DNA Copy Number Aberrations, and Human Papillomavirus Status in Penile Carcinoma. Clinico-Pathological Correlations and Potential Driver Genes

La-Touche, Susannah; Lemetre, Christophe; Lambros, Maryou B.; Stankiewicz, Elżbieta; Ng, Charlotte K.Y.; Weigelt, Britta; Rajab, Ramzi; Tinwell, Brendan; Corbishley, Cathy; Watkin, Nick; Berney, Daniel M.; Reis‐Filho, Jorge S.

doi:10.1371/journal.pone.0146740

Cited by 19 publications

(10 citation statements)

References 45 publications

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“…A high number of Hr-HPV positive tumours were identified in our PSCC cohort (17/24; 71%) and this is higher than other recent studies with detection rates varying between 33 to 50% [ 2 , 22 ]. The higher than expected Hr-HPV rate in this studied is likely due to the small fresh frozen tissue sample size.…”

Section: Discussioncontrasting

confidence: 58%

“…In addition, recent work by our group, La-Touche et al . [ 22 ] found copy number gains in 55/64 (86%) cases within the 3p12.3-q29 loci, similar to Busso-Lopes et al . [ 23 ] in penile cancer via array comparative genomic hybridisation (aCGH).…”

Section: Introductionsupporting

confidence: 72%

“…The first clone (RP11-348P10) was for the control 3p21.3 region and was and the second clone (RP11-245C23) for the gene of interest, PIK3CA located at 3q26.3. The distal 3p21.3 locus was chosen as the control, as this locus showed no copy number change on previous aCGH data [ 22 ]. The PIK3CA gene probe was labelled red and the control gene grobe was labelled green.…”

Section: Methodsmentioning

confidence: 99%

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Analysis of the PI3K-AKT-mTOR pathway in penile cancer: evaluation of a therapeutically targetable pathway

et al. 2018

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ObjectivesTo determine whether phosphatidylinositol-4,5-bisphosphate 3- kinase, catalytic subunit alpha (PIK3CA) copy number gain is common and could prove a useful marker for the activation status of the PI3K-AKT-mTOR pathway in penile squamous cell carcinoma (PSCC).MethodsFresh frozen tissue and archival blocks were collected from 24 PSCC patients with 15 matched normal penile epithelium (NPE) tissue from St George’s Hospital. PIK3CA mutational and copy number status (CNS) was assessed via Sanger sequencing and fluorescence in-situ hybridisation, respectively. PIK3CA RNA expression was quantified using TaqMan gene expression assay. HPV DNA was detected with INNO-LiPA assay. p-AKT and p-mTOR protein expression were assessed using western blot and immunohistochemistry.ResultsPIK3CA copy number gain was found in 11/23 (48%) patients, with mutations present in only 2/24 (8%) patients. In comparison to NPE, PSCC showed significantly lower PIK3CA RNA expression (p=0.0007), p-AKT (Ser473) nuclear immunoexpression (p=0.026) and protein expression of p-AKT (Thr308) (p=0.0247) and p-mTOR (Ser2448) (p=0.0041). No association was found between PIK3CA CNS and p-AKT and p-mTOR protein expression.ConclusionBased on our results the PI3K-AKT-mTOR pathway is not a key driver in PSCC carcinogenesis and the therapeutic targeting of this pathway is unlikely to produce significant clinical benefit.

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Section: Discussioncontrasting

confidence: 58%

Section: Introductionsupporting

confidence: 72%

Section: Methodsmentioning

confidence: 99%

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Analysis of the PI3K-AKT-mTOR pathway in penile cancer: evaluation of a therapeutically targetable pathway

et al. 2018

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“…A few numbers of studies have performed PeCa genomic profiling by array comparative genomic hybridization (aCGH), describing copy number alterations (CNAs), and their potential prognostic values in association with HPV infection. 6,7 Comprehensive genomic profiling (CGP) has also been performed suggesting the involvement of potential driver genes, such as the PIK3CA oncogene (affected mostly by point mutations) and EGFR (amplified). 8 Additionally, other tyrosine kinase receptor family ERBB members (EGFR, ERBB3, and ERBB4), which regulate the cell cycle by activating the PI3K/AKT pathway downstream genes, were associated with PeCa by immunohistochemistry (IHC) analysis, 9 and most recently, it was suggested that specific genes of the mTOR, DNA repair, and tyrosine kinase pathways could be used as potential druggable targets for metastatic penile squamous cell carcinomas.…”

mentioning

confidence: 99%

Genomic profiling reveals the pivotal role of hrHPV driving copy number and gene expression alterations, including mRNA downregulation of TP53 and RB1 in penile cancer

Macedo

Silva

Nogueira³

et al. 2020

Molecular Carcinogenesis

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The incidence of penile cancer (PeCa) is increasing worldwide, however, the highest rates are reported in underdeveloped countries. The molecular mechanisms that underly the onset and progression of these tumors are still unclear. Therefore, our goal was to determine the genome-wide copy number alterations and the involvement of human papiloma virus (HPV) (TP53 and RB1), inflammatory (COX2 and EGFR), and PI3K/AKT pathway (AKT1, AKT2, EGFR, ERBB3, ERBB4, PIK3CA, and PTEN) associated genes in patients with PeCa from a high incidence region in Brazil (Maranhão). HPV genotyping was performed by nest-PCR and genome sequencing, copy number alterations (CNAs) by array comparative genomic hybridization and gene copy number status, gene, and protein expression by quantitative polymerase chain reaction, reverse transcriptasequantitative polymerase chain reaction, and immunohistochemistry, respectively.HPV genotyping revealed one of the highest frequencies of HPV reported in PeCa, affecting 96.4% of the cases. The most common CNAs observed were located at the HPV integration sites, such as 2p12-p11.2 and 14q32.33, where Abbreviations: aCGH, array comparative genomic hybridization; CNA, copy number alteration; Cq, quantification cycle; FFPE, formalin-fixed paraffin-embedded; HPV, human papiloma virus;HrHPV, High risk HPV; IHCi, mmunohistochemistry; PCR, polymerase chain reaction; PeCa, penile cancer; qPCR, quantitative polymerase chain reaction; RT-qPCR, reverse transcriptase-quantitative polymerase chain reaction; TMA, tissue microarray. ADAM 6, KIAA0125, LINC00226, LINC00221, and miR7641-2, are mapped. Increased copy number of ERBB3 and EGFR genes were observed in association with COX2 and EGFR overexpression, reinforcing the role of the inflammatory pathway in PeCa, and suggesting anti-EGFR and anti-COX2 inhibitors as promising therapies for PeCa. Additionally, TP53 and RB1 messenger RNA downregulation was observed, suggesting the occurrence of other mechanisms for repression of these oncoproteins, in addition to the canonical HPV/TP53/RB1 signaling pathway. Our data reinforce the role of epigenetic events in abnormal gene expression in HPV-associated carcinomas and suggest the pivotal role of HPV driving CNAs and controlling gene expression in PeCa. K E Y W O R D Scarcinoma of the penis, genomic alterations, human papillomavirus, molecular markers

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“…The first clone (RP11-348P10) was for the control 3p21.3 region and was and the second clone (RP11-245C23) for the gene of interest, PIK3CA located at 3q26.3. The distal 3p21.3 locus was chosen as the control, as this locus showed no copy number change on our previous array comparative genomic hybridisation data utilising the same PSCC cohort [ 12 ]. The PIK3CA gene probe was labelled red and the control gene probe was labelled green.…”

Section: Methodsmentioning

confidence: 99%

PIK3CA copy number aberration and activation of the PI3K-AKT-mTOR pathway in varied disease states of penile cancer

et al. 2018

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BackgroundTherapeutic targeting of the PI3K-AKT-mTOR pathway may benefit patients with advanced penile squamous cell carcinoma (PSCC).ObjectivesTo determine the prevalence of PIK3CA copy number gain and correlate this with the activity status of PI3K-AKT-mTOR pathway in pre-malignant penile intraepithelial neoplasia (PeIN) and invasive PSCC.Materials and methodsArchival tissue blocks were obtained from 58 PeIN and 244 primary PSCC patients treated at St George’s Hospital. PIK3CA copy number status (CNS) was assessed by fluorescence in-situ hybridisation. High-risk HPV DNA was detected with INNO-LiPA assay. p16INK4A, p-AKT and p-mTOR protein expression were assessed using immunohistochemistry (IHC).ResultsIncreased prevalence of PIK3CA copy number gain was seen in PSCC in comparison to PeIN (84/199 (42%) vs. 10/58 (17%); p = 0.0009). Analysis of the p-AKT and p-mTOR revealed a tendency to a more common expression of cytoplasmic p-AKT (p = 0.1318), nuclear p-AKT (p<0.0001) and cytoplasmic mTOR (p = 0.0006) in PeIN than PSCC. A significant association between p-AKT cytoplasmic immunoexpression and PIK3CA CNS (p = 0.0404) was found in PeIN.ConclusionOverall, PIK3CA copy number gain correlated with activation of the PI3K-AKT-mTOR pathway in PeIN and activation of this pathway is primarily involved in early penile carcinogenesis. Based on these results therapeutic targeting of this pathway in advanced PSCC is unlikely to produce significant clinical benefit. Future studies will need to focus on alternative therapeutic targets.

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DNA Copy Number Aberrations, and Human Papillomavirus Status in Penile Carcinoma. Clinico-Pathological Correlations and Potential Driver Genes

Cited by 19 publications

References 45 publications

Analysis of the PI3K-AKT-mTOR pathway in penile cancer: evaluation of a therapeutically targetable pathway

Analysis of the PI3K-AKT-mTOR pathway in penile cancer: evaluation of a therapeutically targetable pathway

Genomic profiling reveals the pivotal role of hrHPV driving copy number and gene expression alterations, including mRNA downregulation of TP53 and RB1 in penile cancer

PIK3CA copy number aberration and activation of the PI3K-AKT-mTOR pathway in varied disease states of penile cancer

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