title: 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.
authors.affiliation: Department of Dermatology, University of California San Diego, San Diego, CA, USA.
authors.forename: Philip R
authors.initials: PR
authors.lastname: Cohen
authors.affiliation: N-of-One, Inc., Lexington, MA, USA.
authors.forename: Brett N
authors.initials: BN
authors.lastname: Tomson
authors.affiliation: N-of-One, Inc., Lexington, MA, USA.
authors.forename: Sheryl K
authors.initials: SK
authors.lastname: Elkin
authors.affiliation: N-of-One, Inc., Lexington, MA, USA.
authors.forename: Erica
authors.initials: E
authors.lastname: Marchlik
authors.affiliation: N-of-One, Inc., Lexington, MA, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Carter
authors.affiliation: Center for Personalized Cancer Therapy and Division of Hematology and Oncology, Department of Medicine, University of California San Diego Moores Cancer Center, San Diego, CA, USA.
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D015266:Carcinoma, Merkel Cell / Q000188:drug therapy / Q000235:genetics*; D023281:Genomics / Q000379:methods*; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D058990:Molecular Targeted Therapy; D057285:Precision Medicine; D012878:Skin Neoplasms / Q000188:drug therapy / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor
keywords: Merkel cell carcinoma; genomic landscape; next-generation sequencing; personalized therapy; targeted therapy