Frequent allelic loss at 10q23 but low incidence ofPTEN mutations in merkel cell carcinoma

Gele, Mireille Van; Leonard, J. Helen; Roy, Nadine Van; Cook, Anthony; Paepe, Anne De; Speleman, Franki

doi:10.1002/ijc.1209

Cited by 57 publications

(46 citation statements)

References 34 publications

(32 reference statements)

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“…Recurrent chromosomal imbalances detected using CGH analysis were loss of 3p, 4p15-pter, 10q, 13q and 17p and gains of 1q, 3q, 5p, 6, 8q, 18 and 20 [12,24,33,34]. In the present study, we detected some of the previously found regions and also numerous novel regions with chromosomal imbalances.…”

Section: Introductionsupporting

confidence: 68%

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A second field metachronous Merkel cell carcinoma of the lip and the palatine tonsil confirmed by microarray-based comparative genomic hybridisation

Nagy¹,

Feher²,

Sonkodi³

et al. 2005

Virchows Arch

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Merkel cell carcinoma was diagnosed in a 79-year-old Caucasian woman. The tumour was localised to the upper lip and was in stage T2. After successful cryosurgery and a 7-year tumour-free period, a new tumour developed in her palatine tonsil. Histologically and immunohistochemically, this resembled the tumour in the lip. The regional lymph nodes were devoid of metastasis. The paraffin-embedded material of the two tumours and the unaffected lymphatic tissue were analysed with DNA microarrays for comparative genomic hybridisation to assess the genetic relationship of the tumours. In both tumours, regions on 2p and 10p were commonly over-represented, while 41 regions on chromosomes 1-4, 6, 8-9, 11 and 14-22 were commonly under-represented. Chromosomes 1, 3, 4, 16-18 and X were most frequently involved in the DNA losses. In gene copy numbers in the two tumours, 31 chromosome locations were found to be differently affected. The partly similar and partly different molecular patterns indicated a genetic relationship between the tumours and excluded the possibility that the tonsillar tumour was a metastasis. The findings suggest that a genetically altered field was the reason for the development of the tonsillar cancer; thus, it can be regarded pathogenetically as a second field tumour.

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Section: Introductionsupporting

confidence: 68%

“…partial loss of the chromosome 10 long arm in one-third of the MCC cases they analysed with a possible loss of heterozygosity of 10q23, including the PTEN tumoursuppressor gene [33]. In our case, deletion of this region was not observed in either tumour sample.…”

Section: Discussioncontrasting

confidence: 39%

A second field metachronous Merkel cell carcinoma of the lip and the palatine tonsil confirmed by microarray-based comparative genomic hybridisation

Nagy¹,

Feher²,

Sonkodi³

et al. 2005

Virchows Arch

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“…These genes include PIK3-CA, TP53, and PTEN. [40][41][42][43] In our study cases, PIK3CA and TP53, but not PTEN, were found to harbor mutations, but only in small number of cases (Table 5). Using the gene level recurrence as a metric, we identified the retinoblastoma pathway as critical to Merkel cell carcinoma pathogenesis.…”

Section: Discussionmentioning

confidence: 49%

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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“…28 Thus, we can hypothesize that PTEN gene inactivation is caused by other transcriptional or posttranscriptional mechanisms, such as the promoter methylation seen in non-small cell carcinoma of the lung. 29 All our cases of Merkel cell carcinoma showed high rates of nuclear survivin expression, independently of their benign or aggressive evolution. Survivin is overexpressed in many cancers, usually translocated to the nucleus, and associated with metastatic spread, resistance to chemotherapy and bad prognosis.…”

Section: Discussionmentioning

confidence: 59%

Expression profiles associated with aggressive behavior in Merkel cell carcinoma

et al. 2007

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Primary neuroendocrine carcinoma of the skin, or Merkel cell carcinoma, is the most aggressive cutaneous neoplasm. In spite of its similarities to small cell carcinomas from other locations, Merkel cell carcinoma shows many peculiarities probably related to its epidermal origin and the etiologic role of UV radiation. We have immunohistochemically investigated 43 markers on a tissue microarray in which 31 surgically resected Merkel cell carcinomas were represented. Of these, 15 patients remained free of disease after removal, whereas 16 developed metastases. Immunoreactivity was scored according to staining intensity and the percentage of positive cells. We found statistically significant correlations between metastatic tumor spread and overexpression of matrix metalloproteinase (MMP) 7, MMP10/2, tissue inhibitor of metalloproteinase 3, vascular endothelial growth factor (VEGF), P38, stromal NF-kappaB, and synaptophysin. Also detected were statistically significant correlations between the expression levels of MMP7 and VEGF, MMP7 and P21, MMP7 and P38, MMP10/2 and VEGF, P38 and synaptophysin, P38 and P53, and P21 and stromal NF-kappaB. These findings may be helpful in predicting the clinical course of Merkel cell carcinoma and are potentially useful for the development of targeted therapies.

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Frequent allelic loss at 10q23 but low incidence ofPTEN mutations in merkel cell carcinoma

Cited by 57 publications

References 34 publications

A second field metachronous Merkel cell carcinoma of the lip and the palatine tonsil confirmed by microarray-based comparative genomic hybridisation

A second field metachronous Merkel cell carcinoma of the lip and the palatine tonsil confirmed by microarray-based comparative genomic hybridisation

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

Expression profiles associated with aggressive behavior in Merkel cell carcinoma

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