History of chronic inflammatory disorders increases the risk of Merkel cell carcinoma, but does not correlate with Merkel cell polyomavirus infection

Sahi, Helka; Sihto, Harri; Artama, Miia; Koljonen, Virve; Böhling, Tom; Pukkala, Eero

doi:10.1038/bjc.2016.391

Cited by 31 publications

(22 citation statements)

References 11 publications

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“…In the present report, three solid organ transplant recipients, three with chronic autoimmune diseases, and two with hematologic malignancies developed virus-negative MCC. It is well established that the risk for developing MCC is increased in patients with chronic inflammatory disorders such as rheumatoid arthritis or medically induced immunosuppression for solid organ transplantation [58][59][60][61]. Within the latter population, skin cancers account for 40-50% of all posttransplant malignancies with squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) comprising 90-95% of these skin cancers [62].…”

Section: Discussionmentioning

confidence: 99%

Clinical and molecular characterization of virus-positive and virus-negative Merkel cell carcinoma

et al. 2020

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Background: Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine carcinoma of the skin caused by either the integration of Merkel cell polyomavirus (MCPyV) and expression of viral T antigens or by ultravioletinduced damage to the tumor genome from excessive sunlight exposure. An increasing number of deep sequencing studies of MCC have identified significant differences between the number and types of point mutations, copy number alterations, and structural variants between virus-positive and virus-negative tumors. However, it has been challenging to reliably distinguish between virus positive and UV damaged MCC. Methods: In this study, we assembled a cohort of 71 MCC patients and performed deep sequencing with OncoPanel, a clinically implemented, next-generation sequencing assay targeting over 400 cancer-associated genes. To improve the accuracy and sensitivity for virus detection compared to traditional PCR and IHC methods, we developed a hybrid capture baitset against the entire MCPyV genome and software to detect integration sites and structure. Results: Sequencing from this approach revealed distinct integration junctions in the tumor genome and generated assemblies that strongly support a model of microhomology-initiated hybrid, virus-host, circular DNA intermediate that promotes focal amplification of host and viral DNA. Using the clear delineation between virus-positive and virusnegative tumors from this method, we identified recurrent somatic alterations common across MCC and alterations specific to each class of tumor, associated with differences in overall survival. Finally, comparing the molecular and clinical data from these patients revealed a surprising association of immunosuppression with virus-negative MCC and significantly shortened overall survival. Conclusions: These results demonstrate the value of high-confidence virus detection for identifying molecular mechanisms of UV and viral oncogenesis in MCC. Furthermore, integrating these data with clinical data revealed features that could impact patient outcome and improve our understanding of MCC risk factors.

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Section: Discussionmentioning

confidence: 99%

Clinical and molecular characterization of virus-positive and virus-negative Merkel cell carcinoma

et al. 2020

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“…In the present report, three solid organ transplant recipients, three with chronic autoimmune diseases, and two with hematologic malignancies developed virus-negative MCC. The risk for developing MCC is increased in patients with chronic inflammatory disorders such as rheumatoid arthritis or medically induced immunosuppression for solid organ transplantation (38)(39)(40)(41). Skin cancers account for 40-50% of all posttransplant malignancies with squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) comprising 90-95% of these skin cancers (42).…”

Section: Discussionmentioning

confidence: 99%

Clinical and molecular characterization of virus-positive and virus-negative Merkel cell carcinoma

Starrett¹,

Chen

Marcelus

et al. 2019

Preprint

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Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine carcinoma of the skin mediated by the integration of Merkel cell polyomavirus (MCPyV) and expression of viral T antigens or by ultraviolet induced damage to the tumor genome from excessive sunlight exposure. An increasing number of deep sequencing studies of MCC have identified significant differences between the number and types of point mutations, copy number alterations, and structural variants between virus-positive and virus-negative tumors. In this study, we assembled a cohort of 71 MCC patients and performed deep sequencing with OncoPanel, a next-generation sequencing assay targeting over 400 cancer-associated genes. To improve the accuracy and sensitivity for virus detection compared to traditional PCR and IHC methods, we developed a hybrid capture baitset against the entire MCPyV genome. The viral baitset identified integration junctions in the tumor genome and generated assemblies that strongly support a model of a hybrid, virus-host, circular DNA intermediate during integration that promotes focal amplification of host DNA. Using the clear delineation between virus-positive and virus-negative tumors from this method, we identified recurrent somatic alterations common across MCC and alterations specific to each class of tumor, associated with differences in overall survival. Comparing the molecular and clinical data from these patients revealed a surprising association of immunosuppression with virus-negative MCC and significantly shortened overall survival. These results demonstrate the value of high-confidence virus detection for identifying clinically important features in MCC that impact patient outcome. March 23, 2019 not initiating event in virus-positive MCC oncogenesis. MCPyV infects most people, typically at an early age, and results in an asymptomatic and lifelong infection indicated by the presence of antibodies to the viral coat protein VP1 (3, 4). Although MCPyV DNA can be readily detected on the skin, the cell types where the virus replicates in vivo have not been determined (5).Since the original discovery of MCPyV, it has become increasingly clear that virus-positive MCC has a different etiology than virus-negative MCC (1). While virus-positive MCC expresses the viral oncogenes Large T antigen (LT) and Small T antigen (ST), the tumor genome usually contains very few mutations in cellular oncogenes and tumor suppressor genes. In contrast, studies using whole exome or targeted hybrid capture sequencing have revealed that virusnegative MCC has an exceptionally high somatic mutation load predominated by UV-mediated mutations with frequent mutations in RB1, TP53, NOTCH1, and FAT1 (6,7). Whole genome sequencing (WGS) of MCC confirmed virus-positive MCC exhibits a globally lower, non-UVmediated, mutation burden as well as few somatic copy number amplifications, deletions, and rearrangements compared to virus-negative MCC, while providing new insights into the structure and mechanism of virus integration (8).Accurate detection of ...

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“…Notably, the age of onset of MCC is lower and the mortality is higher in immunosuppressed individuals than in immune-competent patients 28 ; these findings emphasize the crucial role of efficient immune surveillance in the control of tumour growth and progression. Chronic inflammatory disorders such as rheumatoid arthritis are also associated with higher incidence of MCC 29 . An association between MCC and chronic arsenic exposure has also been noted 30 .…”

Section: Epidemiologymentioning

confidence: 99%

Merkel cell carcinoma

Becker

Stang

DeCaprio

et al. 2017

Nat Rev Dis Primers

465

565

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Merkel cell carcinoma (MCC) is a rare but highly aggressive skin cancer with neuroendocrine features. MCC pathogenesis is associated with either the presence of Merkel cell polyomavirus or chronic exposure to ultraviolet light (UV), which can cause a characteristic pattern of multiple DNA mutations. Notably, in the Northern hemisphere, the majority of MCC cases are of viral aetiology; by contrast, in areas with high UV exposure, UV-mediated carcinogenesis is predominant. The two aetiologies share similar clinical, histopathological and prognostic characteristics. MCC presents with a solitary cutaneous or subcutaneous nodule, most frequently in sun-exposed areas. In fact, UV exposure is probably involved in both viral-mediated and non-viral-mediated carcinogenesis, by contributing to immunosuppression or DNA damage, respectively. Confirmation of diagnosis relies on analyses of histological features and immunological marker expression profiles of the lesion. At primary diagnosis, loco-regional metastases are already present in ~30% of patients. Excision of the tumour is the first-line therapy; if not feasible, radiotherapy can often effectively control the disease. Chemotherapy was the only alternative in advanced-stage or refractory MCC until several clinical trials demonstrated the efficacy of immune-checkpoint inhibitors.

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History of chronic inflammatory disorders increases the risk of Merkel cell carcinoma, but does not correlate with Merkel cell polyomavirus infection

Cited by 31 publications

References 11 publications

Clinical and molecular characterization of virus-positive and virus-negative Merkel cell carcinoma

Clinical and molecular characterization of virus-positive and virus-negative Merkel cell carcinoma

Clinical and molecular characterization of virus-positive and virus-negative Merkel cell carcinoma

Merkel cell carcinoma

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