Grant Number:	7R01CA059917-05 Interpret this number
Primary Investigator:	Lazarus, Philip
Organization:	University Of South Florida
Project Title:	P53-Marker for Oral Cavity Premalignancy & Cancer Risk
Fiscal Year:	1998

The p53 tumor suppressor gene has been strongly implicated in the process of carcinogenesis. In particular, a strong association exists between mutations of the p53 gene and a variety of tobacco-related cancers, including cancers of head and neck, where p53 mutations were observed in up to 78% of head and neck squamous cell carcinomas from patients who were chronic smokers. The origin of p53 mutations during tumor progression has been studied by determining p53 mutation incidence in premalignant lesions of various organs and may be indicative of the tumorigenic potential of these lesions. We and others have obtained preliminary data demonstrating that premalignant lesions of the oral cavity may possess mutations at the p53 locus and that this may be dependent upon the degree of lesion dysplasia and/or malignant potential. These data suggest that p53 mutation may be an early event in oral cavity cancer progression. Since mutation of the p53 gene is highly correlated with the malignant phenotype, it may be an excellent candidate for risk assessment for oral cavity cancer in individuals with oral cavity preneoplastic lesions, and may serve as an intermediate biomarker in chemoprevention trials. In addition, we have demonstrated what appears to be a direct correlation between p53 mutation incidence in oral cavity premalignant lesions and a specific risk factor for oral cavity cancer - tobacco use. This must be confirmed using a larger subset of tumor tissue samples from tobacco users and non-users. We hypothesize that mutations of the p53 gene may be an important biomarker for determining the tumorigenic potential of premalignant lesions of the oral cavity. The overall goal of this research proposal is to examine the incidence of p53 mutations in premalignant lesions of the oral cavity and correlate this incidence with; i) the known tumorigenic potentials of different oral cavity premalignant lesion classes, ii) the degree of lesion dysplasia, and iii) specific risk factors. Premalignant oral cavity lesion samples will be obtained from patients recruited from five collaborating centers. Lesion tumorigenic potential will be assessed by diagnostic classification of lesions into categories of known tumorigenic potentials, and the degree of dysplasia will be determined histologically. P53 mutations will be assayed using sensitive molecular techniques such as polymerase chain reaction/single strand conformational polymorphism and DNA sequencing. To verify the causal relationship between p53 mutations and cancer in oral cavity premalignant lesions, we will also examine a small group of oral cavity premalignant lesions (in paraffin blocks) obtained prospectively from patients who later developed oral cavity cancer. The p53 mutational incidence and spectrum in these lesions will be compared to the incidence and spectrum observed in the tumors taken from the same patients. These studies should provide us with valuable information on p53 mutation as a biomarker for oral cavity cancer progression and etiology, and should indicate whether an analysis of the p53 mutational status of these lesions may be useful for both cynical diagnosis and patient prognosis and treatment. These studies should aid in the detection of oral cavity premalignant lesions with the highest tumorigenic potential in patients, and should ultimately lead to improved and more aggressive treatment modalities for such lesions.




Characterization Of Udp-glucuronosyltransferase 2a1 (ugt2a1) Variants And Their Potential Role In Tobacco Carcinogenesis
Authors: Bushey R.T. , Chen G. , Blevins-Primeau A.S. , Krzeminski J. , Amin S. , Lazarus P. .
Source: Pharmacogenetics And Genomics, 2011 Feb; 21(2), p. 55-65.
PMID: 21164388
Related Citations

Differential transcription-coupled translational inhibition of human p53 expression: a potentially important mechanism of regulating p53 expression in normal versus tumor tissue.
Authors: Strudwick S. , Carastro L.M. , Stagg T. , Lazarus P. .
Source: Molecular Cancer Research : Mcr, 2003 Apr; 1(6), p. 463-74.
PMID: 12692266
Related Citations

Glucuronidation: An Important Mechanism For Detoxification Of Benzo[a]pyrene Metabolites In Aerodigestive Tract Tissues
Authors: Zheng Z. , Fang J.L. , Lazarus P. .
Source: Drug Metabolism And Disposition: The Biological Fate Of Chemicals, 2002 Apr; 30(4), p. 397-403.
PMID: 11901093
Related Citations

Characterization of benzo(a)pyrene-trans-7,8-dihydrodiol glucuronidation by human tissue microsomes and overexpressed UDP-glucuronosyltransferase enzymes.
Authors: Fang J.L. , Beland F.A. , Doerge D.R. , Wiener D. , Guillemette C. , Marques M.M. , Lazarus P. .
Source: Cancer Research, 2002-04-01 00:00:00.0; 62(7), p. 1978-86.
PMID: 11929814
Related Citations

Tobacco Carcinogen-detoxifying Enzyme Ugt1a7 And Its Association With Orolaryngeal Cancer Risk
Authors: Zheng Z. , Park J.Y. , Guillemette C. , Schantz S.P. , Lazarus P. .
Source: Journal Of The National Cancer Institute, 2001-09-19 00:00:00.0; 93(18), p. 1411-8.
PMID: 11562393
Related Citations

Elucidation of CYP2E1 5' regulatory RsaI/Pstl allelic variants and their role in risk for oral cancer.
Authors: Liu S. , Park J.Y. , Schantz S.P. , Stern J.C. , Lazarus P. .
Source: Oral Oncology, 2001 Jul; 37(5), p. 437-45.
PMID: 11377232
Related Citations

O-Glucuronidation of the lung carcinogen 4-(methylnitrosamino)-1- (3-pyridyl)-1-butanol (NNAL) by human UDP-glucuronosyltransferases 2B7 and 1A9.
Authors: Ren Q. , Murphy S.E. , Zheng Z. , Lazarus P. .
Source: Drug Metabolism And Disposition: The Biological Fate Of Chemicals, 2000 Nov; 28(11), p. 1352-60.
PMID: 11038164
Related Citations

Metabolizing enzyme genotype and risk for upper aerodigestive tract cancer.
Authors: Lazarus P. , Park J.Y. .
Source: Oral Oncology, 2000 Sep; 36(5), p. 421-31.
PMID: 10964048
Related Citations

Role of polymorphisms in codons 143 and 160 of the O6-alkylguanine DNA alkyltransferase gene in lung cancer risk.
Authors: Kaur T.B. , Travaline J.M. , Gaughan J.P. , Richie J.P. , Stellman S.D. , Lazarus P. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2000 Mar; 9(3), p. 339-42.
PMID: 10750675
Related Citations

Comparison of GSTM polymorphisms and risk for oral cancer between African-Americans and Caucasians.
Authors: Park L.Y. , Muscat J.E. , Kaur T. , Schantz S.P. , Stern J.C. , Richie J.P. , Lazarus P. .
Source: Pharmacogenetics, 2000 Mar; 10(2), p. 123-31.
PMID: 10762000
Related Citations

Glucuronidation of the lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) by rat UDP-glucuronosyltransferase 2B1.
Authors: Ren Q. , Murphy S.E. , Dannenberg A.J. , Park J.Y. , Tephly T.R. , Lazarus P. .
Source: Drug Metabolism And Disposition: The Biological Fate Of Chemicals, 1999 Sep; 27(9), p. 1010-6.
PMID: 10460800
Related Citations

Association between glutathione S-transferase pi genetic polymorphisms and oral cancer risk.
Authors: Park J.Y. , Schantz S.P. , Stern J.C. , Kaur T. , Lazarus P. .
Source: Pharmacogenetics, 1999 Aug; 9(4), p. 497-504.
PMID: 10780269
Related Citations

A high prevalence of p53 mutations in pre-malignant oral erythroplakia.
Authors: Qin G.Z. , Park J.Y. , Chen S.Y. , Lazarus P. .
Source: International Journal Of Cancer, 1999-01-29 00:00:00.0; 80(3), p. 345-8.
PMID: 9935172
Related Citations

p53, but not p16 mutations in oral squamous cell carcinomas are associated with specific CYP1A1 and GSTM1 polymorphic genotypes and patient tobacco use.
Authors: Lazarus P. , Sheikh S.N. , Ren Q. , Schantz S.P. , Stern J.C. , Richie J.P. , Park J.Y. .
Source: Carcinogenesis, 1998 Mar; 19(3), p. 509-14.
PMID: 9525287
Related Citations

Risk of lung cancer from environmental exposures to tobacco smoke.
Authors: Muscat J.E. , Lazarus P. .
Source: Cancer Causes & Control : Ccc, 1997 Nov; 8(6), p. 929.
PMID: 9427436
Related Citations

CYP1A1 and GSTM1 polymorphisms and oral cancer risk.
Authors: Park J.Y. , Muscat J.E. , Ren Q. , Schantz S.P. , Harwick R.D. , Stern J.C. , Pike V. , Richie J.P. , Lazarus P. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 1997 Oct; 6(10), p. 791-7.
PMID: 9332761
Related Citations

Re-usable DNA template for the polymerase chain reaction.
Authors: Sheikh S.N. , Lazarus P. .
Source: Nucleic Acids Research, 1997-09-01 00:00:00.0; 25(17), p. 3537-42.
PMID: 9254716
Related Citations

P53 protein overexpression in lung adenocarcinomas in non-smokers.
Authors: Muscat J. , Citron M. , Wang C. , White A. , Lazarus P. .
Source: Oncology Reports, 1997 Jul-Aug; 4(4), p. 825-7.
PMID: 21590150
Related Citations

p53 alteration and human papilloma virus infection in paranasal sinus cancer.
Authors: Caruana S.M. , Zwiebel N. , Cocker R. , McCormick S.A. , Eberle R.C. , Lazarus P. .
Source: Cancer, 1997-04-01 00:00:00.0; 79(7), p. 1320-8.
PMID: 9083153
Related Citations

Typing of common human papilloma virus strains by multiplex PCR.
Authors: Lazarus P. , Caruana S. .
Source: Analytical Biochemistry, 1996-12-01 00:00:00.0; 243(1), p. 198-201.
PMID: 8954550
Related Citations

Relationship between p53 mutation incidence in oral cavity squamous cell carcinomas and patient tobacco use.
Authors: Lazarus P. , Stern J. , Zwiebel N. , Fair A. , Richie J.P. , Schantz S. .
Source: Carcinogenesis, 1996 Apr; 17(4), p. 733-9.
PMID: 8625484
Related Citations

p53 mutations in head and neck squamous cell carcinomas from Sudanese snuff (toombak) users.
Authors: Lazarus P. , Idris A.M. , Kim J. , Calcagnotto A. , Hoffmann D. .
Source: Cancer Detection And Prevention, 1996; 20(4), p. 270-8.
PMID: 8818386
Related Citations

A low incidence of p53 mutations in pre-malignant lesions of the oral cavity from non-tobacco users.
Authors: Lazarus P. , Garewal H.S. , Sciubba J. , Zwiebel N. , Calcagnotto A. , Fair A. , Schaefer S. , Richie J.P. .
Source: International Journal Of Cancer, 1995-02-08 00:00:00.0; 60(4), p. 458-63.
PMID: 7829258
Related Citations