Expression of p63 is the sole independent marker of aggressiveness in localised (stage I–II) Merkel cell carcinomas

Asioli, Sofia; Righi, Alberto; Biase, Dario de; Morandi, Luca; Caliendo, Virginia; Picciotto, Franco; Macripò, Giuseppe; Maletta, Francesca; Cantogno, Ludovica Verdun di; Chiusa, Luigi; Eusebi, Vincenzo; Bussolati, Gianni

doi:10.1038/modpathol.2011.100

Cited by 71 publications

(58 citation statements)

References 25 publications

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“…In a smaller United States study (23 cases) by Bhatia et al, 22 median survival was approximately fourfold longer in polyomavirus-positive cases (86 months) than in polyomavirus-negative cases (20 months). In contrast, three subsequent studies by Handschel et al 23 (44 German cases), Schrama et al 24 (146 Australian and German cases), and Asioli et al 25 (70 Italian cases) demonstrated that 5-year overall survival is independent of Merkel cell polyomavirus status. Additionally, it does not appear that polyomavirus status influences recurrence-free survival.…”

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confidence: 89%

Retinoblastoma gene mutations detected by whole exome sequencing of Merkel cell carcinoma

et al. 2014

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Merkel cell carcinoma is a highly aggressive cutaneous neuroendocrine tumor that has been associated with Merkel cell polyomavirus in up to 80% of cases. Merkel cell polyomavirus is believed to influence pathogenesis, at least in part, through expression of the large T antigen, which includes a retinoblastoma protein-binding domain. However, there appears to be significant clinical and morphological overlap between polyomaviruspositive and polyomavirus-negative Merkel cell carcinoma cases. Although much of the recent focus of Merkel cell carcinoma pathogenesis has been on polyomavirus, the pathogenesis of polyomavirus-negative cases is still poorly understood. We hypothesized that there are underlying human somatic mutations that unify Merkel cell carcinoma pathogenesis across polyomavirus status, and to investigate we performed whole exome sequencing on five polyomavirus-positive cases and three polyomavirus-negative cases. We found that there were no significant differences in the overall number of single-nucleotide variations, copy number variations, insertion/deletions, and chromosomal rearrangements when comparing polyomavirus-positive to polyomavirus-negative cases. However, we did find that the retinoblastoma pathway genes harbored a high number of mutations in Merkel cell carcinoma. Furthermore, the retinoblastoma gene (RB1) was found to have nonsense truncating protein mutations in all three polyomavirus-negative cases; no such mutations were found in the polyomavirus-positive cases. In all eight cases, the retinoblastoma pathway dysregulation was confirmed by immunohistochemistry. Although polyomavirus-positive Merkel cell carcinoma is believed to undergo retinoblastoma dysregulation through viral large T antigen expression, our findings demonstrate that somatic mutations in polyomavirus-negative Merkel cell carcinoma lead to retinoblastoma dysregulation through an alternative pathway. This novel finding suggests that the retinoblastoma pathway dysregulation leads to an overlapping Merkel cell carcinoma phenotype and that oncogenesis occurs through either a polyomavirusdependent (viral large T antigen expression) or polyomavirus-independent (host somatic mutation) mechanism. Modern Pathology (2014) 27, 1073-1087; doi:10.1038/modpathol.2013.235; published online 10 January 2014Keywords: Merkel cell carcinoma; retinoblastoma; whole exome sequencing; polyomavirus Merkel cell carcinoma is a rare neuroendocrine tumor of the skin with an aggressive clinical course and an increased prevalence in the elderly and immunosuppressed. 1 The incidence of Merkel cell carcinoma has increased in the last several decades, and the United States has an estimated incidence rate of 0.32 per 100 000 persons per year. 2 Merkel cell carcinoma has a predilection for sun exposed areas, most often occurring in the head and neck region. 3 There is an overall 5-year survival rate of 40%, with stage being a significant prognosticator. 3,4 Merkel cell polyomavirus was discovered in Merkel cell carcinoma and found to be clonally integ...

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confidence: 89%

Retinoblastoma gene mutations detected by whole exome sequencing of Merkel cell carcinoma

et al. 2014

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“…Two studies have indicated that patients with virus-negative MCC experience decreased survival as compared with patients with virus-positive MCC [83,84]. Conversely, several others have reported no significant survival difference between the two groups [85][86][87]. Importantly, genetic analysis indicates that these two subsets are etiologically distinct [88][89][90].…”

Section: Virus-negative Mccs and Uv-induced Neoantigensmentioning

confidence: 99%

Rationale For Immune-Based Therapies in Merkel Polyomavirus-Positive and -Negative Merkel Cell Carcinomas

Vandeven

Nghiem

2016

Immunotherapy

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Merkel cell carcinoma (MCC) is a rare but often deadly skin cancer that is typically caused by the Merkel cell polyomavirus (MCPyV). Polyomavirus T-antigen oncoproteins are persistently expressed in virus-positive MCCs (∼80% of cases), while remarkably high numbers of tumor-associated neoantigens are detected in virusnegative MCCs, suggesting that both MCC subsets may be immunogenic. Here we review mechanisms by which these immunogenic tumors evade multiple levels of host immunity. Additionally, we summarize the exciting potential of diverse immunebased approaches to treat MCC. In particular, agents blocking the PD-1 axis have yielded strikingly high response rates in MCC as compared with other solid tumors, highlighting the potential for immune-mediated treatment of this disease.

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“…Factors recognized as associated with poor prognosis are size of the tumor and presence of metastases according to the AJCC staging (4,47,55,(64)(65)(66)(67)(68), and immunosuppression (65,69,70). Recently, histological and immunochemistry markers have been described as potentially associated with poor outcome like low tumor infiltrating CD8 + T cells (101) and P53 and P63 expression and gen mutations (54, 68, 74) ( Table 2).…”

Section: Mcpyv Status and MCC Prognosismentioning

confidence: 99%

Human Merkel cell polyomavirus: virological background and clinical implications

Coursaget

Samimi

Nicol

et al. 2013

APMIS

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The Merkel cell polyomavirus (MCPyV), identified in humans in 2008, is associated with a relatively rare but aggressive neuroendocrine skin cancer, the Merkel cell carcinoma (MCC). MCC incidence is increasing due to the advancing age of the population, the increase in damaging sun exposure and in the number of immunocompromised individuals. MCPyV must be considered as the etiological agent of MCC and thus is the first example of a human oncogenic polyomavirus. MCPyV infection is common, and seroprevalence studies indicate that widespread exposure begins early in life. The majority of adults have anti-MCPyV antibodies and there is a growing body of evidence that healthy human skin harbors resident or transient MCPyV suggesting that MCPyV infection persists throughout life. However, the mode of transmission, the host cells, and the latency characteristics of this virus remain to be elucidated. In addition, it is still not clear whether MCPyV is associated with diseases or lesions other than Merkel cell carcinoma. The etiologic role of MCPyV in MCC opens up opportunities to improve the understanding of this cancer and to potentially improve its treatment.

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Expression of p63 is the sole independent marker of aggressiveness in localised (stage I–II) Merkel cell carcinomas

Cited by 71 publications

References 25 publications

Retinoblastoma gene mutations detected by whole exome sequencing of Merkel cell carcinoma

Retinoblastoma gene mutations detected by whole exome sequencing of Merkel cell carcinoma

Rationale For Immune-Based Therapies in Merkel Polyomavirus-Positive and -Negative Merkel Cell Carcinomas

Human Merkel cell polyomavirus: virological background and clinical implications

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