Genomic Alterations and Tumor Mutation Burden in Merkel Cell Carcinoma

• DOI: 10.1001/jamanetworkopen.2022.49674
• Publication Date: 2023-01-05T16:34:10Z
• Authors: Danielle Brazel; Priyanka Kumar; Hung Doan; Tianyu Pan; Weining Shen; Ling Gao; Justin T. Moyers
• Keywords: Merkel cell polyomavirus

Merkel cell carcinoma (MCC) is a rare and highly aggressive cutaneous neuroendocrine with increasing incidence. Cytotoxic chemotherapy checkpoint inhibitors provide treatment options in the metastatic setting; however, there are no approved or standard of care targeted therapy options.To identify actionable alterations annotated by OncoKB database therapeutic evidence level association tumor mutation burden (TMB).This retrospective, cross-sectional study using data from American Association for Cancer Research Genomics Evidence Neoplasia Information Exchange, multicenter international cancer consortium database. Patients MCC were enrolled participating institutions between 2017 2022. Data version 11.0 released January 2022 analyzed April to June 2022.The main outcome was percentage patients high TMB 3B 4 alterations.A total 324 samples 313 (107 women [34.2%]; 287 White [91.7%]; 7 Black [2.2%]) cataloged The median (range) number 4.0 (0.0-178.0), mean (SD) 13.6 (21.2) alterations. Oncogenic represented 20.2% all (862 4259 alterations). Tissue originated primary 55.0% (172 patients) vs metastasis 39.6% (124 patients). TMB-high (≥10 mutations per megabase) present 26.2% cases (82 Next-generation sequencing identified 55 (17.6%) variation Food Drug Administration-approved drug use biomarker-approved indication another indication. An additional 8.6% (27 had variation. Actionable more common among cases, 37 82 (45.1%) harboring 3 compared only 18 231 (7.8%) low TMB. most gene variants included PIK3CA (12 [3.8%]), BRCA1/2 (13 [4.2%]), ATM (7 [2.2%]), HRAS (5 [1.6%]), TSC1/2 (6 [1.9%]). include PTEN [4.1%]), ARID1A (9 [2.9%]), NF1 CDKN2A [2.2%]). Copy fusions infrequent. In 61.0% (191 cases), PanCancer pathway altered, 39.9% (125 cases) multiple pathways. Commonly altered pathways RTK-RAS (119 [38.0%]), TP53 (103 [32.9%]), cycle (104 [33.2%]), PI3K (99 [31.6%]), NOTCH (93 [29.7%]). addition, oncogenic DNA mismatch repair 8.0% (25 patients).In this retrospective MCC, minority potentially These findings support investigation therapies as single agent combination immunotherapy cytotoxic selected populations.