Genomic portfolio of Merkel cell carcinoma as determined by comprehensive genomic profiling: implications for targeted therapeutics

Abstract

Merkel cell carcinoma is an ultra-rare cutaneous neuroendocrine cancer for which approved treatment options are lacking. To better understand potential actionability, the genomic landscape of Merkel cell cancers was assessed. The molecular aberrations in 17 patients with Merkel cell carcinoma were, on physician request, tested in a Clinical Laboratory Improvement Amendments (CLIA) laboratory (Foundation Medicine, Cambridge, MA) using next-generation sequencing (182 or 236 genes) and analyzed by N-of-One, Inc. (Lexington, MA). There were 30 genes harboring aberrations and 60 distinct molecular alterations identified in this patient population. The most common abnormalities involved the TP53 gene (12/17 [71% of patients]) and the cell cycle pathway (CDKN2A/B, CDKN2C or RB1) (12/17 [71%]). Abnormalities also were observed in the PI3K/AKT/mTOR pathway (AKT2, FBXW7, NF1, PIK3CA, PIK3R1, PTEN or RICTOR) (9/17 [53%]) and DNA repair genes (ATM, BAP1, BRCA1/2, CHEK2, FANCA or MLH1) (5/17 [29%]). Possible cognate targeted therapies, including FDA-approved drugs, could be identified in most of the patients (16/17 [94%]). In summary, Merkel cell carcinomas were characterized by multiple distinct aberrations that were unique in the majority of analyzed cases. Most patients had theoretically actionable alterations. These results provide a framework for investigating tailored combinations of matched therapies in Merkel cell carcinoma patients.

Merkel Cell Polyomavirus Exhibits Dominant Control of the Tumor Genome and Transcriptome in Virus-Associated Merkel Cell Carcinoma

“…1A and B; Table 1). This mutation load is consistent with recent reports from targeted sequencing (18–20). Within all tumors, the majority of mutations fell into intergenic regions, but a large fraction of these mutations (37.7%) occurred near or within genes that did not significantly differ based on tumor type (Table 2).…”

Tumor Mutational Burden as an Independent Predictor of Response to Immunotherapy in Diverse Cancers

“…The other patient had Merkel cell carcinoma (TMB = 1 mutation/mb). Virus-associated Merkel cell carcinomas are known to carry a low mutational burden (43–45); however, these tumors are responsive to PD-1/PD-L1 blockade (46). Viral disease, which may up-regulate specific genes such as APOBEC (responsible for mRNA editing)(47), could create immunogenic neoantigens(48).…”

Merkel cell carcinoma

“…3). Loss-of-function mutations in NOTCH1 and NOTCH2 have been reported in MCPyV − MCCs 7,20,57,65 . It is possible that, in MCPyV + MCCs, LT and ST functionally perturb these signalling pathways, thereby bypassing the requirement for the respective inactivating mutations.…”

“…Several studies have noted that both MCPyV + MCCs and MCPyV − MCCs contain mutations that activate receptor tyrosine kinases (RTKs) and the downstream PI3K–AKT–mTOR growth signalling pathway. Gain-of-function mutations in AKT1, HRAS and PIK3CA or loss-of-function mutations in PTEN, NF1 and TSC1 have been reported in both MCPyV + MCCs and MCPyV − MCCs 7,20,57,65,66 . Several in vivo and in vitro models of MCC are available (BOX 3).…”