Genetic Profiles of Different Subsets of Merkel Cell Carcinoma Show Links between Combined and Pure MCPyV-negative Tumors

Publication date: Available online 24 October 2017
Source:Human Pathology
Author(s): Michael D. Carter, Dan Gaston, Weei-Yuarn Huang, Wenda L. Greer, Sylvia Pasternak, Thai Yen Ly, Noreen M. Walsh
Tumorigenesis in Merkel cell carcinoma (MCC) is driven by (i) clonal integration of the Merkel cell polyomavirus (MCPyV) in neoplastic cells and/or (ii) genetic damage by ultraviolet (UV) light. A higher mutational burden, a UV-mutational signature, and many mutations in the TP53 and RB1 genes characterize the virus-negative subset. MCPyV-negative MCCs include combined (often squamous and neuroendocrine) and pure (neuroendocrine) tumors. Because a combined morphology could elude detection microscopically, we sought a genetic link between combined and pure virus-negative tumors. From a global cohort of 46 cases, 9 pure MCPyV-positive, 9 pure MCPyV-negative, and 10 combined MCPyV-negative MCCs were studied by genome-wide microarray in search of copy number aberrations (CNAs). The entire cohort (n=46) was evaluated by next-generation sequencing (NGS) for mutations in selected tumor suppressor genes and oncogenes. More CNAs and a greater fraction of the genome was changed in combined and pure MCPyV-negative tumors relative to MCPyV-positive cases (P<.01 for all comparisons). No difference in these parameters was found between the two MCPyV-negative groups. Copy number loss of RB1 or an inactivating RB1 mutation (either or both) was common in combined (8/10, 80%) and pure (7/9, 78%) MCPyV-negative tumors, but not MCPyV-positive cases (1/9, 11%). A similar trend was seen for TP53, [combined (2/10, 20%) and pure virus-negative tumors (5/9, 56%) showed gene copy number loss or mutations, contrasted with pure virus positive cases (0/9, 0%)]. The shared genetic profiles of combined and pure MCPyV-negative tumors link these subsets and separate them from MCPyV-positive tumors.



http://ift.tt/2z3vjEw