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J Clin Invest. Oct 15, 1997; 100(8): 2133–2137.
PMCID: PMC508406

Widely dispersed p53 mutation in respiratory epithelium. A novel mechanism for field carcinogenesis.

Abstract

Individuals with one aerodigestive tract malignancy have a high incidence of second primary aerodigestive tumors. The mechanism for this field effect has not been determined. We studied an individual with widespread dysplastic changes in the respiratory epithelium but no overt carcinoma. The entire tracheobronchial tree obtained at autopsy was embedded in paraffin, and bronchial epithelial cells were isolated by microdissection. DNA extracted from the microdissected cells was analyzed for point mutations in the p53 tumor suppressor gene. A single, identical point mutation consisting of a G:C to T:A transversion in codon 245 was identified in bronchial epithelium from 7 of 10 sites in both lungs. Epithelium at sites containing the p53 mutation was morphologically abnormal, exhibiting squamous metaplasia and mild to moderate atypia. No invasive tumor was found in the tracheobronchial tree or any other location. Cells from peripheral blood, kidney, liver, and lymph node exhibited no abnormality in the p53 gene. The widespread presence of a single somatic p53 point mutation in the bronchi of a smoker suggests that a single progenitor bronchial epithelial clone may expand to populate broad areas of the bronchial mucosa-a novel mechanism for field carcinogenesis in the respiratory epithelium that may be of importance in assessing individuals for risk of a second primary tumor as well as in devising effective strategies for chemoprevention of lung cancer.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • SLAUGHTER DP, SOUTHWICK HW, SMEJKAL W. Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin. Cancer. 1953 Sep;6(5):963–968. [PubMed]
  • Mathisen DJ, Jensik RJ, Faber LP, Kittle CF. Survival following resection for second and third primary lung cancers. J Thorac Cardiovasc Surg. 1984 Oct;88(4):502–510. [PubMed]
  • Ferguson MK, DeMeester TR, DesLauriers J, Little AG, Piraux M, Golomb H. Diagnosis and management of synchronous lung cancers. J Thorac Cardiovasc Surg. 1985 Mar;89(3):378–385. [PubMed]
  • Wu SC, Lin ZQ, Xu CW, Koo KS, Huang OL, Xie DQ. Multiple primary lung cancers. Chest. 1987 Nov;92(5):892–896. [PubMed]
  • Deschamps C, Pairolero PC, Trastek VF, Payne WS. Multiple primary lung cancers. Results of surgical treatment. J Thorac Cardiovasc Surg. 1990 May;99(5):769–778. [PubMed]
  • Ferguson MK. Synchronous primary lung cancers. Chest. 1993 Apr;103(4 Suppl):398S–400S. [PubMed]
  • Antakli T, Schaefer RF, Rutherford JE, Read RC. Second primary lung cancer. Ann Thorac Surg. 1995 Apr;59(4):863–867. [PubMed]
  • Martini N, Bains MS, Burt ME, Zakowski MF, McCormack P, Rusch VW, Ginsberg RJ. Incidence of local recurrence and second primary tumors in resected stage I lung cancer. J Thorac Cardiovasc Surg. 1995 Jan;109(1):120–129. [PubMed]
  • Pommier RF, Vetto JT, Lee JT, Johnston KM. Synchronous non-small cell lung cancers. Am J Surg. 1996 May;171(5):521–524. [PubMed]
  • Johnson BE, Linnoila RI, Williams JP, Venzon DJ, Okunieff P, Anderson GB, Richardson GE. Risk of second aerodigestive cancers increases in patients who survive free of small-cell lung cancer for more than 2 years. J Clin Oncol. 1995 Jan;13(1):101–111. [PubMed]
  • Thomas P, Rubinstein L. Cancer recurrence after resection: T1 N0 non-small cell lung cancer. Lung Cancer Study Group. Ann Thorac Surg. 1990 Feb;49(2):242–247. [PubMed]
  • Heyne KH, Lippman SM, Lee JJ, Lee JS, Hong WK. The incidence of second primary tumors in long-term survivors of small-cell lung cancer. J Clin Oncol. 1992 Oct;10(10):1519–1524. [PubMed]
  • Johnson BE, Ihde DC, Matthews MJ, Bunn PA, Zabell A, Makuch RW, Johnston-Early A, Cohen MH, Glatstein E, Minna JD. Non-small-cell lung cancer. Major cause of late mortality in patients with small cell lung cancer. Am J Med. 1986 Jun;80(6):1103–1110. [PubMed]
  • Sidransky D, Frost P, Von Eschenbach A, Oyasu R, Preisinger AC, Vogelstein B. Clonal origin bladder cancer. N Engl J Med. 1992 Mar 12;326(11):737–740. [PubMed]
  • Sozzi G, Miozzo M, Pastorino U, Pilotti S, Donghi R, Giarola M, De Gregorio L, Manenti G, Radice P, Minoletti F, et al. Genetic evidence for an independent origin of multiple preneoplastic and neoplastic lung lesions. Cancer Res. 1995 Jan 1;55(1):135–140. [PubMed]
  • Saccomanno G, Archer VE, Auerbach O, Saunders RP, Brennan LM. Development of carcinoma of the lung as reflected in exfoliated cells. Cancer. 1974 Jan;33(1):256–270. [PubMed]
  • Hung J, Kishimoto Y, Sugio K, Virmani A, McIntire DD, Minna JD, Gazdar AF. Allele-specific chromosome 3p deletions occur at an early stage in the pathogenesis of lung carcinoma. JAMA. 1995 Feb 15;273(7):558–563. [PubMed]
  • Soto D, Sukumar S. Improved detection of mutations in the p53 gene in human tumors as single-stranded conformation polymorphs and double-stranded heteroduplex DNA. PCR Methods Appl. 1992 Aug;2(1):96–98. [PubMed]
  • Phelps RM, Johnson BE, Ihde DC, Gazdar AF, Carbone DP, McClintock PR, Linnoila RI, Matthews MJ, Bunn PA, Jr, Carney D, et al. NCI-Navy Medical Oncology Branch cell line data base. J Cell Biochem Suppl. 1996;24:32–91. [PubMed]
  • Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990 Jun 1;61(5):759–767. [PubMed]
  • Knudson AG. Antioncogenes and human cancer. Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):10914–10921. [PMC free article] [PubMed]
  • Dutrillaux B. Pathways of chromosome alteration in human epithelial cancers. Adv Cancer Res. 1995;67:59–82. [PubMed]
  • Vogelstein B, Kinzler KW. The multistep nature of cancer. Trends Genet. 1993 Apr;9(4):138–141. [PubMed]
  • Cho KR, Vogelstein B. Genetic alterations in the adenoma--carcinoma sequence. Cancer. 1992 Sep 15;70(6 Suppl):1727–1731. [PubMed]
  • Greenblatt MS, Bennett WP, Hollstein M, Harris CC. Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res. 1994 Sep 15;54(18):4855–4878. [PubMed]
  • Yuspa SH, Poirier MC. Chemical carcinogenesis: from animal models to molecular models in one decade. Adv Cancer Res. 1988;50:25–70. [PubMed]
  • Strauss BS. The 'A rule' of mutagen specificity: a consequence of DNA polymerase bypass of non-instructional lesions? Bioessays. 1991 Feb;13(2):79–84. [PubMed]
  • Sundaresan V, Ganly P, Hasleton P, Rudd R, Sinha G, Bleehen NM, Rabbitts P. p53 and chromosome 3 abnormalities, characteristic of malignant lung tumours, are detectable in preinvasive lesions of the bronchus. Oncogene. 1992 Oct;7(10):1989–1997. [PubMed]
  • Sozzi G, Miozzo M, Donghi R, Pilotti S, Cariani CT, Pastorino U, Della Porta G, Pierotti MA. Deletions of 17p and p53 mutations in preneoplastic lesions of the lung. Cancer Res. 1992 Nov 1;52(21):6079–6082. [PubMed]
  • Chung GT, Sundaresan V, Hasleton P, Rudd R, Taylor R, Rabbitts PH. Clonal evolution of lung tumors. Cancer Res. 1996 Apr 1;56(7):1609–1614. [PubMed]
  • Chung GT, Sundaresan V, Hasleton P, Rudd R, Taylor R, Rabbitts PH. Sequential molecular genetic changes in lung cancer development. Oncogene. 1995 Dec 21;11(12):2591–2598. [PubMed]
  • Kishimoto Y, Sugio K, Hung JY, Virmani AK, McIntire DD, Minna JD, Gazdar AF. Allele-specific loss in chromosome 9p loci in preneoplastic lesions accompanying non-small-cell lung cancers. J Natl Cancer Inst. 1995 Aug 16;87(16):1224–1229. [PubMed]
  • Mao L, Lee JS, Kurie JM, Fan YH, Lippman SM, Lee JJ, Ro JY, Broxson A, Yu R, Morice RC, et al. Clonal genetic alterations in the lungs of current and former smokers. J Natl Cancer Inst. 1997 Jun 18;89(12):857–862. [PubMed]
  • Fontanini G, Vignati S, Bigini D, Merlo GR, Ribecchini A, Angeletti CA, Basolo F, Pingitore R, Bevilacqua G. Human non-small cell lung cancer: p53 protein accumulation is an early event and persists during metastatic progression. J Pathol. 1994 Sep;174(1):23–31. [PubMed]
  • Bennett WP, Colby TV, Travis WD, Borkowski A, Jones RT, Lane DP, Metcalf RA, Samet JM, Takeshima Y, Gu JR, et al. p53 protein accumulates frequently in early bronchial neoplasia. Cancer Res. 1993 Oct 15;53(20):4817–4822. [PubMed]
  • Walker C, Dixon GR, Myskow M. Human non-small cell lung cancer: p53 protein accumulation is an early event and persists during metastatic progression. J Pathol. 1995 Jul;176(3):319–320. [PubMed]
  • Rusch V, Klimstra D, Linkov I, Dmitrovsky E. Aberrant expression of p53 or the epidermal growth factor receptor is frequent in early bronchial neoplasia and coexpression precedes squamous cell carcinoma development. Cancer Res. 1995 Mar 15;55(6):1365–1372. [PubMed]
  • Boers JE, ten Velde GP, Thunnissen FB. P53 in squamous metaplasia: a marker for risk of respiratory tract carcinoma. Am J Respir Crit Care Med. 1996 Jan;153(1):411–416. [PubMed]
  • Hartwell L. Defects in a cell cycle checkpoint may be responsible for the genomic instability of cancer cells. Cell. 1992 Nov 13;71(4):543–546. [PubMed]
  • Levine AJ, Momand J, Finlay CA. The p53 tumour suppressor gene. Nature. 1991 Jun 6;351(6326):453–456. [PubMed]
  • Lane DP. Cancer. p53, guardian of the genome. Nature. 1992 Jul 2;358(6381):15–16. [PubMed]
  • Wang P, Reed M, Wang Y, Mayr G, Stenger JE, Anderson ME, Schwedes JF, Tegtmeyer P. p53 domains: structure, oligomerization, and transformation. Mol Cell Biol. 1994 Aug;14(8):5182–5191. [PMC free article] [PubMed]
  • Sakamoto H, Lewis MS, Kodama H, Appella E, Sakaguchi K. Specific sequences from the carboxyl terminus of human p53 gene product form anti-parallel tetramers in solution. Proc Natl Acad Sci U S A. 1994 Sep 13;91(19):8974–8978. [PMC free article] [PubMed]
  • Milner J, Medcalf EA, Cook AC. Tumor suppressor p53: analysis of wild-type and mutant p53 complexes. Mol Cell Biol. 1991 Jan;11(1):12–19. [PMC free article] [PubMed]
  • Stürzbecher HW, Brain R, Addison C, Rudge K, Remm M, Grimaldi M, Keenan E, Jenkins JR. A C-terminal alpha-helix plus basic region motif is the major structural determinant of p53 tetramerization. Oncogene. 1992 Aug;7(8):1513–1523. [PubMed]
  • Sheppard D. Dominant negative mutants: tools for the study of protein function in vitro and in vivo. Am J Respir Cell Mol Biol. 1994 Jul;11(1):1–6. [PubMed]
  • Herskowitz I. Functional inactivation of genes by dominant negative mutations. Nature. 1987 Sep 17;329(6136):219–222. [PubMed]
  • Frebourg T, Sadelain M, Ng YS, Kassel J, Friend SH. Equal transcription of wild-type and mutant p53 using bicistronic vectors results in the wild-type phenotype. Cancer Res. 1994 Feb 15;54(4):878–881. [PubMed]

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