.
33 +
Hall JG.  Genomic imprinting and its clinical implications. N Engl J Med . 1992;;326:827-829.
34 +
Suzuki H, Veda R, Takahashi T, Takahashi T.  Altered imprinting in lung cancer. Nat Genet . 1994;; 6:332-333.
35 +
O'Connell P, Pekkel V, Fuqua S, Osborne CK, Allred DC.  Molecular genetic studies of early breast cancer evolution. Breast Cancer Res Treat . 1994;; 32:5-12.
36 +
Chen B, You L, Wang Y, Stoner GD, You M.  Allele-specific activation and expression of the K-ras gene in hybrid mouse lung tumors induced by chemical carcinogens. Carcinogenesis . 1994;;15:2031-2035.
37 +
Hegi ME, Devereux TR, Dietrich WF, et al.  Allelotype analysis of mouse lung carcinomas reveals frequent allelic losses on chromosome 4 and an association between allelic imbalances on chromosome 6 and K-ras activation. Cancer Res . 1994;; 54:6257-6264.
38 +
Cheng JM, Hiemstra JL, Schneider SS, et al.  Preferential amplification of the paternal allele of the N-myc gene in human neuroblastomas. Nat Genet . 1993;;4:191-194.

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