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Revista Portuguesa de Pneumologia

Print version ISSN 0873-2159

Rev Port Pneumol vol.13 no.1 Lisboa Jan. 2007


Alterações genéticas no cancro do pulmão: Avaliação das limitações ao seu uso na rotina clínica

Genetic alterations in lung cancer: Assessing limitations in routine clinical use


Joana Espiga Macedo1

Inês A M Barbosa2,3

Sandra Rebelo1,4

Conceição Souto de Moura1,5

Luís Teixeira da Costa2,6

Venceslau Hespanhol1,7



O cancro do pulmão é a causa mais frequente de mortalidade por cancro no mundo, sendo responsável por cerca de 1,1 milhões de mortes por ano. A sobrevivência média dos doentes é geralmente curta, por a doença se encontrar em estádios avançados na altura do diagnóstico, mas também devido à falta de eficácia dos tratamentos disponíveis. O advento da genética molecular dos tumores trouxe consigo a possibilidade de modificar esta situação, quer através do refinamento do diagnóstico, quer da identificação de alvos terapêuticos específicos, quer sobretudo por – pelo menos em teoria – permitir o diagnóstico precoce da doença. No entanto, e apesar de numerosos trabalhos terem já demonstrado a utilidade das técnicas da genética molecular no estudo do cancro do pulmão, o seu uso na rotina clínica em Portugal tem sido limitado. No presente estudo, utilizou-se a pesquisa de mutações no anti-oncogene p53 em amostras clínicas de doentes com diagnóstico de cancro do pulmão como método para identificar as dificuldades práticas à integração da genética molecular na rotina clínica. Os resultados obtidos sugerem que o principal factor limitante a essa integração é a obtenção de amostras de ADN de qualidade, um problema que pode ser superado pela alteração das práticas correntes de recolha de amostras.

Palavras-chave: Cancro, pulmão, clínica, genética molecular, mutação, p53.



Lung cancer is the most frequent cause of cancer mortality worldwide, responsible for approximately 1.1 million deaths per year. Median survival is short, both as most tumours are diagnosed at an advanced stage and because of the limited efficacy of available treatments. The development of tumour molecular genetics carries the promise of altering this state of affairs, as it should lead to a more precise classification of tumours, identify specific molecular targets for therapy and, above all, allow the development of new methods for early diagnosis. Despite numerous studies demonstrating the usefulness of molecular genetic techniques in the study of lung cancer, its routine clinical use in Portugal has, however, been limited. In this study, we used a p53 mutation screen in multiple clinical samples from a series of lung cancer patients to attempt to identify the main practical limitations to the integration of molecular genetics in routine clinical practice. Our results suggest that the main limiting factor is the availability of samples with good quality DNA; a problem that could be overcome by alterations in common sample collection and storage procedures.

Key-words: Cancer, lung, clinical, molecular genetics, mutation, p53.


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Bibliografia / Bibliography

1. Boyle P, Ferlay J. Cancer incidence and mortality in Europe, 2004. Ann Oncol 2005; 16: 481-488.        [ Links ]

2. Cayuela A, Rodríguez-Domínguez S, López-Campos JL, Candelera RO, Matutes CR. Joinpoint regression analysis of lung cancer mortality, Andalusia 1975-2000. Ann Oncol 2004; 15: 793-796.

3. Boyle P DreslerC. Preventing the lung cancer epidemic. Ann Oncol 2005; 16: 1565-1566.

4. Jemal A, Murray T, Samuel A, Ghafoor A,Ward E, Thun MJ. Cancer statistics, 2003. CA Cancer J Clin. 53:5-26

5. Mountain CF. Revisions in the International Systems for Staging Lung Cancer. Chest 1997; 111:1710-1717.

6. Nowell PC. The clonal evolution of tumor cell populations. Science. 1976; 194:23-8.

7. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell 1990; 61:759-67.

8. Sjoblom T, Jones S, Wood LD, Parsons DW et al. The consensus coding sequences of human breast and colorectal cancers. Science 2006; 314:268-74.

9. American Joint commission for cancer. AJCC Cancer Staging Handbook. 5th ed. Philadelphia, PA: Lippincott-Raven 1998.

10. Mao L, Hruban RH, Boyle JO, Tockman M, Sidransky D. Detection of oncogene mutations in sputum precedes diagnosis of lung cancer. Cancer Res 1994;54:1634-1637.

11. Keohavong P, Gao W-M, Zheng K-C, Mady H, Lan Q, Melhaen M, Mumford J. Detection of K-ras and p53 mutations in sputum samples of lung cancer patients using laser capture microdessection microscope and mutation analysis. Analyt Biochem 2004;324:92-99.

12. Ahrendt SA, Chow JT, Li-Hua Xu, Yang SC, Eisenberger CF, Esteller M, Herman JG, Wu L, Decker AP, Jen J, Sidransky D. Molecular detection of tumor cells in bronchoalveolar lavage fluid from patients with early stage lung cancer. J Nat Cancer Inst 1999;91:4: 332-339.

13. Ferretti G, Curigliano G, Pastorino U, Cittadini A, Eflamini G, Grazia M, De Pas CT, Orlando L, Mandala M, Colleoni M, Spaggiari L, Granone PL, Pagliari G, Braud P, Fazio N, Goldhirsch A. Detection by denaturant gradient gel electrophoresis of tumor-specific mutations in biopsies and relative bronchoalveolar lavage fluid from resectable non-small cell lung cancer. Clin Cancer Res 2000; 6:2393-2400.

14. Powell CA, Klares S, O’Connor G, Brody JS. Loss of Heterozygosity in epithelial cells obtained by bronchial brushing: Clinical utility in lung cancer. Clin Cancer Res 1999; 5:2025-2034.

15. Sozi G, Conte D, Mariani L, Lo Vullo S, Roz L, Lombardo C, Pierotti MA, Tavecchio L. Analysis and circulating tumor DNA in plasma at diagnosis and during follow-up of lung cancer patients. Cancer Res 2001; 61:4675-4678.

16. Joseph Sambrook, David W Russell. Molecular Cloning: A Laboratory Manual. 3rd ed. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press, 2001.

17. Viktorsson K, Petris LD, Lewensohn R. The role of p53 in treatment responses of lung cancer. Biochem Biophys Res Commun 2005; 331:868-880.

18. Singhal S, Vachani A, Antin-Ozerkis D,Kaiser LR, Abelda SM. Prognostic implications of cell cycle, apoptosis and angiogenesis and biomarkers in non-small cell lung cancer: A Review. Clin Cancer Res 2005; 11 (11): 3974-3986.

19. Mitsudomi T, Hamajima N, Ogawa, Takahashi. Prognostic significance of p53 alterations in patients with nonsmall cell lung cancer: a Meta-analysis. Clin Cancer Res 2000; 6: 4055-4063

20. Meyerson M, Franklin WA, Kelly MJ. Molecular classification and molecular genetics of human lung cancer. Sem in Oncol 2004; 31(1;Suppl 1):4-19.

21. Ferlay J, Bray F, Pisani P et al. GLOBOCAN 2002: Cancer Incidence, Mortality and Prevalence Worldwide IARC CancerBAse Nº. 5, Version 2.0. Lyon, IARCPress: 2004

22. Borràs JM, Fernandez E, Gonzalez JR, Negri E, Lucchini F, La Vecchia C, Levi F. Lung cancer mortality in European regions (1955-1997). Ann Oncol 2003;14:159-161.

23. Hernandez-Boussard TM, Hainaut P. A specific spectrum of p53 Mutations in lung cancer from smokers: Review of mutations Complied in the IARC p53 database. Environmental Heallth Perspecyives 1998; 106 (7).

24. Eberhard DA, Johnson BE, Ameler LC et al. Mutations in the epidermal growth factor and in KRAS are predictive and prognostic indicators in patients with nonsmall cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol 2005; 23:5900-5909.

25. Tsao MS, Sakurada A, Cutz JC et al. Erlotinib in lung cancer – molecular and clinical predictors of outcome. N Eng J Med 2005; 353:133-144.

26. Ahrendt SA, Yang SC, Wu L, Roig CM, Russell P, Westra WH, Jen J, Brock MV, Heitmiller RF, Sidransky D. Molecular assessment of lymph nodes in patients with resected stage I non-small cell lung cancer: Preliminary results of a prospective study. J Thorac Cardiovas Surg 2002; 123:3:466-474.

27. Dressman D, Yan H, Traverso G, Kinzler KW, Vogelstein B. Transforming single DNA molecules into fluorescent magnetic particles for detection and enumeration of genetic variations. Proc Natl Acad Sci U S A. 2003;100:8817-22.

28. Li M, Diehl F, Dressman D, Vogelstein B, Kinzler KW. BEAMing up for detection and quantification of rare sequence variants. Nat Methods 2006; 3:95-7.

29. Jassem J, Jassem E, Bkiewicz-Banecka JJ, Rzyman W, Badzio A, Dziadziuszko R, Kobierska-Gulida G, Szymanowska A, Skrzypski M, Zylicz M. P53 and K-ras mutations are frequent events in microscopically negative surgical margins from patients with nonsmall cell lung carcinoma. Cancer 2004;100:1951-1960.

30. Masasyesva BG, Tong BC, Brock MV, Pilkington T, Goldenberg D, Sidransky D, Harden S, Westra WH, Califano J. Molecular margin analysis predicts local recurrence after sublobar resection of lung cancer. Int J Cancer 2005; 113:1022-1025.

31. Dai Y, Morishita Y, Mase K, Sato N, Akaogi E, Mitsui T, Noguchi M. Application of the p53 and K-ras gene mutation patterns for cytologic diagnosis of recurrent lung carcinomas. Combined Analysis with Microdissection and Polymerase Chain Reaction–Single-Strand Conformation Polymorphism. Cancer 2000; 90:258-263

32. Salvatore G, Giannini R, Faviana P, Caleo A, Migliaccio I, Fagin JA, Nikiforov YE, Troncone G, Palombini L, Basolo F, Santoro M. Analysis of BRAF point mutation and RET/PTC rearrangement refines the fine-needle aspiration diagnosis of papillary thyroid carcinoma. J Clin Endocrinol Metab 2004; 89:5175-80.

33. Redston MS, Caldas C, Seymour AB, Hruban RH, da Costa L, Yeo CJ, Kern SE. p53 mutations in pancreatic carcinoma and evidence of common involvement of homocopolymer tracts in DNA microdeletions. Cancer Res. 1994; 54:3025-33.


1 Faculdade de Medicina da Universidade do Porto / University of Porto Faculty of Medicine


3 Faculdade de Ciências da Universidade do Porto / University of Porto Faculty of Science

4 Serviço de Histologia, Hospital de S. João / Hospital de S. João, Histology Unit

5 Serviço de Anatomia Patológica, Hospital de S. João / Hospital de S. João, Anatomic Pathology Unit

6 ICAM, Universidade de Évora / ICAM, University of Évora

7 Serviço de Pneumologia, Hospital de S. João / Hospital de S. João, Pulmonolgy Unit


Recebido para publicação/received for publication: 06.10.31

Aceite para publicação/accepted for publication: 06.12.12