Polymorphism at Codon 72 of p53 Is Not Associated with Cervical Cancer Risk

Abstract

P53 allelic polymorphism at codon 72 has been studied as a possible predisposing factor for cervical carcinogenesis with inconsistent results. Storey and colleagues recently published the interesting finding of a 7-fold increased risk for cervical cancer in women homozygous for the arginine allele at codon 72. This stimulated a number of independent investigations, the majority of which found no association of cervical cancer and arginine homozygosity.With the use of a modified Storey method for determining codon 72 allelotypes, DNA was examined from 431 microdissected, formalin-fixed, archival cervical conization specimens ranging from low-grade squamous lesions to invasive cancer. An alternative independent method using restriction fragment length polymorphism analysis was performed on all arginine homozygotes and all indeterminate cases for confirmation and final allelotype assignment.With the use of Storey's method alone, logistic regression suggested an association (odds ratio, 1.42) between arginine homozygosity and invasive disease. However, with the use of the combined method for accurate allelotyping, this trend disappeared (odds ratio, 1.00), the discordance was clearly resolvable as being due to methodologic variables.With the use of two separate methods for codon 72 allelotyping and accounting for a number of the issues raised in previously published reports, there is no increased risk for invasive cervical cancer associated with arginine homozygosity at codon 72 of p53.KEY WORDS: Cervix, Neoplasia, p53, Papillomavirus, Polymorphism.Mod Pathol 2000;13(4):373-378Human papillomaviruses (HPVs) are epitheliotropic double-stranded DNA viruses that have been implicated in cervical carcinogenesis. More than 100 HPV genotypes have been identified. Traditionally, HPV genotypes, which are frequently identified in cervical neoplasms, have been segregated into those with a low risk and those with a high risk for malignant transformation. HPV types 6 and 11 are the prototypes of low-risk viruses that are most frequently found in low-grade squamous intraepithelial lesions (LSIL) and condylomata. HPV 16, 18, 31, and 45 account for approximately 80% of invasive cervical carcinomas, and the HPV 16 -related group is overrepresented in high-grade squamous intraepithelial lesions (HSIL) and squamous cancers compared with the HPV 18 -related viruses. The expression of HPV mRNA and proteins provides a coherent model for cervical carcinogenesis (1-3). Within the HPV genomes, the E6 and E7 genes are the driving forces behind epithelial proliferation and transformation. These transcribed genes are conserved and expressed within all HPV-infected pathologies. In many high-risk cervical dysplasias and invasive carcinomas, the E6 and E7 proteins are restrictively transcribed from the HPV genome integrated into the host DNA (4 -6). The link between oncogenesis and the transforming properties of HPV infection was identified by the interaction between these proteins and host cellular tumor suppressor gene products. Specifically, E7...

Prevalence of codon 72 P53 polymorphism in Brazilian women with cervix cancer

“…In Central America, results are available from Mexico, showing a 45% frequency of p53arg (Suarez-Rincon et al, 2002). Against this background, the 67% prevalence of the arg/arg polymorphism in Brazilian women seems to be high, but it is still consistent with the American data reported (Madeleine et al, 2000;Malcolm et al, 2000;Klug et al, 2001;Suarez-Rincon et al, 2002).…”

“…Similar reports are available on cervical cancer patients from America, suggesting that in South and North America the frequency of p53arg is higher than in Central America. The results of a study carried out in Peruvian women revealed a 50.4% frequency of p53arg (Klug et al, 2001), and in two series of American women, the figures were 55.9% (Madeleine et al, 2000) and 67% (Malcolm et al, 2000), respectively. In Central America, results are available from Mexico, showing a 45% frequency of p53arg (Suarez-Rincon et al, 2002).…”

Associação entre o polimorfismo no códon 72 da p53 e as lesões pré-malignas e malignas cervicais

“…A histologia é o exame adotado pela maioria dos trabalhos para identificar os casos estudados 2,3,7,15,19 . A formação do grupo controle difere porém de estudo para estudo, mas geralmente considera aquelas pacientes saudáveis com citologia cervical negativa ou sem história de câncer cervical, não se fazendo alusão à colposcopia 4,[20][21][22] .…”

Polimorfismo do códon 72 do gene <i>p</i>53 e risco de infecções persistentes por papiloma vírus humano (HPV) e neoplasia do colo uterino

“…Isso porque não só o trabalho de STOREY e colaboradores (1998) mas muitos outros (AGORASTOS et al, 2000;BAEK et al, 2000;BASTIENS et al, 2001;BERTORELLE et al, 1999;DYBIKOWSKA et al, 2000;GIANNOUDIS et al 1999;KIM et al, 2001;LANHAM et al, 1998;MADELEINE et al, 2000;MALCOLM et al, 2000;MINAGUCHI et al, 1998;NGAN et al, 1999;NGAN et al, 2000;NISHIKA W A et al, 2000;PEGO RARO, et al, 2000;PEGORARO, et al, 2002;ROSENTHAL et al, 1998;SARANATH et al, 2002;SKARKA, et al, 1999;SKARKA, et al, 2000;TACHEZY et al, 1999;TENTI et al, 2000;VAN DUIN et al, 2000;YAMASHITA et al, 1999) É interessante ressaltar que os dados observados por todos os trabalhos que apresentaram associação positiva foram obtidos através de PCR alelo-específica (AGORASTOS et al, 2000;DOKIANAKIS et al, 2000;MAKNI et al, 2000;86 PEGORARO et al, 2002;SARANATH et al, 2002;STOREY et al, 1998;VAN DUIN et al, 2000) ou SSCP (Single Strand Conformational Polymorphism) (ANDERSSON et al, 2002;ZEHBE et al, 1999;ZEHBE et al, 2001). Interessantemente, a eficiência de detecção de SSCP vem sendo contestada por trabalhos que compararam os resultados obtidos por esta metodologia com àqueles obtidos por DHPLC (CARGILL et al, 1999e O'DONOVAN et al, 1998.…”

“…Tem sido relatado que a apoptose dependente de p53, em resposta ao dano no DNA, é independente de síntese de novos RNA ou proteínas (CAELLES et al, 1994 Esses resultados, entretanto, são alvos de grande controvérsia. Um grande número de estudos subseqüente não encontrou a mesma associação (BAEK et al, 2000;BASTIENS et al, 2001;BERTORELLE et al, 1999;CALHOUN et al, 2002;DYBIKOWSKA et al, 2000;GIANNOUDIS et al 1999;GUSTAFSSON et al, 2001;HAYES et al , 1998;HELLAND et al, 1998;HILDESHEIM et al, 1998;JOSEFSSON et al, 1998;KIM et al, 2001;KLAES et al, 1999;KUCERA, et al, 2000;LANHAM et al, 1998;MADELEINE et al, 2000;MALCOLM et al, 2000;MINAGUCHI et al, 1998;NGAN et al, 1999;NGAN et al, 2000;NISHIKA WA et al , 2000;PEGORARO, et al, 2000;REZZA et al, 2001 ;ROSENTHAL et al, 1998;SKARKA, et al, 1999;SONODA et al, 1999;SUAREZ-RINCON et al, 2002;TACHEZY et al, 1999 A amplificação alelo-específica também foi utilizada para identificação deste polimorfismo.…”