The molecular pathogenesis of penile carcinoma—current developments and understanding

Emmanuel, Anthony; Nettleton, Jeremy; Watkin, Nick; Berney, Daniel M.

doi:10.1007/s00428-019-02607-8

Cited by 29 publications

(39 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…CDKN2A is a tumor suppressor that encodes p16 and p14 proteins, which normally bind to cell-cycle regulating proteins CDK4 and CDK6 as well as prevent degradation of a tumor suppressor protein p53. 6 , 14 Alterations of CDKN2A occur in 40% of penile carcinoma cases. 12 Other common genomic alterations in penile carcinomas include CCND1, RAS, EGFR, TP53, and PIK3CA, which occur with variable frequency and may represent possible future therapeutic drug targets.…”

Section: Discussionmentioning

confidence: 99%

“…Molecular pathogenesis of pSCC can be divided into human papilloma virus (HPV)-dependent and HPV-independent pathways. 6 Recent studies have demonstrated increased expression of programmed death ligand-1 (PD-L1) in 48–62% of penile tumors. 7,8 PD-L1-rich tumors arise more frequently within HPV-negative patient cohorts 7,8 and are associated with worse clinical outcomes.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Metastatic penile squamous cell carcinoma with dramatic response to combined checkpoint blockade with ipilimumab and nivolumab

Baweja

Mar

2020

J Oncol Pharm Pract

View full text Add to dashboard Cite

Introduction Prognosis for patients with lymph node positive or metastatic penile squamous cell carcinoma remains poor. Chemotherapy with paclitaxel, ifosfamide, and cisplatin (TIP regimen) is recommended as a first-line option in this cohort of patients. No standard preferred subsequent-line therapy exists for patients with relapsed or refractory penile carcinoma following TIP chemotherapy. Molecular pathogenesis of penile cancer can be subdivided into human papilloma virus-dependent and human papilloma virus-independent pathways. Recent studies have demonstrated increased expression of programmed death ligand-1 in some penile tumors, commonly those that are human papilloma virus-negative. Given the rarity of penile carcinoma in industrialized countries and lack of effective therapies, checkpoint inhibitors may be an attractive treatment option for this subset of patients. Case report We report a case of metastatic penile cancer refractory to TIP chemotherapy, with a dramatic treatment response to ipilimumab and nivolumab. Molecular profiling of this tumor showed a high programmed death ligand-1 expression, high tumor mutational burden, high microsatellite instability, and alterations in DNA mismatch repair genes. Discussion This case highlights another dimension of information that may be gained with molecular genomic profiling of penile tumors, providing insight into the biologic behavior of this neoplasm and assessing for predictive biomarkers of response to immune checkpoint inhibitors.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Metastatic penile squamous cell carcinoma with dramatic response to combined checkpoint blockade with ipilimumab and nivolumab

Baweja

Mar

2020

J Oncol Pharm Pract

View full text Add to dashboard Cite

show abstract

“…High-risk HPV particles infect the basal cells of the epithelial mucosa, via micro-abrasions and specific receptors. The integration of HPV DNA into the host cell genome leads to the overexpression of viral oncoproteins (such as E6 and E7) [11].…”

Section: Hpv-dependent Penile Carcinogenesismentioning

confidence: 99%

“…This results in the activation of DNA synthesis genes and the cell cycle becomes uncontrolled. Due to the disturbance of the negative feedback via pRB, an overexpression of P16 INK4A can be observed [11]. Hence, p16 INK4A may be used as a surrogate marker for the detection of active high-risk HPV infection in penile cancer [11,12].…”

Section: Hpv-dependent Penile Carcinogenesismentioning

confidence: 99%

“…Due to the disturbance of the negative feedback via pRB, an overexpression of P16 INK4A can be observed [11]. Hence, p16 INK4A may be used as a surrogate marker for the detection of active high-risk HPV infection in penile cancer [11,12]. Oncoprotein E6 inactivates the tumor suppressor protein p53, leading to a disruption of DNA repair, growth arrest and apoptosis.…”

Section: Hpv-dependent Penile Carcinogenesismentioning

confidence: 99%

See 1 more Smart Citation

Penile cancer: potential target for immunotherapy?

2020

View full text Add to dashboard Cite

Purpose Penile cancer (PeCa) is a rare malignancy with a poor prognosis in advanced disease. There is still a limited understanding of the biological mediators that are important in the prognosis and therapy of the disease. This review aims to provide a summary of the immune micro-environment, molecular oncogenesis and the role of HPV in the disease applying to the potential of the use of immunotherapy. Methods Narrative, non-systematic review based on publications retrieved by PubMed and EMBASE search. Results The molecular mechanisms underlying penile carcinogenesis are complex, and human papillomavirus (HPV) infection is a well-characterized driver of penile cancer. Up to 50% of the penile carcinomas are HPV related. There is potential to improve prevention, treatment and follow-up strategies pertaining to the role of HPV in penile cancer. Immune response modifiers such as toll-like receptor agonists are being used in a topical fashion for penile intraepithelial neoplasia while immune checkpoint inhibitors are currently under clinical investigation for its application in penile cancer. Conclusions The knowledge of prognosis-relevant biological pathways in penile cancer is expanding. HPV plays an important role in the carcinogenesis. This can lead to the identification of therapeutic targets which could significantly influence the prognosis of advanced penile cancer. Clinical trials are being conducted to pave the way for immune-modifying treatment modalities.

show abstract