Abstract
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
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References
Altshuler D, Kruglyak L and Lander E (1998) Genetic polymorphisms and disease (correspondance). N Engl J Med 338: 1626
Barrett M, Sanchez C, Prevo L, Wong D, Galipeau P, Paulson T, Rabinovitch P and Reid B (1999) Evolution of neoplastic cell lineages in Barrett oesophagus. Nature Genet 22: 106–109
Barrett MT, Galipeau PC, Sanchez CA, Emond MJ and Reid BJ (1996) Determination of the frequency of loss of heterozygosity in esophageal adenocarcinoma by cell sorting, whole genome amplification and microsatellite polymorphisms. Oncogene 12: 1873–1878
Bosset J, Gignoux M, Triboulet J, Tiret E, Mantion G, Elias D, Lozach P, Ollier J, Pavy J, Mercier M and Sahmoud T (1997) Chemoradiotherapy followed by surgery compared with surgery alone in squamous cell cancer of the esophagus. N Engl J Med 337: 161–167
Cai Y, Yang G-Y, Nie Y, Wang L-D, Zhao X, Song Y-L, Seril D, Liao J, Xing E and Yang C (2000) 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. Carcinogenesis 21: 683–689
Cohen S and Parkman H (1999) Heartburn-A Serious Symptom (editorial). N Engl J Med 340: 878–879
De Laurenzi V, Costanzo A, Barcaroli D, Terrinoni A, Falco M, Annicchiarico-Petruzzelli M, Levrero M and Melino G (1998) Two new p73 splice variants, g and d, with different transcriptional activity. J Exp Med 188: 1763–1768
Gong J, Constanzo A, Yang HQ, Melino G, Kaelin WG, Levrero M and Wang JYJ (1999) The tyrosine-kinase c-Abl regulates p73 in apoptotic response to cisplatin-induced DNA damage. Nature 399: 806–809
Ichimiya S, Nimura Y, Kageyama H, Takada N, Sunahara M, Shishikura T, Nakamura Y, Sakiyama S, Seki N, Ohira M, Kaneko Y, McKeon F, Caput D and Nakagawara A (1999) p73 at chromosome 1p36.3 is lost in advanced stage neuroblastoma but its mutation is infrequent. Oncogene 18: 1061–1066
Jost CA, Marin MC and Kaelin WG (1997) p73 is a human p53- related protein that can induce apoptosis. Nature 389: 191–194
Kaghad M, Bonnet H, Yang A, Creancier L, Biscan JC, Valent A, Minty A, Chalon P, Lellas JM, Dumont X, Ferrara P, McKeon F and Caput D (1997) Monoallelically expressed gene related to p53 at 1p36, a region frequently deleted in neuroblastoma and other human cancers. Cell 90: 809–819
Lagergren J, Bergstrom R, Lindgren A and Nyren O (1999) Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. N Engl J Med 340: 825–831
Levine AJ (1997) P53, the cellular gatekeeper for growth and division (review). Cell 88: 323–331
Mai M, Qian C, Yokomizo A, Tindall DJ, Bostwick D, Polychronakos C, Smith DI and Liu W (1998a) Loss of imprinting and allele switching in renal cell carcinoma. Oncogene 17: 1739–1741
Mai M, Yokomizo A, Qian C, Yang P, Tindall DJ, Smith DI and Liu W (1998b) Activation of p73 silent allele in lung cancer. Cancer Res 58: 2347–2349
Montesano R, Hollstein M and Hainaut P (1996) Genetic alterations in esophageal cancer and their relevance to etiology and pathogenesis: A review. Int J Cancer 69: 225–235
Nimura Y, Mihara M, Ichimiya S, Sakiyama S, Seki N, Ohira M, Nomura N, Fujimori M, Adachi W, Amano J, He M, Ping YM and Nakagawara A (1998) P73, a gene related to p53, is not mutated in esophageal carcinomas. Int J Cancer 78: 437–440
Nomoto S, Haruki N, Kondo M, Konishi H, Takahashi T, Takahashi T and Takahashi T (1998) Search for mutations and examination of allalic expression imbalance of the p73 gene at 1p36.33 in human lung cancers. Cancer Res 58: 1380–1383
Raymond M and Rousset F (1995) GENEPOP (version 1.2): population genetics software for exact tests and ecumenicism. J Heredity 86: 248–249
Takahashi H, Ichimiya S, Nimura Y, Watanabe M, Furusato M, Wakui S, Yatani R, Aizawa S and Makagawara A (1998) Mutation, allelotyping and transcription analyses of the p73 gene in prostatic carcinoma. Cancer Res 58: 2076–2077
Walsh T, Noonan N, Hollywood D, Kelly A, Keeling N and Hennessy T (1996) A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med 335: 462–467
Yang A, Walker N, Bronson R, Kaghad M, Oosterwegel M, Bonnin J, Vagner C, Bonnet H, Dikkes P, Sharpe A, McKeon F and Caput D (2000) p73-deficient mice have neurological, pheromonal and inflammatory defects but lack spontaneous tumours. Nature 404: 99–103
Yokomizo A, Mai M, Tindall DJ, Cheng L, Bostwick DG, Naito S, Smith DI and Liu W (1999) Overexpression of the wild type p73 gene in human bladder cancer. Oncogene 18: 1629–1633
Zhu J, Jiang J, Zhou W and Chen X (1998) The potential tumour suppressor p73 differentially regulates cellular p53 target genes. Cancer res 58: 5061–5965
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Ryan, B., McManus, R., Daly, J. et al. A common p73 polymorphism is associated with a reduced incidence of oesophageal carcinoma. Br J Cancer 85, 1499–1503 (2001). https://doi.org/10.1054/bjoc.2001.2066
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DOI: https://doi.org/10.1054/bjoc.2001.2066
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