p63 Expression in Merkel Cell Carcinoma Predicts Poorer Survival yet May Have Limited Clinical Utility

Stetsenko, Galina Y.; Malekirad, Jacqueline; Paulson, Kelly G.; Iyer, Jayasri G.; Thibodeau, Renee; Nagase, Kotaro; Schmidt, Maxine; Storer, Barry E.; Argényi, Zsolt B.; Nghiem, Paul

doi:10.1309/ajcpe4pk6ctbnqjy

Cited by 46 publications

(41 citation statements)

References 18 publications

(36 reference statements)

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“…Positivity for the oncoprotein huntingtin-interacting protein 1 (HIP1) has been observed in the majority of cases 93 . Staining for tumour protein 63 (p63) has been observed in one-third of cases and has been linked to a worse prognosis 94,95 , but available data suggest that it cannot prognosticate patients independent of stage.…”

Section: Diagnosis Screening and Preventionmentioning

confidence: 99%

Merkel cell carcinoma

Becker

Stang

DeCaprio

et al. 2017

Nat Rev Dis Primers

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438

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Merkel cell carcinoma (MCC) is a rare but highly aggressive skin cancer with neuroendocrine features. MCC pathogenesis is associated with either the presence of Merkel cell polyomavirus or chronic exposure to ultraviolet light (UV), which can cause a characteristic pattern of multiple DNA mutations. Notably, in the Northern hemisphere, the majority of MCC cases are of viral aetiology; by contrast, in areas with high UV exposure, UV-mediated carcinogenesis is predominant. The two aetiologies share similar clinical, histopathological and prognostic characteristics. MCC presents with a solitary cutaneous or subcutaneous nodule, most frequently in sun-exposed areas. In fact, UV exposure is probably involved in both viral-mediated and non-viral-mediated carcinogenesis, by contributing to immunosuppression or DNA damage, respectively. Confirmation of diagnosis relies on analyses of histological features and immunological marker expression profiles of the lesion. At primary diagnosis, loco-regional metastases are already present in ~30% of patients. Excision of the tumour is the first-line therapy; if not feasible, radiotherapy can often effectively control the disease. Chemotherapy was the only alternative in advanced-stage or refractory MCC until several clinical trials demonstrated the efficacy of immune-checkpoint inhibitors.

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Section: Diagnosis Screening and Preventionmentioning

confidence: 99%

Merkel cell carcinoma

Becker

Stang

DeCaprio

et al. 2017

Nat Rev Dis Primers

Self Cite

438

565

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“…44 Several studies have suggested that p63 expression is an indicator of poor prognosis in MCC. 45–47 In a univariate analysis of localized MCCs, Asioli et al 45 reported a 20% 5-year survival rate for 21 patients with MCC with p63-positive tumors compared with 100% for 19 patients with p63-negative MCC (hazard ratio [HR], 7.26; P <.001). In an independent and larger cohort, Stetsenko et al 47 also found that p63 expression was significantly correlated with decreased survival, but the magnitude of the association was smaller (HR, 2.05; P =.02).…”

Section: Prognosismentioning

confidence: 99%

“…In multivariate subgroup analysis, p63 expression did not significantly predict mortality within a given stage. 47 Currently, the additional prognostic value p63 expression adds to MCC staging or clinical management is unclear.…”

Section: Prognosismentioning

confidence: 99%

Milestones in the Staging, Classification, and Biology of Merkel Cell Carcinoma

Moshiri¹,

Nghiem²

2014

J Natl Compr Canc Netw

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Merkel cell carcinoma (MCC) is an aggressive skin cancer that is causally associated with ultraviolet light exposure and a recently discovered polyomavirus. Before 2010, MCC was staged using any of 5 unique systems in active use. In 2010, a consensus staging system for MCC was adopted worldwide and replaced these systems. This consensus system includes substages that reflect prognostic differences based on whether nodal evaluation was performed by pathologic analysis or clinical assessment alone. MCC-specific disease classification in ICD-9, to be expanded in the upcoming ICD-10, has improved the ability to track and manage this malignancy. Several biomarkers and histopathologic features have been identified that improve understanding of this cancer and may lead to future refinement of the current staging system. In 2008, the Merkel cell polyomavirus was discovered and is now thought to be a critical mechanism of transformation in at least 80% of MCCs. In patients who produce antibodies to the viral T-antigen oncoprotein, the titer increases and decreases with MCC disease burden and can be a clinically useful marker of recurrence. Diverse studies link CD8-positive T-cell function with outcomes in MCC and serve as the rational basis for ongoing trials of therapies to augment cellular immunity. This article reviews basic and translational research insights that will lead to improved staging, prognostic accuracy, and mechanism-based therapy for this often-lethal skin cancer.

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“…On the contrary, Lim et al suggested that p63 expression was not significantly correlated with disease outcome, since positive p63 expression could only be observed in 9% of the patients [28]. The role of p63 as a prognostic factor has been studied in MCC using a multivariate model, which predicted that the p63 expression in MCC tumor cells was closely related to worse disease-specific survival and increased the mortality of MCC by approximately two-fold [29]. In this study, the effect of miR-140 on cell survival, cell apoptosis and cell cycle was investigated using MTT assay and cell cycle analysis, respectively, and it was found that the transfection of miR-140 mimics significantly increased the viability of HGC-27 and BGC-823 cells in a time-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

A functional Variant (Rs35592567) in TP63 at 3q28 is Associated with Gastric Cancer Risk via Modifying its Regulation by MicroRNA-140

Lu¹,

Yang²,

Ma³

2018

Cell Physiol Biochem

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Background/Aims: TP63 was believed to play an important role in the development of many malignancies, while the polymorphisms located at the miRNA binding sites within the 3’UTR of TP63 mRNA may interfere with its expression. In this study, we aimed to study the role of TP63 regulation in the tumorigenesis of gastric cancer (GC). Methods: Computational and luciferase analysis were used to search and confirm the target of miR-140. Real-time PCR, western-blot, MTT assay, and flow cytometry cell cycle analysis were utilized to explore the molecular pathway of miR-140 involved in the progression of GC. Results: TP63 was identified as a direct target gene of miR-140. In HT-29 cells over-expressing miR-140, the luciferase activity was decreased when the cells were transfected with wild-type TP63 3’UTR, but remained unchanged when the cells were transfected with mutant 1 and mutant 2 TP63 3’UTR. In addition, the level of TP63 in HT-29 cells transfected with miR-140 mimic was evidently down-regulated, whereas the level of TP63 in HT-29 cells transfected with miR-140 inhibitor was significantly up-regulated. Furthermore, based on the results from MTT assay and flow cytometry cell cycle analysis, HT-29 cells transfected with miR-140 mimics were associated with significantly higher viability compared to the cells transfected with the control plasmid, suggesting that an increased expression of miR-140 protected HT-29 cells against apoptosis. Finally, when miR-140 expression was high, the number of cells at the G1 phase was notably increased, accompanied by a remarkably diminished number of cells at the S phase. Conclusions: The rs35592567 polymorphism in TP63 affected the expression of TP63 by interfering with its interaction with miR-140, and could serve as an explanation for the increased risk of GC.

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p63 Expression in Merkel Cell Carcinoma Predicts Poorer Survival yet May Have Limited Clinical Utility

Cited by 46 publications

References 18 publications

Merkel cell carcinoma

Merkel cell carcinoma

Milestones in the Staging, Classification, and Biology of Merkel Cell Carcinoma

A functional Variant (Rs35592567) in TP63 at 3q28 is Associated with Gastric Cancer Risk via Modifying its Regulation by MicroRNA-140

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