A common p73 polymorphism is associated with a reduced incidence of oesophageal carcinoma

The incidence of oesophageal adenocarcinoma is rising; to date, no susceptibility genes have been identified. p73, a novel p53 homologue, maps to chromosome 1p36, a region commonly deleted in oesophageal cancers. p73 shares some p53-like activity, but in addition, may also play a role in gastrointestinal epithelial inflammatory responses. A non-coding p73 polymorphism (denoted AT or GC) may be functionally significant. We investigated whether this polymorphism might play a role in the aetiopathogenesis of oesophageal cancer. This was a case–control, retrospective study. 84 cases of oesophageal cancer (25 squamous and 59 adenocarcinoma) and 152 normal population controls were genotyped for this polymorphism. Informative cases were examined for p73 LOH within the tumour. AT/AT homozygotes were significantly less prevalent in the oesophageal cancer population (1/84 = 1.2%) compared to controls (15/152 = 9.9%) (P < 0.02), corresponding to an odds ratio of 0.11 (95% C.I. 0.02–0.6, P < 0.02), or 9-fold reduced risk. Moreover, AT/AT homozygotes were significantly less frequent in the cancer population than would be expected under the Hardy–Weinberg hypothesis (P = 0.0099). LOH at the p73 locus was observed in 37.8% (14/37) of the AT/GC heterozygotes studied; in all cases there was loss of the AT allele. Our findings indicate that p73 AT/AT homozygotes appear to be protected against the development of oesophageal cancer. Clinically, this observation could have implications in aiding identification of high-risk Barrett's oesophagus patients. © 2001 Cancer Research Campaign http://www.bjcancer.com

[1]  G. Yang,et al.  Molecular alterations of p73 in human esophageal squamous cell carcinomas: loss of heterozygosity occurs frequently; loss of imprinting and elevation of p73 expression may be related to defective p53. , 2000, Carcinogenesis.

[2]  A. Yang,et al.  p73-deficient mice have neurological, pheromonal and inflammatory defects but lack spontaneous tumours , 2000, Nature.

[3]  Antonio Costanzo,et al.  The tyrosine kinase c-Abl regulates p73 in apoptotic response to cisplatin-induced DNA damage , 1999, Nature.

[4]  W. Kaelin,et al.  Correction: p73 is a human p53-related protein that can induce apoptosis , 1999, Nature.

[5]  Carissa A. Sanchez,et al.  Evolution of neoplastic cell lineages in Barrett oesophagus , 1999, Nature Genetics.

[6]  A. Lindgren,et al.  Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. , 1999, The New England journal of medicine.

[7]  H. Parkman,et al.  Heartburn--a serious symptom. , 1999, The New England journal of medicine.

[8]  D. Tindall,et al.  Overexpression of the wild type p73 gene in human bladder cancer , 1999, Oncogene.

[9]  F. McKeon,et al.  p73 at chromosome 1p36.3 is lost in advanced stage neuroblastoma but its mutation is infrequent , 1999, Oncogene.

[10]  Xinbin Chen,et al.  The potential tumor suppressor p73 differentially regulates cellular p53 target genes. , 1998, Cancer research.

[11]  N. Nomura,et al.  p73, a geme related to p53, is not mutated in esophageal carcinomas , 1998, International journal of cancer.

[12]  G. Melino,et al.  Two New p73 Splice Variants, γ and δ, with Different Transcriptional Activity , 1998, Journal of Experimental Medicine.

[13]  David I. Smith,et al.  Loss of imprinting and allele switching of p73 in renal cell carcinoma , 1998, Oncogene.

[14]  D. Tindall,et al.  Activation of p73 silent allele in lung cancer. , 1998, Cancer research.

[15]  D. Altshuler,et al.  Genetic polymorphisms and disease. , 1998, The New England journal of medicine.

[16]  A. Nakagawara,et al.  Mutation, allelotyping, and transcription analyses of the p73 gene in prostatic carcinoma. , 1998, Cancer Research.

[17]  S. Nomoto,et al.  Search for mutations and examination of allelic expression imbalance of the p73 gene at 1p36.33 in human lung cancers. , 1998, Cancer research.

[18]  W. Kaelin,et al.  p73 is a human p53-related protein that can induce apoptosis , 1997, Nature.

[19]  A. Yang,et al.  Monoallelically Expressed Gene Related to p53 at 1p36, a Region Frequently Deleted in Neuroblastoma and Other Human Cancers , 1997, Cell.

[20]  A. Levine p53, the Cellular Gatekeeper for Growth and Division , 1997, Cell.

[21]  T. Walsh,et al.  A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. , 1996, The New England journal of medicine.

[22]  Ruggero Montesano,et al.  Genetic alterations in esophageal cancer and their relevance to etiology and pathogenesis: A review , 1996, International journal of cancer.

[23]  Carissa A. Sanchez,et al.  Determination of the frequency of loss of heterozygosity in esophageal adenocarcinoma by cell sorting, whole genome amplification and microsatellite polymorphisms. , 1996, Oncogene.

[24]  François Rousset,et al.  GENEPOP (version 1.2): population genetic software for exact tests and ecumenicism , 1995 .

[25]  J. Bosset,et al.  Chemotherapy followed by surgery compared with surgery alone in squamous-cell cancer of the esophagus , 1998 .