Neuroendocrine Merkel Cell Carcinoma is Associated with Mutations in Key DNA Repair, Epigenetic and Apoptosis Pathways: A Case-Based Study using Targeted Massively Parallel Sequencing

TY - JOUR

T1 - Neuroendocrine Merkel Cell Carcinoma is Associated with Mutations in Key DNA Repair, Epigenetic and Apoptosis Pathways

T2 - A Case-Based Study using Targeted Massively Parallel Sequencing

AU - Graves, Christian A.

AU - Jones, Ashley

AU - Reynolds, Justin

AU - Stuart, Jeremy

AU - Pirisi, Lucia

AU - Botrous, Peter

AU - Wells, James

PY - 2014

Y1 - 2014

N2 - Merkel cell carcinoma (MCC) is a rare neuroendocrine carcinoma with poorly understood molecular etiology. We implemented a comprehensive deep sequencing approach to identify mutations in the tumor DNA from a cohort of patients treated at our institution over the past 15 years. Our results indicate mutations that may constitute therapeutic targets in MCC. Methods: Five patients were treated for MCC within the study interval. Patients with adequate tissue (n = 4), positive neuroendocrine differentiation (Chromogranin, Synaptophysin, and CK20), and histopathological confirmation of MCC were included in the study. DNA was extracted from archival tumor tissue samples and analyzed by massively parallel sequencing using a targeted, multiplex PCR approach followed by semiconductor sequencing. Results: We demonstrate high penetrance nonsense mutations in PDE4DIP (n = 4) as well as various missense mutations in the DNA Damage Response (PRKDC, AURKB, ERCC5, ATR, and ATRX) and epigenetic modulating enzymes (MLL3). Conclusion: We describe several mutations in potential disease-relevant genes and pathways. These targets should be evaluated in a larger cohort to determine their role in the molecular pathogenesis of MCC.

AB - Merkel cell carcinoma (MCC) is a rare neuroendocrine carcinoma with poorly understood molecular etiology. We implemented a comprehensive deep sequencing approach to identify mutations in the tumor DNA from a cohort of patients treated at our institution over the past 15 years. Our results indicate mutations that may constitute therapeutic targets in MCC. Methods: Five patients were treated for MCC within the study interval. Patients with adequate tissue (n = 4), positive neuroendocrine differentiation (Chromogranin, Synaptophysin, and CK20), and histopathological confirmation of MCC were included in the study. DNA was extracted from archival tumor tissue samples and analyzed by massively parallel sequencing using a targeted, multiplex PCR approach followed by semiconductor sequencing. Results: We demonstrate high penetrance nonsense mutations in PDE4DIP (n = 4) as well as various missense mutations in the DNA Damage Response (PRKDC, AURKB, ERCC5, ATR, and ATRX) and epigenetic modulating enzymes (MLL3). Conclusion: We describe several mutations in potential disease-relevant genes and pathways. These targets should be evaluated in a larger cohort to determine their role in the molecular pathogenesis of MCC.

UR - http://www.scopus.com/inward/record.url?scp=84920024034&partnerID=8YFLogxK

U2 - 10.1159/000370310

DO - 10.1159/000370310

M3 - Article

SN - 0028-3835

JO - Neuroendocrinology

JF - Neuroendocrinology

ER -