Clinical and molecular characterization of virus-positive and virus-negative Merkel cell carcinoma.
Adolescent
Adult
Aged
Aged, 80 and over
Carcinoma, Merkel Cell
/ genetics
Child
DNA, Neoplasm
/ genetics
DNA, Viral
/ genetics
Female
Genetic Testing
/ methods
Humans
Male
Middle Aged
Mutation
Polyomavirus
/ genetics
Polyomavirus Infections
/ genetics
Skin Neoplasms
/ genetics
Survival Analysis
Tumor Virus Infections
/ genetics
Cancer genomics
Integration
Mutagenesis
Polyomavirus
Somatic variants
Journal
Genome medicine
ISSN: 1756-994X
Titre abrégé: Genome Med
Pays: England
ID NLM: 101475844
Informations de publication
Date de publication:
18 03 2020
18 03 2020
Historique:
received:
23
09
2019
accepted:
27
02
2020
entrez:
20
3
2020
pubmed:
20
3
2020
medline:
5
1
2021
Statut:
epublish
Résumé
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 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. However, it has been challenging to reliably distinguish between virus positive and UV damaged MCC. 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. 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 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. 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. 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.
Sections du résumé
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 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. 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 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. 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.
Identifiants
pubmed: 32188490
doi: 10.1186/s13073-020-00727-4
pii: 10.1186/s13073-020-00727-4
pmc: PMC7081548
doi:
Substances chimiques
DNA, Neoplasm
0
DNA, Viral
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
30Subventions
Organisme : NCI NIH HHS
ID : P01 CA203655
Pays : United States
Organisme : NIH HHS
ID : R01CA173023
Pays : United States
Organisme : NIH HHS
ID : R35CA232128
Pays : United States
Organisme : NIH HHS
ID : P01CA203655
Pays : United States
Organisme : NCI NIH HHS
ID : R50 CA243777
Pays : United States
Organisme : NIH HHS
ID : R01CA63113
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA232128
Pays : United States
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