Association of Merkel cell polyomavirus infection with clinicopathological differences in Merkel cell carcinoma

Higaki-Mori, Hiromi; Kuwamoto, Satoshi; Iwasaki, Takeshi; Kato, Masako; Murakami, Ichiro; Nagata, Kazuhiro; Sano, Hitoshi; Horie, Yasushi; Yoshida, Yuichi; Yamamoto, Osamu; Adachi, Kaori; Nanba, Eiji; Hayashi, Kazuhiko

doi:10.1016/j.humpath.2012.04.002

Cited by 107 publications

(90 citation statements)

References 21 publications

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“…In our previous study, we showed that the frequency of TP53 nonultraviolet signature mutation was significantly higher in MCPyV-negative MCCs than in MCPyV-positive MCCs [3]. Recent studies have shown that the p53 pathway monitors the insulin-like growth factor-I/Akt and mTOR pathways.…”

Section: Discussionmentioning

confidence: 95%

“…Approximately 80% of MCCs harbor a novel polyomavirus named Merkel cell polyomavirus (MCPyV), which is believed to be a carcinogenic agent [1]. We recently demonstrated that MCPyVpositive MCC from a case with spontaneous regression differed in morphology and showed a better prognosis and significantly higher expression of the retinoblastoma protein and lower expression of p53 than MCPyV-negative MCCs [1][2][3]. The tumorigenic pathway of MCPyV-negative MCCs is hypothesized to be different from that of MCPyV-positive MCCs, but the differences have not been clearly elucidated.…”

Section: Introductionmentioning

confidence: 99%

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Comparison of Akt/mTOR/4E-BP1 pathway signal activation and mutations of PIK3CA in Merkel cell polyomavirus–positive and Merkel cell polyomavirus–negative carcinomas

et al. 2015

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Comparison of Akt/mTOR/4E-BP1 pathway signal activation and mutations of PIK3CA in Merkel cell polyomavirus–positive and Merkel cell polyomavirus–negative carcinomas

et al. 2015

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“…Furthermore, MCPyV-negative and MCPyV-positive MCCs were found to have distinct tumour cell morphology [46]. MCPyV-negative and MCPyV-positive MCCs seem to display different tumourigenic pathways [45,46,47]. As formerly hypothesized for retinoblastoma expression [43], the overexpression of SSTR2A in MCPyV-positive MCC tumours may be related either to its activation by MCPyV T antigens, or to a loss of SSTR2A expression in MCPyV-negative tumours.…”

Section: Discussionmentioning

confidence: 99%

Somatostatin Receptors 2A and 5 Are Expressed in Merkel Cell Carcinoma with No Association with Disease Severity

Gardair¹,

Samimi

Touzé

et al. 2015

Neuroendocrinology

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Background/Aims: Merkel cell carcinoma (MCC) is a rare high-grade neuroendocrine tumour of the skin. It has been speculated that MCCs express somatostatin receptors (SSTRs), but this has never been assessed in a large series of MCCs. The main aim of this study was to assess the expression of SSTR2A and SSTR5 in MCC tumours. The secondary aims were to assess whether expression of SSTR was associated with the Ki67 proliferative index, Merkel cell polyomavirus (MCPyV) status, clinical characteristics and outcome. Methods: Clinical data and tumours were collected from an ongoing cohort of French patients with MCC. Immunohistochemistry was performed with anti-SSTR2A and anti-SSTR5 monoclonal antibodies, and tumours were classified into 3 groups: ‘no expression', ‘low expression' and ‘moderate expression' using an SSTR staining score. Results: SSTR expression was assessed for 105 MCC tissue samples from 98 patients, and clinical characteristics were available for 87 of them. SSTR expression was consistent between the primary skin tumour and the corresponding metastases for SSTR2A and SSTR5 in 3/7 and 6/7 cases, respectively. SSTR2A and SSTR5 were expressed in 58 cases (59.2%) and in 44 cases (44.9%), respectively. Overall, at least one SSTR was expressed in 75 tumours (76.5%). SSTR expression was not associated with clinical characteristics, Ki67 proliferative index, recurrence-free survival or MCC-specific survival. Expression of SSTR2A was associated with MCPyV status in MCC tumours but not SSTR5. Conclusion: SSTRs were expressed in a high proportion of MCCs, although expression was heterogeneous between tumours and was not associated with disease severity.

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“…Although a small number of cases, this is consistent with some of the controversial literature reporting a more aggressive clinical course related to polyomavirusnegative cases. 7,22,38 Whole human exome sequencing was performed on each of the eight Merkel cell carcinoma cases using formalin-fixed paraffin-embedded tissue. The average number of reads generated per case was 130 477 404 (26 GBases).…”

Section: Demographics and Sequence Metricsmentioning

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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Association of Merkel cell polyomavirus infection with clinicopathological differences in Merkel cell carcinoma

Cited by 107 publications

References 21 publications

Comparison of Akt/mTOR/4E-BP1 pathway signal activation and mutations of PIK3CA in Merkel cell polyomavirus–positive and Merkel cell polyomavirus–negative carcinomas

Comparison of Akt/mTOR/4E-BP1 pathway signal activation and mutations of PIK3CA in Merkel cell polyomavirus–positive and Merkel cell polyomavirus–negative carcinomas

Somatostatin Receptors 2A and 5 Are Expressed in Merkel Cell Carcinoma with No Association with Disease Severity

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

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