In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 3875-3875
Kurzfassung:
Background/Aims: Merkel cell carcinoma (MCC) is rare but aggressive cutaneous high-grade neuroendocrine cancer. Viral infection and sun-exposure are known risk factors for development of MCC, the latter being important in Australia, which has the highest reported incidence of MCC worldwide. There is growing evidence to suggest that MCC associated with the Merkel cell polyoma virus (MCPyV) is clinically, biologically and genetically distinct to those tumors without viral infection. We aimed to assess mutations arising in MCC in the Australian population by targeted massively-parallel sequencing (MPS) to gain new biological insight and identify novel therapeutic opportunities in this disease. Methods: MCPyV was detected in tumours by PCR amplification of large-T antigen coding DNA. The tumor cohort was comprised of seven MCPyV-positive and 16 MCPyV-negative tumors reflecting the reported prevalence of these subtypes in the Australian population. We also sequenced two viral negative MCC cell lines. Hybridization-based DNA capture was used for enrichment of 625 cancer genes for high-depth MPS of tumor and the matching germline DNA, where available. Single nucleotide variants and small insertions and deletions were detected using GATK and muTect variant calling tools and annotated using ENSEMBL variant effect predictor. Somatic variants were enriched in the data by filtering out any variants found in matching germline samples or population-based polymorphism databases Results: High mutation burden was found exclusively in the MCPyV-negative cases with the hallmark signature of UV induced DNA damage. Somatic mutations were identified in known cancer genes specific to the MCPyV-negative tumors. Deleterious RB1 and TP53 mutations were found in 17 and 16 of the MCPyV-negative cases, respectively. Canonical mutations were identified in PIK3CA, HRAS as well as truncating NF1 mutations, indicating that activation of the PI3K and RAS-MAPK pathways are important for pathogenesis of MCPyV-negative tumors. Treatment of two cell lines harboring either PIK3CA or HRAS mutations, respectively, showed in vitro sensitivity to the dual PI3K/mTOR inhibitor PF-04691502. Conclusions: The identification of a UV-induced DNA damage signature and mutations in PI3K and MAPK pathways specific to viral negative tumors confirms the distinct routes to pathogenesis in this disease subtype. This study provides new insight into the biology of viral negative MCC and potential opportunities for the deployment of targeted therapies in this patient group. Citation Format: Stephen Q. Wong, Kelly Waldeck, Ismael A. Vergara, Jason Li, Richard Lupat, Timothy Semple, Carleen Cullinane, Gisela Mir Arnau, Meredith Johnston, Annette Hogg, Anthony T. Papenfuss, Stephen Fox, Grant McArthur, Anthony Gill, Rodney J. Hicks, Richard W. Tothill. Merkel cell carcinomas in Australia have distinct mutation profiles reflecting viral etiology and UV-related DNA damage. [abstract] . In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3875. doi:10.1158/1538-7445.AM2015-3875
Materialart:
Online-Ressource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2015-3875
Sprache:
Englisch
Verlag:
American Association for Cancer Research (AACR)
Publikationsdatum:
2015
ZDB Id:
2036785-5
ZDB Id:
1432-1
ZDB Id:
410466-3
