Merkel cell carcinoma in a patient with
            <scp>GATA</scp>
            2 deficiency: a novel association with primary immunodeficiency

Crall, Cary; Morley, Keith; Rabinowits, Guilherme; Schmidt, Birgitta; Broyles, Ana Dioun; Huang, Jennifer T.

doi:10.1111/bjd.14062

Cited by 17 publications

(9 citation statements)

References 10 publications

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“…Virus-negative MCC was present in three patients with solid organ transplantation, three with auto-immune disease including myasthenia gravis, rheumatoid arthritis, or granulomatosis with polyangiitis, one with monoclonal gammopathy of undetermined significance (MGUS) , and another with Waldenstrom's macroglubulinemia. In contrast, virus-positive MCC was identified in a patient with mantle zone lymphoma having been treated with Rituximab for 3 years and another with somatic mutations in NF1 and GATA2 (33). The median OS for patients with immunosuppression was 17.5 months (95% CI: 5.6-24.4) months, significantly shorter than patients without immunosuppression (48.5 months, 95% CI: 35.4-113.3, p<0.01) ( Figure 7B, Table 5).…”

Section: Statistical Comparison Of Clinical and Molecular Characterismentioning

confidence: 89%

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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Section: Statistical Comparison Of Clinical and Molecular Characterismentioning

confidence: 89%

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

Starrett¹,

Chen

Marcelus

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…Virus-negative MCC was present in three patients with solid organ transplantation; three with autoimmune diseases including myasthenia gravis, rheumatoid arthritis, and granulomatosis with polyangiitis; one with monoclonal gammopathy of undetermined significance (MGUS); and another with Waldenstrom's macroglobulinemia. In contrast, virus-positive MCC was identified in a patient with mantle zone lymphoma having been treated with Rituximab for 3 years and another with germline mutations in NF1 and GATA2 [49]. The median OS for patients with immunosuppression was 17.5 months (95% CI 5.6-24.4 months), significantly shorter than patients without immunosuppression (48.5 months, 95% CI 35.4-113.3 months, p < 0.01) ( Fig.…”

Section: Statistical Comparison Of Clinical and Molecular Characterismentioning

confidence: 90%

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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“…Accordingly, PIDD patients’ malignancies are often associated with chronic infections. MCPV-associated Merkel cell carcinoma has now been described in GATA2 and TMC8 (EVER2) deficiencies as well as other forms of PIDD [ 330 , 342 – 346 ]. Large follow-up cohorts are needed to refute or confirm associations between novel PIDDs and malignancies, such as hyperactivating PIK3CD and ovarian dysgerminoma or GATA2 deficiency and leiomyosarcoma [ 329 , 347 ].…”

Section: Section 3: Manifestations and Infection Unique To The Immunementioning

confidence: 99%

Emerging Infections and Pertinent Infections Related to Travel for Patients with Primary Immunodeficiencies

et al. 2017

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In today’s global economy and affordable vacation travel, it is increasingly important that visitors to another country and their physician be familiar with emerging infections, infections unique to a specific geographic region, and risks related to the process of travel. This is never more important than for patients with primary immunodeficiency disorders (PIDD). A recent review addressing common causes of fever in travelers provides important information for the general population Thwaites and Day (N Engl J Med 376:548-560, 2017 ). This review covers critical infectious and management concerns specifically related to travel for patients with PIDD. This review will discuss the context of the changing landscape of infections, highlight specific infections of concern, and profile distinct infection phenotypes in patients who are immune compromised. The organization of this review will address the environment driving emerging infections and several concerns unique to patients with PIDD. The first section addresses general considerations, the second section profiles specific infections organized according to mechanism of transmission, and the third section focuses on unique phenotypes and unique susceptibilities in patients with PIDDs. This review does not address most parasitic diseases. Reference tables provide easily accessible information on a broader range of infections than is described in the text.

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Merkel cell carcinoma in a patient with GATA 2 deficiency: a novel association with primary immunodeficiency

Cited by 17 publications

References 10 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

Emerging Infections and Pertinent Infections Related to Travel for Patients with Primary Immunodeficiencies

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