p53 protein accumulation and genomic instability in head and neck multistep tumorigenesis.

Head and neck cancer develops in a multistep process and is associated with increasing frequencies of p53 alterations and with increasing genomic instability. To study the relationship of p53 alterations and genomic instability during head and neck tumorigenesis, we analyzed p53 protein expression and chromosome 9 and 17 polysomy in 48 squamous cell carcinomas of the head and neck and their adjacent normal epithelium (31 sites), hyperplastic (24 sites), and dysplastic lesions (26 sites). Normal oral epithelium obtained from seven nonsmoking, cancer-free individuals served as negative controls. Six (19%) of 31 lesions in adjacent normal epithelium, 7 (29%) of 24 hyperplastic lesions, 12 (46%) of 26 dysplastic lesions, and 28 (58%) of 48 squamous cell carcinomas expressed p53. In contrast, no normal control epithelium had detectable p53 expression. To determine the relationship between dysregulated p53 expression and genomic instability during tumorigenesis, we compared p53 immunohistochemistry distributions and chromosome polysomy levels (by chromosome in situ hybridization) in different histological groups associated with tissue progression. Although the degree of chromosome polysomy increased for all of the groups during histological progression, lesions with dysregulated p53 expression showed nearly 2-4-fold increased levels of chromosome polysomy. This trend was significant for dysplastic lesions (P = 0.005 and P = 0.002 for chromosomes 9 and 17, respectively) and for squamous cell carcinoma (P = 0.005 and P = 0.002 for chromosomes 9 and 17, respectively). Image analysis studies for 28 p53-expressing tumors and their adjacent premalignant lesions demonstrated a strong spatial correlation between stepwise transitions from low to high p53 expression and increased chromosome polysomy frequencies in 13 (46%) of 28 cases. These findings suggest that altered p53 expression is associated with increased genetic instability in preneoplastic epithelium and may play a driving force for increasing the rate of accumulation of genetic events during head and neck tumorigenesis.

[1]  F. Bosch,et al.  Expression of mutated p53 occurs in tumor-distant epithelia of head and neck cancer patients: a possible molecular basis for the development of multiple tumors. , 1993, Cancer research.

[2]  F. Collins,et al.  Mutations in the p53 gene occur in diverse human tumour types , 1989, Nature.

[3]  A. Fornace,et al.  Genomic instability and the role of p53 mutations in cancer cells. , 1995, Current opinion in oncology.

[4]  Bert Vogelstein,et al.  Mutations of mitotic checkpoint genes in human cancers , 1998, Nature.

[5]  S. Lippman,et al.  Detection of chromosome instability of tissue fields at risk: In situ hybridization , 1996, Journal of cellular biochemistry. Supplement.

[6]  S. Yuspa,et al.  Transforming growth factor beta 1 suppresses genomic instability independent of a G1 arrest, p53, and Rb. , 1996, Cancer research.

[7]  N. Tsuchida,et al.  Most human squamous cell carcinomas in the oral cavity contain mutated p53 tumor-suppressor genes. , 1992, Oncogene.

[8]  Y. Nakamura,et al.  Genetic alterations during colorectal-tumor development. , 1988, The New England journal of medicine.

[9]  G. Wahl,et al.  Wild-type p53 restores cell cycle control and inhibits gene amplification in cells with mutant p53 alleles , 1992, Cell.

[10]  R. Hruban,et al.  The incidence of p53 mutations increases with progression of head and neck cancer. , 1993, Cancer research.

[11]  W. Hong,et al.  Increased polysomies of chromosomes 7 and 17 during head and neck multistage tumorigenesis. , 1993, Cancer research.

[12]  S. Lippman,et al.  Chromosome polysomy and histological characteristics in oral premalignant lesions. , 2001, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[13]  A. Malliri,et al.  Elevated P53 expression correlates with a history of heavy smoking in squamous cell carcinoma of the head and neck. , 1991, British Journal of Cancer.

[14]  A. Levine,et al.  The p53 proto-oncogene can act as a suppressor of transformation , 1989, Cell.

[15]  S. Lippman,et al.  Biochemopreventive therapy for patients with premalignant lesions of the head and neck and p53 gene expression. , 2000, Journal of the National Cancer Institute.

[16]  N. Petrelli,et al.  p53 tumor suppressor gene status and the degree of genomic instability in sporadic colorectal cancers. , 1996, Journal of the National Cancer Institute.

[17]  R. Fine,et al.  Increased fragile sites and sister chromatid exchanges in bone marrow and peripheral blood of young cigarette smokers. , 1987, Cancer research.

[18]  S. Hilsenbeck,et al.  Increased tumor proliferation and genomic instability without decreased apoptosis in MMTV-ras mice deficient in p53 , 1997, Molecular and cellular biology.

[19]  D. Brash,et al.  Sunlight and the onset of skin cancer. , 1997, Trends in genetics : TIG.

[20]  A. Levine,et al.  p53 and its 14 kDa C-terminal domain recognize primary DNA damage in the form of insertion/deletion mismatches , 1995, Cell.

[21]  Leland Hartwell,et al.  Defects in a cell cycle checkpoint may be responsible for the genomic instability of cancer cells , 1992, Cell.

[22]  M. Sporn,et al.  Recent advances in chemoprevention of cancer. , 1997, Science.

[23]  T. Jacks,et al.  Deletion of p21 cannot substitute for p53 loss in rescue of mdm2 null lethality , 1997, Nature Genetics.

[24]  S. Lippman,et al.  p53 and retinoid chemoprevention of oral carcinogenesis. , 1995, Cancer research.

[25]  Y. Miller,et al.  Widely dispersed p53 mutation in respiratory epithelium. A novel mechanism for field carcinogenesis. , 1997, The Journal of clinical investigation.

[26]  M. Meyers,et al.  Chromosomal instability and its relationship to other end points of genomic instability. , 1997, Cancer research.

[27]  G. Lozano,et al.  Targeted expression of MDM2 uncouples S phase from mitosis and inhibits mammary gland development independent of p53. , 1997, Genes & development.

[28]  W. Hong,et al.  Dysregulated cyclin D1 expression early in head and neck tumorigenesis: in vivo evidence for an association with subsequent gene amplification , 1998, Oncogene.

[29]  S. Girod,et al.  p53 and Ki 67 expression in preneoplastic and neoplastic lesions of the oral mucosa. , 1993, International journal of oral and maxillofacial surgery.

[30]  D. Spandidos,et al.  p53 mutations in squamous cell carcinoma of the head and neck predominate in a subgroup of former and present smokers with a low frequency of genetic instability. , 1997, Cancer research.

[31]  H P Koeffler,et al.  P53 mutations in human cancer. , 1993, Leukemia.

[32]  S. Lippman,et al.  Detection of chromosomal polysomy in oral leukoplakia, a premalignant lesion. , 1993, Journal of the National Cancer Institute.

[33]  A. Sood,et al.  Ovarian cancer genomic instability correlates with p53 frameshift mutations. , 1997, Cancer research.

[34]  E. Farber The multistep nature of cancer development. , 1984, Cancer research.

[35]  T. Uchida,et al.  Genomic instability of microsatellite repeats and mutations of H-, K-, and N-ras, and p53 genes in renal cell carcinoma. , 1994, Cancer research.

[36]  S. Lippman,et al.  Biochemoprevention for dysplastic lesions of the upper aerodigestive tract. , 1999, Archives of otolaryngology--head & neck surgery.

[37]  K. Mills,et al.  p53 mutations, methylation and genomic instability in the progression of chronic myeloid leukaemia. , 1997, Leukemia & lymphoma.

[38]  J. Eyfjörd,et al.  p53 abnormalities and genomic instability in primary human breast carcinomas. , 1995, Cancer research.

[39]  M. Tatsuka,et al.  Requirement for tyrosine phosphorylation of Cdk4 in Gl arrest induced by ultraviolet irradiation , 1995, Nature.

[40]  W. Hong,et al.  Activation of p53 gene expression in premalignant lesions during head and neck tumorigenesis. , 1994, Cancer research.

[41]  L. Strong,et al.  Analysis of genomic instability in Li-Fraumeni fibroblasts with germline p53 mutations. , 1996, Oncogene.

[42]  A. Knudson Hereditary cancer, oncogenes, and antioncogenes. , 1985, Cancer research.

[43]  D. Lane,et al.  T antigen is bound to a host protein in SY40-transformed cells , 1979, Nature.

[44]  A. Gown,et al.  Monoclonal antibodies to human intermediate filament proteins. II. Distribution of filament proteins in normal human tissues. , 1984, The American journal of pathology.

[45]  J. K. Sharma,et al.  Sister chromatid exchanges in the lymphocytes of patients with oral leukoplakia. , 1988, Cancer genetics and cytogenetics.

[46]  M. Oren,et al.  Wild-type p53 can inhibit oncogene-mediated focus formation. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[47]  H. Kitamura,et al.  Cytogenetic changes in rat tracheal epithelial cells during early stages of carcinogen-induced neoplastic progression. , 1988, Cancer research.

[48]  B. Vogelstein,et al.  p53 mutations in human cancers. , 1991, Science.