A clinical, pathologic, and molecular study of p53 and murine double minute 2 in penile carcinogenesis and its relation to prognosis

Ignácio, Julianna Alves; Jordan, J.; Carraro, Dirce Maria; Lisboa, Bianca; Lopes, Ademar; Carvalho, Kátia Cândido; Cunha, Isabela Werneck da; Cubilla, Antonio L.; Guimarães, Gustavo Cardoso; Vassallo, José; Soares, Fernando Augusto

doi:10.1016/j.humpath.2011.06.013

Cited by 20 publications

(9 citation statements)

References 22 publications

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“…dynamic sentinel node biopsy or ultrasound-guided fine needle aspiration) suffer from false-negative rates, and none of the recently reported prognostic biomarkers has been implemented on a regular basis in clinical practice yet [10,17,18,19,20,21,22,23]. …”

Section: Discussionmentioning

confidence: 99%

Inherent Grading Characteristics of Individual Pathologists Contribute to Clinically and Prognostically Relevant Interobserver Discordance Concerning Broders' Grading of Penile Squamous Cell Carcinomas

Gunia¹,

Burger

Hakenberg

et al. 2012

Urol Int

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Introduction: We assessed the reproducibility and prognostic impact of the Broders' grading system (BGS) in a cohort of 147 patients with surgically treated penile squamous cell carcinomas. Materials and Methods: Conventionally stained histology slides were graded according to the BGS in two rounds by two study pathologists. Reproducibility was assessed using ĸ statistics. Multivariable analyses were calculated to predict cancer-specific survival (CSS). The ‘mean grade' per pathologist per round was calculated by allocating grade points to each study case (G1-G4: 1-4 points) and dividing the sum of all grade points by the number of cases examined. Results: The BGS showed substantial interobserver variation (59-87% with ĸ = 0.38-0.69) but almost perfect intraobserver reproducibility (91% with ĸ = 0.86 and 96% with ĸ = 0.94, respectively). The ‘mean grade' per pathologist remained nearly constant in both rounds of examination (differences ≤0.05 grade points) but differed between the two pathologists (up to 0.4 grade points). In multivariable analyses, the prognostic impact of the BGS in terms of CSS was strongly pathologist-dependent. Conclusions: Clinically and prognostically relevant interobserver discordance concerning the BGS seems, at least in part, to be attributable to inherent ‘aggressive' versus ‘reserved' grading characteristics of individual pathologists.

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Section: Discussionmentioning

confidence: 99%

Inherent Grading Characteristics of Individual Pathologists Contribute to Clinically and Prognostically Relevant Interobserver Discordance Concerning Broders' Grading of Penile Squamous Cell Carcinomas

Gunia¹,

Burger

Hakenberg

et al. 2012

Urol Int

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“…The overall five-year survival in patients with lymph node metastasis is 27% [10]. Novel molecular markers in association with lymph node metastasis [11], disease free survival or overall survival [12–14], recurrence and perineural invasion [15] have been described in PeCa. However, to date, none of them are used in the clinical practice to predict lymph node metastasis and prognosis.…”

Section: Introductionmentioning

confidence: 99%

Integrative miRNA and mRNA analysis in penile carcinomas reveals markers and pathways with potential clinical impact

et al. 2017

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Penile carcinoma (PeCa) is an important public health issue in poor and developing countries, and has only recently been explored in terms of genetic and epigenetic studies. Integrative data analysis is a powerful method for the identification of molecular drivers involved in cancer development and progression. miRNA and mRNA expression profiles followed by integrative analysis were investigated in 23 PeCa and 12 non-neoplastic penile tissues (NPT). Expression levels of eight miRNAs and 10 mRNAs were evaluated in the same set of samples used for microarray and in a validation set of cases (PeCa = 36; NPT = 27). Eighty-one miRNAs and 2,697 mRNAs were identified as differentially expressed in PeCa. Integrative data analysis revealed 255 mRNAs potentially regulated by 68 miRNAs. Using RT-qPCR, eight miRNAs and nine transcripts were confirmed as altered in PeCa. We identified that MMP1, MMP12 and PPARG and hsa-miR-31-5p, hsa-miR-224-5p, and hsa-miR-223-3p were able to distinguish tumors from NPT with high sensitivity and specificity. Higher MMP1 expression was detected as a better predictor of lymph node metastasis than the clinical-pathological data. In addition, PPARG and EGFR were highlighted as potential pathways for targeted therapy in PeCa. The analysis based on HPV positivity (7 of 23 cases) revealed five miRNA and 13 mRNA differentially expressed. Although in a limited number of cases, HPV positive PeCa presented less aggressive phenotype in comparison with negative cases. Overall, an integrative analysis using mRNA and miRNA profiles revealed markers related with tumor development and progression. Furthermore, MMP1 expression level was a predictive marker for lymph node metastasis in patients with PeCa.

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“…However, inconsistent data can be found on the frequency of p53 mutations. Previous studies reported only a lower frequency (17% - 25%) of p53 mutations, whereas recent genomic profiling studies reported p53 alterations in up to 76% of the cases analyzed 6 , 7 , 35 - 37 . These discrepancies might be explained with the methodological background of the studies (e.g.…”

Section: Discussionmentioning

confidence: 73%

P53 Codon 72 Polymorphism and Risk for Squamous Cell Carcinoma of the Penis: A Caucasian Case-Control Study

et al. 2018

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Squamous cell carcinoma of the penis is a rare but often aggressive disease. A large proportion of penile cancers are associated with HPV infection, mainly with HPV high-risk subtypes 16 and 18. From other HPV-related malignancies a link between a functional SNP in the p53 gene (rs1042522, p.Arg72Pro) and a higher disease risk in the presence of HPV is documented. The p53 p.Arg72 variant was described as a risk factor for developing a malignancy in combination with the presence of HPV as the p.72Arg variant is more prone to HPV E6 protein-mediated degradation than the p.72Pro variant. For penile carcinoma there are only sparse data available on this topic. We therefore analyzed the distribution of this p53 codon 72 SNP in a cohort of 107 penile cancer patients and a healthy control group (n=194) using Restriction Fragment Length Polymorphism (RFLP) analysis. After DNA isolation a PCR amplicon including the variant nucleotide was generated. Based on the variant nucleotide this amplicon can be cleaved into two parts or remain unaffected by a restriction enzyme. Subsequent electrophoresis allowed the discrimination of SNP alleles in the investigated sample. Comparison of the allelic variants revealed no significant differences in the distribution of this SNP between cases and controls (p=0,622). There was also no difference in SNP distribution between cases with/without HPV infection (p=0,558) or histologic variants (p=0.339). In order to strengthen the impact of our data we performed a combined analysis of all published data on this topic with our results. This ended up in SNP distribution data from 177 cases and 1149 controls. Overall, there were also no significant differences in the allelic distribution of the p53 codon 72 SNP between either cases and controls (p=0,914) or HPV-positive and HPV-negative cases (p=0,486). From this most comprehensive data available to date we conclude that there is no influence of the p53 codon 72 SNP on the risk of development of penile carcinoma in Caucasians even in the presence of HPV.

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A clinical, pathologic, and molecular study of p53 and murine double minute 2 in penile carcinogenesis and its relation to prognosis

Cited by 20 publications

References 22 publications

Inherent Grading Characteristics of Individual Pathologists Contribute to Clinically and Prognostically Relevant Interobserver Discordance Concerning Broders' Grading of Penile Squamous Cell Carcinomas

Inherent Grading Characteristics of Individual Pathologists Contribute to Clinically and Prognostically Relevant Interobserver Discordance Concerning Broders' Grading of Penile Squamous Cell Carcinomas

Integrative miRNA and mRNA analysis in penile carcinomas reveals markers and pathways with potential clinical impact

P53 Codon 72 Polymorphism and Risk for Squamous Cell Carcinoma of the Penis: A Caucasian Case-Control Study

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