Keywords
CyclinD1
polymorphism
diagnosis
How to Cite
Abstract
Background: The incidence of breast cancer in Egyptian women is rising; to date, a few susceptibility genes have been identified. p73 protein (also known as p53-like transcription factor or p53-related protein) is one of the ancestors of the tumor suppressor p53 protein, whose gene is located within the chromosomal loci1p36; a region most frequently deleted in human cancers. As a consequence of sharing same domain architecture with p53; p73 might regulate p53- response genes and induced cell cycle arrest/ apoptosis in response to DNA damage. A commonly studied non-coding polymorphism consisting of a double nucleotide substitutions (G→A) and (C→T) at position 4 and14 exon 2, situated upstream of the initial AUG regionsofp73. This functional consequence of p73 polymorphism may serve as a susceptibility marker for human cancer, but the results are inconsistent.
Patients and Methods: Eighty newly diagnosed females representing Egyptian population confirmed breast cancer patients and forty healthy controls, recruited from the departments of Experimental and Clinical Surgery and Cancer Management and Research, Medical Research Institute, Alexandria University. Single Nucleotides Polymorphism (SNP) in p73 gene (G4C14-to-A4T14) was determined in these samples by PCR-CTPP techniques.
Results: Insignificant differences in the distributions of p73 genotypes between patients and controls were observed (p=0.126). When p73 GC/GC genotype was used as the reference, the combined variant genotypes (AT/AT)/(GC/AT) was significantly associated with the risk for breast cancer [OR= 2.418, 95% CI(1.018-5.746); p= 0.042]. p73[(GC/AT)/(AT/AT) genotypes] was found to be associated with increased risk for breast cancer among women with pathological grade III, clinical stage III, tumor size ≥ 5cm, axillary lymph node involvement and the +ve (Her2/neu) expression, but not significantly associated with +ve ER/PR status, vascular invasion and metastasis. Furthermore, patients carrying AT variant has a favorable prognosis (p <0.001) and longer survival (41.33±1.45 months) than did patients carrying GC/GC genotype (24.0±1.13 months).
Conclusion: In conclusion, this study provides the first indication that p73 variants (AT/AT)/ (GC/ AT) are risk factors for breast cancer susceptibility in Egyptian women. Thus analysis of p73 G4C14- to- A4T14 polymorphism may be useful for identifying females with higher risk to develop cancer. Additional studies are needed to confirm these findings.
References
Alexandria Cancer Registry Annual. Report 2010. Medical Research Institute, Alexandria University, Egypt.
Barry Trink, Kenji Okami, Li Wu, Virote Sriuranpong, Jin Jen and David Sidransky. 1998. A new human p53 homologue. Nature Medicine. 4(7): 747 – 748.
Benard J, Douc-Rasy S and Ahomadegbe JC 2003. TP53 family members and human cancers Hum Mutat. 21(3):182-191.
Cai YC, Yang GY, Nie Y, Wang LD, Zhao X, Song YL, Seril DN, Liao J, Xing EP and Yang CS. 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(4):683-689.
Casciano I, Mazzocco K, Boni L, Pagnan G, Banelli B, Allemanni G, Ponzoni M, Tonini GP and Romani
M. 2002. Expression of ΔNp73 is a molecular marker for adverse outcome in neuroblastoma patients. Cell Death Differ., 9(3):246-51.
Choi JE, Kang HG, Chae MH, Kim EJ, Lee WK, Cha SI, Kim CH, Jung TH and Park JY. 2006. No association between p73 G4C14-to-A4T14 polymorphism and the risk of lung cancer in a Korean population. Biochemical genetics 4444(11-12): 533-540.
Coral O and Amy T. 2010. The Differences between Male and Female Breast Cancer In Principles of gender-specific medicine (2th ed.). Marianne J L (eds). Elsevier Inc (pub), 42(7): 459-472.
De Feo E, Persiani R, La Greca A, Amore R, Arzani D, Rausei S, D'Ugo D, Magistrelli P, van Duijn CM, Ricciardi G and Boccia S. 2009. A case-control study on the effect of p53 and p73 gene polymorphisms on gastric cancer risk and progression. Mutat Res., 675(1-2):60-5.
Dominguez G, Silva JM, Silva J, Garcia JM, Sanchez A, Navarro A, Gallego I, Provencio M, España P and Bonilla F. 2001. Wild type p73 overexpression and high-grade malignancy in breast cancer. Breast Cancer Res Treat. 66 (3):183-90.
Douc-Rasy S, Barrois M, Echeynne M, Kaghad M, Blanc E, Raguenez G, Goldschneider D, Terrier-Lacombe MJ, Hartmann O, Moll U, Caput D and Bénard J. 2002. ΔN-p73 α accumulates in human neuroblastic tumors. Am J Pathol., 160(2):631-9.
Grob TJ, Novak U, Maisse C, Barcaroli D, Luthi AU, Pirnia F, Hugli B, Graber HU, De Laurenzi V, Fey MF, Melino G and Tobler A. 2001. Human ΔNp73 regulates a dominant negative feedback loop for TAp73 and p53 Cell Death Differ., 8(12):1213-1223.
Hamajima N, Saito T, Matsuo K, Kozaki K I, Takahashi T and Tajima K. 2000. Polymerase Chain Reaction with Confronting two-pair Primers for Polymorphism Genotyping. Jpn J Cancer Res., 91(9): 865–868.
Hu Y, Jiang L, Zheng J, You Y, Zhou Y and Jiao S. 2012. Association between the p73 exon 2 G4C14-toA4T14 polymorphism and cancer risk: a meta-analysis. DNA Cell Biol., 31(2):230-7.
Hu Z, Miao X, Ma H, Tan W, Wang X, Lu D, Wei Q, Lin D and Shen H. 2005. Dinucleotide polymorphism of p73 gene is associated with a reduced risk of lung cancer in a Chinese population. International journal of cancer. 114(3):455-460.
Huang XE, Hamajima N, Katsuda N, Matsuo K, Hirose K, Mizutani M, Iwata H, Miura S, Xiang J, Tokudome S and Tajima K. 2003. 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(4):307-311.
Ishimoto O, Kawahara C, Enjo K, Obinata M, Nukiwa T and Ikawa S. 2002. Possible oncogenic potential of ΔNp73: a newly identified isoform of human p73 Cancer Res., 62(3):636-641.
Jost CA, Marin MC and Kaelin WG Jr. 1997. p73 is a human p53-related protein that can induce apoptosis. Nature; 389(6647): 191-194.
Kaghad M, Bonnet H, Yang A, Creancier L, Biscan JC, Valent A, Minty A, Chalon P, Lelias 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(4): 809-819.
Kang MJ, Park BJ, Byun DS, Park JI, Kim HJ, Park JH and Chi SG. 2000. Loss of imprinting and elevated expression of wild-type p73 in human gastric adenocarcinoma.Clin CancerRes.,6(5):1767-71.
Li G, Wang LE, Chamberlain RM, Amos CI, Spitz MR and Wei Q. 2004. p73 G4C14-to-A4T14 polymorphism andrisk of lung cancer.Cancer Res.,64 (19):6863–6866.
LiH,YaoL,Ouyang T,LiJ,WangT,FanZ,FanT, Dong B,LinB,LijandYuntaoXie.2006.Association of p73 G4C14-to-A4T14 (GC/AT) Polymorphism with BreastCancerSurvival,Carcinogenesis.28(2):372-377.
Lyla MHandDanGB.2006.Genes,Behavior,andthe Social Environment. National Academy of Sciences USA(pub)44-8.
MelinoG,DeLaurenziVandVousdenKH.2002.p73: friend orfoeintumorigenesis.NatRevCancer.2 (8):605 –615.
Niwa Y, Hamajima N, Atsuta Y, Yamamoto K, Tamakoshi A, Saito T, Hirose K, Nakanishi T,
Nawa A, Kuzuya K and Tajima K. 2004. Genetic polymorphisms of p73 G4C14-to-A4T14 at exon 2 and p53 Arg72Pro and the risk of cervical cancer in Japanese.CancerLett.,205(1):55-60.
Perera FP and Weinstein IB. 2000. Molecular epidemiology: recent advances and future directions. Carcinogenesis.21(3):517-24.
Pfeifer D, Arbman G and Sun XF. 2005. Polymorphism of the p73 gene in relation to colorectal cancerriskand survival.Carcinogenesis.26(1):103–7.
SchultzJ,Ponting CP,HofmannKandBorkP.1997. SAM as a protein interaction domain involved in developmentalregulation ProteinSci.,6(1):249-53.
Stiewe T and Putzer BM. 2002. Role of p73 in malignancy: tumor suppressor or oncogene?. Cell death and differentiation.9(3):237-45.
Stiewe T, Zimmermann S, Frilling A, Esche H and Putzer BM. 2002. Transactivation-deficient ΔTA-p73 actsasan oncogene.CancerRes.,62(13):3598–3602.
Tamakoshi A, Hamajima N, Kawase H, Wakai K, Katsuda N,SaitoT,ItoH,HiroseK,TakezakiTand Tajima K.2003.Duplex polymerasechainreaction with confronting two-pair primers (PCR-CTPP) for
genotyping alcohol dehydrogenase β subunit (ADH2) and aldehyde dehydrogenase 2 (ALDH2). Alcohol 38 (5):407-10.
ThanosCDandBowieJU.1999.p53 Familymembers p63 and p73 are SAM domain-containing proteins. ProteinSci.,8(8):1708-10.
Uramoto H, Sugio K, Oyama T, Nakata S, Ono K, MoritaM,Funa KandYasumotoK.2004.Expression of ΔNp73 predicts poor prognosis in lung cancer. Clin CancerRes.,10(20):6905-11.
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(6773):99-103.
Zaika AI, Kovalev S, Marchenko ND and Moll UM.1999. Overexpression of the wild type p73 genein breast cancer tissues and cell lines Cancer Res., 59 (13):3257-3263.
Zaika AI, Slade N, Erster SH, Sansome C, Joseph TW, Pearl M, Chalas E and Moll UM. 2002. DeltaNp73, a dominant-negative inhibitor of wild-type p53 and TAp73,isup-regulated in human tumors.JExp Med.,16;196(6):765-80.
Copyright license for the research articles published in Journal of Research in Biology are as per the license given below
Creative Commons License
Journal of Research in Ecology is licensed under a Creative Commons Attribution 4.0 International (CC BY 4.0). (www.creativecommons.org)
Based on a work at www.jresearchbiology.com
What this License explains us?
You are free to:
Share — copy and redistribute the material in any medium or format
Adapt — remix, transform, and build upon the material
for any purpose, even commercially.
This license is acceptable for Free Cultural Works. The licensor cannot revoke these freedoms as long as you follow the license terms.
[As given in the www.creativecommons.org website]
Under the following terms:
Attribution — You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use.
No additional restrictions — You may not apply legal terms or technological measures that legally restrict others from doing anything the license permits.