Genetic Risk Factors for Early-Onset Merkel Cell Carcinoma

January 23, 2024


JAMA Dermatology

Publication Date

January 23, 2024


Mohsin N, Hunt D, Yan J, Jabbour A, Nghiem P, Choi J, Zhang Y, Freeman A, Bergerson J, Dell'Orso S, Lachance K, Kulikauskas R, Collado L, Cao W, Lack J, Similuk M, Seifert B, Ghosh R, Walkiewicz M, Brownell I Summary

Only 4% of MCC cases happen in people under 50 years old – this is called early-onset MCC. Researchers wanted to know if early-onset MCC patients got MCC so young because of any differences in their genes that might make them more likely to develop cancer. In a study of about 1,000 people (37 with early-onset MCC, 45 with late-onset MCC, and 900 without MCC), researchers found that early-onset MCC patients had differences in certain genes that increase the risk of cancer. These genes are named ATM, BRCA1, BRCA2, TP53, and MATG1. 20% of early-onset MCC patients had these differences, whereas no differences could be found in the group of patients with later-onset MCC. This suggests genetic testing and counseling could help early-onset MCC patients, and that exploring these genes may help discover how MCC develops in other patients too.


Importance  Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine skin cancer. Of the patients who develop MCC annually, only 4% are younger than 50 years.

Objective  To identify genetic risk factors for early-onset MCC via genomic sequencing.

Design, Setting, and Participants  The study represents a multicenter collaboration between the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Institute of Allergy and Infectious Diseases (NIAID), and the University of Washington. Participants with early-onset and later-onset MCC were prospectively enrolled in an institutional review board–approved study at the University of Washington between January 2003 and May 2019. Unrelated controls were enrolled in the NIAID Centralized Sequencing Program (CSP) between September 2017 and September 2021. Analysis was performed from September 2021 and March 2023. Early-onset MCC was defined as disease occurrence in individuals younger than 50 years. Later-onset MCC was defined as disease occurrence at age 50 years or older. Unrelated controls were evaluated by the NIAID CSP for reasons other than familial cancer syndromes, including immunological, neurological, and psychiatric disorders.

Results  This case-control analysis included 1012 participants: 37 with early-onset MCC, 45 with later-onset MCC, and 930 unrelated controls. Among 37 patients with early-onset MCC, 7 (19%) had well-described variants in genes associated with cancer predisposition. Six patients had variants associated with hereditary cancer syndromes (ATM = 2, BRCA1 = 2, BRCA2 = 1, and TP53 = 1) and 1 patient had a variant associated with immunodeficiency and lymphoma (MAGT1). Compared with 930 unrelated controls, the early-onset MCC cohort was significantly enriched for cancer-predisposing pathogenic or likely pathogenic variants in these 5 genes (odds ratio, 30.35; 95% CI, 8.89-106.30; P < .001). No germline disease variants in these genes were identified in 45 patients with later-onset MCC. Additional variants in DNA repair genes were also identified among patients with MCC.

Conclusions and Relevance  Because variants in certain DNA repair and cancer predisposition genes are associated with early-onset MCC, genetic counseling and testing should be considered for patients presenting at younger than 50 years.

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