Einfluss von Glutathion S-Transferase und Cytochrom P450 Genpolymorphismen auf das Verhalten von Kopf-Hals-Karzinomen

Zusammenfassung

Hintergrund: Die polymorphen Genorte der entgiftenden Enzyme Glutathion S-Transferase und Cytochrom P450 sind neben ihrer klassischen Rolle als risikobeeinflussende Genvariationen mit der Prognose von Tumorerkrankungen in Verbindung gebracht worden. Methode: Wir beschreiben den Einfluss von GST- und CYP-Polymorphismen auf die Prognoseparameter initialer Tumorausdehnung, initialer Halslymphknotenbefall, histologischer Differenzierungsgrad und das rezidivfreie Überleben über fünf Jahre. Ergebnisse: GSTT1 0 war mit fortgeschrittenen und lymphogen metastasierten Pharynxkarzinomen assoziiert. CYP2D6 PM war mit einem malignen Halslymphknotenbefall assoziiert. Eine Beeinflussung der 5-Jahresheilung durch ein einzelnes Gen konnte nicht nachgewiesen werden. Schlussfolgerungen: Erstmalig konnten genetisch determinierte Wirtsfaktoren an den Genorten der entgiftenden Enzyme mit prognostisch wichtigen Faktoren der Kopf-Hals-Tumorerkrankung in Verbindung gebracht werden.

Abstract

Background: The polymorphic gene loci of the detoxifying enzymes GST and CYP are susceptibility factors for head and neck cancer. Recently, they have been associated with outcome in several cancers. Methods: Accordingly, we have examined, in patients with squamous cell carcinoma (SCC) of the head and neck, associations between GSTM1, GSTT1, GSTM3, GSTP1, CYP2D6, CYP1A1 and CYP2E1 genotypes and outcome parameters, tumor extension, histological grade, presence of lymph nodes, and recurrence free survival over 5 years. Genotypes were determined by PCR; logistic regression and a step-wise model were used to investigate the influence of the individual genes. Results: GSTT1 0 was associated with T3/T4 tumor lesions in the pharynx and oral cavity (p = 0.029), but not laryngeal SCC cases. GSTT1 0 was also associated with histological differentiation (G3) in the oral cavity /pharynx, but not laryngeal SCC cases, although this association only approached significance (p = 0.069). CYP2D6 PM and HET were associated with lymph node involvement in the laryngeal SCC cases. Conclusions: The data demonstrate site-dependent associations between GSTT1 null and CYP2D6 PM and tumor extension and lymph node involvement in SCC of the head and neck.

Glutathion S-Transferase - Cytochrom P450 - Larynxkarzinom - Pharynxkarzinom - Tumorprognose

Glutathione S-transferase - Cytochrome P450 - Pharyngeal cancer - Laryngeal cancer - Cancer prognosis

Literatur

• 1 Blot W J, McLaughlin J K, Winn D M. Smoking and drinking in relation to oral and pharyngeal cancer.  Cancer Res. 1988;  48 3282-3287
• 2 Elwood J M, Pearson J CG, Skippen D H, Jackson S M. Alcohol, smoking, social and occupational factors in the etiology of cancer of the oral cavity, pharynx and larynx.  Int J Cancer. 1984;  34 603-612
• 3 Jahnke V. Bösartige Tumoren des Larynx. In: Naumann HH, Helms J, Herberhold C, Kastenbauer E (Hrsg) Oto-Rhino-Laryngologie in Klinik und Praxis, Band 3, Hals. Stuttgart, New York; Georg Thieme Verlag 1995: 388-421
• 4 Maier H, Gewelke U, Dietz A. Risk factors for cancer of the larynx: results of the Heidelberg case-control study.  Otolaryngol Head Neck Surg. 1992;  107 577-582
• 5 Bongers V, Braakhuis B JM, Tobi H, Lubsen H, Snow G B. The relation between cancer incidence among relatives and the occurrence of multiple primary carcinomas following head and neck cancer.  Cancer Epidemiol Biomarkers Prev. 1996;  5 585-598
• 6 Copper M P, Jovanovic A, Nauta J JP, Braakhuis B JM, DeVries N, van der Waal L P, Snow G B. Role of genetic factors in the etiology of squamous cell carcinoma of the head and neck.  Arch Otolarynogol. 1995;  121 157-160
• 7 Gonzalez M V, Alvarez V, Pello M F, Menendez M J, Suarez C, Coto E. Genetic polymorphism of N-acetyltransferase-2, glutathione S-transferase M1, and cytochromes P450 2E1 and P450 2D6 in the susceptibility to head and neck cancer.  J Clin Pathol. 1998;  51 294-298
• 8 Jahnke V, Strange R C, Matthias C, Fryer A A. Erste Ergebnisse über Glutathion-S-Transferase GSTM1 und GSTT1 Genotypen und die genetische Prädisposition beim Larynxkarzinom.  Laryngol Rhinol Otol. 1995;  74 691-694
• 9 Trizna Z, Clayman G L, Spitz M R, Goepfert H. Glutathione S-transferase genotypes as risk factors for head and neck cancer.  Am J Surg. 1995;  170 499-501
• 10 Matthias C, Bockmühl U, Jahnke V, Lorries L W, Wolf C R, Jones P W, Alldersea J, Worrall S F, Hand P, Fryer A A, Strange R C. The glutathione S-transferase GSTP1 polymorphism: effects on susceptibility to oral/pharyngeal and laryngeal carcinomas.  Pharmacogenetics. 1998;  8 1-6
• 11 Matthias C, Bockmühl U, Jahnke V, Jones P W, Hayes J, Alldersea J, Gilford J, Bailey L, Bath J, Worrall S F, Hand P, Fryer A A, Strange R C. Polymorphism in cytochrome P450 CYP2D6, CYP1A1, CYP2E1 and glutathione-S-transferase, GSTM1, GSTM3, GSTT1 and susceptibility to tobacco-related cancers: studies in upper aerodigestive tract cancers.  Pharmacogenetics. 1998;  8 91-100
• 12 Oude-Ophuis M B, van Lieshout E M, Roelofs H M, Peters W H, Manni J J. Glutathione S-transferase M1 and T1 and cytochrome P450 1A1 polymorphisms in relation to the risk for benign and malignant head and neck lesions.  Cancer. 1998;  82 936-43
• 13 Park J Y, Muscat J E, Ren Q, Schantz S P, Harwick R D, Stern J C, Pike V, Richie J P, Lazarus P. CYP1A1 and GSTM1 polymorphisms and oral cancer risk.  Cancer Epidemiol Biomarkers Prev. 1997;  6 791-797
• 14 Janot F, Klijanienko J, Russo A, Mamet J P, de Braud F, El-Naggar A K, Pignon J P, Luboinski B, Cvitkovic E. Prognostic value of clinicopathological parameters in head and neck squamous cell carcinoma: a prospective analysis.  Br J Cancer. 1996;  73 531-538
• 15 Magnano M, Bussi M, de Stefani A, Milan F, Lerda W, Ferrero V, Gervasio F, Ragona R, Gabriele P, Valente G, Cortesina G. Prognostic factors for head and neck tumor recurrence.  Acta Otolaryngol (Stockh). 1995;  115 833-838
• 16 Issing W J, Wustrow T PU, Heppt W. Onkogene und ihre Bedeutung für Kopf- und Halskarzinome.  HNO. 1992;  40 283-291
• 17 Müller D, Millon R, Lidereau R, Engelmann A, Bronner G, Flesh H, Eber M, Methlin G, Abecassis J. Frequent amplification of 11q13 DNA markers is associated with lymph node involvement in human head and neck squamous cell carcinomas.  Eur J Cancer. 1994;  30 113-120
• 18 Watling D L, Gown A M. Overexpression p53 in head and neck cancer.  Head Neck. 1992;  14 437-444
• 19 Bockmühl U, Petersen S, Schmidt S, Petersen I, Dietel M. Patterns of chromosomal alterations in metastasizing and non-metastasizing primary head and neck carcinomas.  Cancer Res. 1997;  57 5213-5216
• 20 Field J K, Kiaris H, Risk J M, Tsiriyotis C, Adamson R, Zoumpourlis V, Rowley H, Taylor K, Whittaker J, Howard P, Beirne J C, Gosney J R, Woolgar J, Vaughan E D, Spandidos D A, Jones A S. Allelotype of squamous cell carcinoma of the head and neck: fractional allele loss correlates with survival.  Br J Cancer. 1995;  72 1180-1188
• 21 Kawajiri K, Eguchi H, Nakachi K, Sekija T, Yamamoto M. Association of CYP1A1 germ line polymorphisms with mutations of the p53 gene in lung cancer.  Cancer Res. 1996;  56 72-76
• 22 Lazarus P, Sheikh S N, Ren Q, Schantz S P, Stern J C, Richie J P, Park J Y. p53, but not p16 mutations in oral squamous cell carcinomas are associated with specific CYP1A1 and GSTM1 polymorphic genotypes and patient tobacco use.  Carcinogenesis. 1998;  19 509-514
• 23 Perera F P. Molecular epidemiology: insights into cancer susceptibility, risk assessment and prevention.  J Natl Cancer Inst. 1996;  88 496-509
• 24 Chouaib S C, Asselin-Paturel F, Mami-Chouaib F, Caignard A, Blay J Y. The host-immune conflict: from immunosuppression to resistance and destruction.  Immunol Today. 1997;  18 493-497
• 25 Brockmöller J, Cascorbi I, Kerb R, Roots I. Combined analysis of inherited polymorphisms in arylamine N-acetyltransferase 2, glutathione S-transferase M1 an T1, microsomal epoxide hydrolase, and cytochrome P450 enzymes as modulators of bladder cancer risk.  Cancer Res. 1996;  56 3915-3925
• 26 Worrall S F, Corrigan M, High A, Starr D, Matthias C, Wolf R C, Jones P W, Hand P, Gilford J, Farrell W E, Hoban P, Fryer A A, Strange R C. Susceptibility and outcome in oral cancer: preliminary data showing an association with polymorphism in cytochrome P450 CYP2D6.  Pharmacogenetics. 1998;  8 433-439
• 27 Ingelman-Sundberg M, Johansson I, Persson I, Yue Q Y, Dahl M L, Bertilsson L, Sjoqvist F. Genetic polymorphism of cytochrome P450: interethnic differences and relationship to incidence of lung cancer.  Pharmacogenetics. 1992;  2 264-271
• 28 Goto I, Yoneda S, Yamamoto M, Kawajiri K. Prognostic significance of germ line polymorphisms of the CYP1A1 and glutathione S-transferase genes in patients with non-small cell lung cancer.  Cancer Res. 1996;  56 3725-3730
• 29 Harries L W, Stubbins M J, Forman D, Howard G CW, Wolf C R. Identification of genetic polymorphism at the GSTP1 locus and association with susceptibility to bladder, testicular and prostate cancer.  Carcinogenesis. 1997;  18 1221-1226
• 30 Matthias C, Branigan K, Jahnke V, Leder K, Haas J, Heighway J, Jones P W, Strange R C, Fryer A A, Hoban P R. Polymorphism within the cyclin D1 gene is associated with prognosis in patients with squamous cell carcinoma of the head and neck.  Clin Cancer Res. 1998;  4 2411-2418