Merkel Cell Carcinoma and Merkel Cell Polyomavirus: Evidence for Hit-and-Run Oncogenesis

Houben, Roland; Grimm, Johannes; Willmes, Christoph; Weinkam, Rita; Becker, Jürgen C.; Schrama, David

doi:10.1038/jid.2011.260

Cited by 56 publications

(54 citation statements)

References 14 publications

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“…An alternative explanation for RB1 mutation in Merkel cell carcinoma might include the proposed model of hit-and-run oncogenesis in which Merkel cell polyomavirus integrates in to the host genome of all Merkel cell carcinoma cases, does genetic damage, either persists as clonally integrated virus or is expelled from the human genome by various repair mechanisms. 51 Integrating our data with this model, Merkel cell polyomavirus may initiate Merkel cell carcinoma tumorogenesis in a subset of cases, including a genetic 'hit' to RB1 such as nonsense truncating mutations. After this 'hit' occurs, Merkel cell polyomavirus is no longer necessary for Merkel cell carcinoma progression and maintenance and the virus leaves ('runs' from) the human host genome.…”

Section: Modern Pathology (2014) 27 1073-1087mentioning

confidence: 70%

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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Section: Modern Pathology (2014) 27 1073-1087mentioning

confidence: 70%

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

et al. 2014

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“…In our analysis we could detect virus-T integration in 36% of the virus positive patients (total 83%) and the highest number of these integrations was detected in stage III/IV patients with progressive disease. The fact that only a portion, but not all of the positive patients display integrated virus, may be supported by the proposed hit-and-run oncogenesis model [10]. According to this hypothetical working model, the virus may be present for the initial transformation, but once into the cells, and after inducing genetic damages, it is either integrated in the genome or is released from cells.…”

Section: Discussionmentioning

confidence: 97%

“…Although MCPyV was found ubiquitously throughout the population, we and others have shown that viral DNA was integrated in the genome of MCC but not in other skin tumours [7][8][9]. However, a correlation between MCPyV positivity of MCC and survival rate of affected patients is still controversially discussed [10][11][12][13].…”

Section: Introductionmentioning

confidence: 88%

Correlation of Merkel cell polyomavirus positivity with PDGFRα mutations and survivin expression in Merkel cell carcinoma

Batinica

Akgül

Silling

et al. 2015

Journal of Dermatological Science

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“…Although, Houben et al (2011) presented results that the MCC MCV-positive lineage Loke did not subside even with the silencing of viral T antigens. Thus, it was suggested that MCV operates only in the early carcinogenic process in some MCC cases, and that the loss of MCV after this step may take the cancer to a more aggressive behavior [76,96].…”

Section: Possible Carcinogenic Mechanisms Of MCVmentioning

confidence: 99%

Involvement of Merkel Cell Polyomavirus in the Etiology and Pathogenesis of Merkel Cell Carcinoma: A Systematic Review

Morais¹

2014

CRJ

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Abstract:Merkel Cell Polyomavirus (MCV) is a virus belonging to the human Polyomavirus family. After its discovery and detection in approximately 80% of Merkel Cell Carcinoma (MCC) tumors, it has been associated with this rare and aggressive skin cancer that primarily affects elderly and immunosuppressed people. In this study, a systematic review was developed to gather and evidence information about the involvement of MCV infection in the development of MCC. An analysis was performed in the PubMed database in order to find articles to answer the purpose of this present study. Ninety-seven articles met the criteria, forty-six of them investigated the prevalence of MCV in MCC clinical samples, and all showed that the MCV-MCC association exists, with the viral presence ranging from 18 to 100% in MCC tumors. In addition, results pointing to the MCV potential carcinogenic, infection, transmission and replication mechanisms, or even possible disease markers or therapeutic evaluations were found. Current literature has demonstrated frequent involvement of MCV in MCC, with survey of some disease indicative laboratory markers and possible therapeutic evaluations.

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Merkel Cell Carcinoma and Merkel Cell Polyomavirus: Evidence for Hit-and-Run Oncogenesis

Abstract: IKK-gamma protein is a target of BAG3 regulatory activity in human tumor growth.

Cited by 56 publications

References 14 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

Correlation of Merkel cell polyomavirus positivity with PDGFRα mutations and survivin expression in Merkel cell carcinoma

Involvement of Merkel Cell Polyomavirus in the Etiology and Pathogenesis of Merkel Cell Carcinoma: A Systematic Review

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