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Genomic portfolio of Merkel cell carcinoma as determined by comprehensive genomic profiling: implications for
Philip R Cohen1, Brett N Tomson2, Sheryl K Elkin2
1Department of Dermatology, University of California San Diego, San Diego, CA, USA.
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.
Insights
Genomic analysis of Merkel cell carcinoma reveals frequent TP53 and cell cycle pathway alterations. Most patients with this rare cancer showed actionable targets for potential tailored therapies.
Area of Science:
- Oncology
- Genomics
- Cancer Biology
Background:
- Merkel cell carcinoma is an ultra-rare skin cancer with limited approved treatments.
- Understanding its genomic landscape is crucial for developing targeted therapies.
Purpose of the Study:
- To assess the molecular aberrations in Merkel cell carcinoma.
- To identify actionable genomic alterations for potential targeted therapy.
Main Methods:
- Next-generation sequencing (182 or 236 genes) was performed on 17 Merkel cell carcinoma patient samples.
- Molecular alterations were analyzed to identify common abnormalities and potential therapeutic targets.
Main Results:
- TP53 gene mutations (71%) and cell cycle pathway aberrations (71%) were most common.
- PI3K/AKT/mTOR pathway (53%) and DNA repair genes (29%) also showed alterations.
- Actionable targets for therapy were identified in 94% of patients.
Conclusions:
- Merkel cell carcinomas exhibit diverse and often unique molecular aberrations.
- The majority of patients possess theoretically actionable alterations, supporting tailored therapy investigations.
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