New Insights Into Merkel Cell Carcinoma

Calder, Kenneth B.; Smoller, Bruce R.

doi:10.1097/pap.0b013e3181d97836

Cited by 69 publications

(61 citation statements)

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“…Moreover, it has been shown that, for example, JC polyomaviruses preferentially infect stem cells or progenitor cells (reviewed in ref. 25). The finding of Ig and kappa and lambda expression in MCCs on the protein level, as has been described in 2 previous independent cDNA microarray studies on the transcriptional level strongly support our model.…”

Section: Discussionsupporting

confidence: 73%

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Early B-Cell Differentiation in Merkel Cell Carcinomas: Clues to Cellular Ancestry

et al. 2013

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Section: Discussionsupporting

confidence: 73%

“…On the basis of MCC mouse models, it has been speculated that the cell of origin of MCC derives from epidermal stem cells or other primitive totipotent stem cells (reviewed in refs. 25,26).…”

Section: Discussionmentioning

confidence: 99%

Early B-Cell Differentiation in Merkel Cell Carcinomas: Clues to Cellular Ancestry

et al. 2013

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“…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.…”

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confidence: 99%

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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“…MCC is extremely unusual before the age of 50 (~5% of the cases) and people at risk include those with fair skin, excessive UV-light exposure and immunosuppressed patients. The median age at presentation is 76 years for women and 74 years for men and there is a slight male predominance [Calder & Smoller, 2010]. The majority of the patients are white (94.9%) and chronically immunosuppressed individuals are 10 to 15 times more likely to develop MCC than age-matched controls.…”

Section: Introductionmentioning

confidence: 99%

“…Whether MCC arises from normal Merkel cells is still controversial [The Rockville MCC group, 2009]. Currently, MCC is thought to originate from a primitive totipotent stem cell with the ability to differentiate along divergent histological phenotypes [Calder & Smoller, 2010]. MCC is a rare but aggressive skin cancer of neuroendocrine origin with propensity for local recurrence and regional lymph node metastasis.…”

Section: Introductionmentioning

confidence: 99%