Abstract
We examined the association of one linked GC/AT polymorphism at p73 with the risk of colorectal cancer. In the present study, we investigated whether this polymorphism was related to the risk of colorectal cancer, and whether there were relationships between the polymorphism and LOH, protein expression or clinicopathological variables. The p73 genotypes were determined by PCR-restriction fragment length polymorphism in 150 Tunisians patients with colorectal cancer and in 204 healthy control subjects. Immunohistochemistry was performed on normal mucosa, primary tumour and metastasis. The frequencies of the genotypes were 52% for wild-type (GC/GC), 31% for heterozygotes (GC/AT) and 17% for variants (AT/AT) in patients, and 54%, 35% and 11% in controls, respectively. There were no significant differences of the frequencies of the three genotypes between the patients and controls (p = 0.11). We did not find any relationship of the genotypes with clinicopathological features of patients. We found that patients with the AT/AT genotype had a significantly worse clinical outcome than those with the GC/AT and GC/GC genotype. There were no significant differences between tumoural immunostaining of the total p73 and p73 polymorphism (p = 0.16). However, we found a significant difference between the expression profile of ΔNp73 isoform and frequencies of the three genotypes (p = 0.0001). No LOH was observed at p73 locus. Our results suggest that the AT/AT genotype is significantly associated with poor prognosis in colorectal cancer. All these findings suggest that p73 polymorphism analysis may provide useful prognostic information for colorectal cancer patients.
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Kaghad M, Bonnet H, Yang A et al (1997) Monoallelically expressed gene related to p53 at 1p36, a region frequently deleted in neuroblastoma and other human cancers. Cell 90:809–819
Flores ER, Tsai KY, Crowley D et al (2002) p63 and p73 are required for p53-dependent apoptosis in response to DNA damage. Nature 416:560–564
Wang XQ, Ongkeko WM, Lau AW, Leung KM, Poon RY (2001) A possible role of p73 on the modulation of p53 level through MDM2. Cancer Res 61:1598–1603
Mai M, Yokomizo A, Qian C et al (1998) Activation of p73 silent allele in lung cancer. Cancer Res 58:2347–2349
Takahashi H, Ichimiya S, Nimura Y et al (1998) Mutation, allelotyping and transcription analyses of the p73 gene in prostatic carcinoma. Cancer Res 58:2076–2077
Yokomizo A, Mai M, Tindall DJ et al (1999) Overexpression of the wild type p73 gene in human bladder cancer. Oncogene 18:1629–1633
Yang A, Walker N, Bronson R et al (2000) p73-deficient mice have neurological, pheromonal and inflammatory defects but lack spontaneous tumours. Nature 404:99–103
Moll UM, Erster S, Zaika A (2001) p53, p63 and p73—solos, alliances and feuds among family members. Biochim Biophys Acta 1552:47–59
Benard J, Douc-Rasy S, Ahomadegbe JC (2003) TP53 family members and human Cancers. Hum Mutat 21:182–191
Coates PJ (2006) Regulating p73 isoforms in human tumours. J Pathol 210:385–389
Ichimiya S, Nimura Y, Kageyama H et al (1999) p73 at chromosome 1p36.3 is lost in advanced stage neuroblastoma but its mutation is infrequent. Oncogene 18:1061–1066
Nomoto S, Haruki N, Kondo M, Konishi H, 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
Nimura Y, Mihara M, Ichimiya S et al (1998) P73, a gene related to p53, is not mutated in esophageal carcinomas. Int J Cancer 78:437–440
Cai Y, Yang GY, Nie Y et al (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
Sun XF (2002) p73 Overexpression is a prognostic factor in patients with colorectal adenocarcinoma. Clin Cancer Res 8:165–170
Guan M, Peng HX, Yu B, Lu Y (2003) p73 overexpression and angiogenesis in human colorectal carcinoma. Jpn J Clin Oncol 33:215–220
Herath NI, Kew MC, Whitehall VL et al (2000) p73 is up-regulated in a subset of hepatocellular carcinomas. Hepatology 31:601–605
Zaika AI, Kovalev S, Marchenko ND et al (1999) Overexpression of the wild type p73 gene in breast cancer tissues and cell lines. Cancer Res 59:3257–3263
Hamajima N, Matsuo K, Suzuki T et al (2002) No association of p73 G4C14-to-A4T14 at exon 2 and p53 Arg72Pro polymorphism with the risk of digestive tract cancers in Japanese. Cancer Lett 181:81–85
Ryan BM, McManus R, Daly JS et al (2001) A common p73 polymorphism is associated with a reduced incidence of oesophageal carcinoma. Br J Cancer 85:1499–1503
Li G, Sturgis EM, Wang LE et al (2004) Association of a p73 exon 2 G4C14-to-A4T14 polymorphism with risk of squamous cell carcinoma of the head and neck. Carcinogenesis 25:1911–1916
Pfeifer D, Arbman G, Sun X-F (2005) Polymorphism of the p73 gene in relation to colorectal cancer risk and survival. Carcinogenesis 26:103–107
Hiraki A, Matsuo K, Hamajima N et al (2003) Different risk relations with smoking for non–small-cell lung cancer: comparison of TP53 and TP73 genotypes. Asian Pac J Cancer Prev 4:107–112
Huang XE, Hamajima N, Katsuda N et al (2000) Association of p53 codon Arg72Pro and p73 G4C14-to-A4T14 at exon 2 genetic polymorphisms with the risk of Japanese breast cancer. Breast Cancer 10:307–311
Niwa Y, Hamajima N, Atsuta Y et al (2004) Genetic polymorphisms of p73 G4C14-to-A4T14 at exon 2 and p53 Arg72Pro and the risk of cervical cancer in Japanese. Cancer Lett 205:55–60
Li H, Yao L, Ouyang T et al (2007) Association of p73 G4C14-to-A4T14 (GC/AT) polymorphism with breast cancer survival. Carcinogenesis 28:372–377
Li G, Wang Li-E, Chamberlain RM, Amos CI, Spitz MR, Wei Q (2004) p73 G4C14-to-A4T14 Polymorphism and Risk of Lung Cancer. Cancer Res 64:6863–6866
Melino G, De Laurenzi V, Vousden KH (2002) P73: friend or foe in tumorigenesis. Nat Rev Cancer 2:605–615
Grob TJ, Novak U, Maisse C et al (2001) Human delta Np73 regulates a dominant negative feedback loop for TAp73 and p53. Cell Death Differ 8:1213–1223
Ishimoto O, Kawahara C, Enjo K et al (2002) Possible oncogenic potential of DeltaNp73: a newly identified isoform of human p73. Cancer Res 62:636–641
Stiewe T, Theseling CC, Putzer BM (2002) Transactivation-deficient Delta TA-p73 inhibits p53 by direct competition for DNA binding: implications for tumorigenesis. J Biol Chem 277:14177–14185
Lööf J, Pfeifer D, Adell G, Sun X-F (2009) Significance of an exon 2 G4C14-to-A4T14 polymorphism in the p73 gene on survival in rectal cancer patients with or without preoperative radiotherapy. Radiother Oncol 92:215–220
Petrenko O, Zaika A, Moll UM (2003) deltaNp73 facilitates cell immortalization and cooperates with oncogenic Ras in cellular transformation in vivo. Mol Cell Biol 23:5540–5555
Fernandez-Garcia B, Vaque JP, Herreros-Villanueva M et al (2007) p73 cooperates with Ras in the activation of MAP kinase signaling cascade. Cell Death Differ 14:254–265
Melino G, Lu X, Gasco M, Crook T, Knight RA (2003) Functional regulation of p73 and p63: development of cancer. Trends Biochem Sci 28:663–670
Shan L, Yang Q, Nakamura M et al (2001) Frequent loss of heterozygosity at 1p36.3 and p73 abnormality in parathyroid adenomas. Mod Pathol 14:273–278
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This study was supported by a grant from the Ministry of the technology and the scientific research.
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Arfaoui, A.T., Kriaa, L.B.M., El Hadj, O.E.A. et al. Association of a p73 exon 2 GC/AT polymorphism with colorectal cancer risk and survival in Tunisian patients. Virchows Arch 457, 359–368 (2010). https://doi.org/10.1007/s00428-010-0942-4
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DOI: https://doi.org/10.1007/s00428-010-0942-4