Predisposition to Early-Onset Merkel Cell Carcinoma Linked to Genetic Variants

Genetic testing should be recommended for patients diagnosed with Merkel cell carcinoma (MCC) before age 50, as well as their family members, as early-onset MCC has been associated with inheritable genetic variations, according to a study recently published in JAMA Dermatology.

Skin Cancer Development Concept | image credit: Christoph Burgstedt - stock.adobe.com

MCC is a rare form of neuroendocrine skin cancer primarily caused by the integration of Merkel cell polyomavirus (MCPyV). Among the affected population, only around 4% of individuals are diagnosed with MCC before 50 years (characterized as early-onset MCC). An important avenue of research has concerned understanding the etiology of MCC to continue advancing prevention and treatment methods.

Individuals who develop cancer at younger ages have demonstrated to harbor certain germline cancer predispositions. Because genetics can create significant risk factors, the authors of the current study investigated whether any patterns of germline cancer risk variants could be detected in patients with early-onset MCC.

This study enrolled patients with MCC between January 2003 and May 2019. The early-onset MCC cohort was compared with a control cohort of 930 individuals enrolled from the National Institute of Allergy and Infectious Disease Centralized Sequencing Program. Those in the control group had been undergoing evaluation for noncancer reasons and were referred from September 2017 through September 2021. There was also a later-onset MCC cohort (diagnosed after age 50) who acted as matched controls for tumor analysis. The later-onset group underwent whole-exome sequencing for comparison.

In total, 37 patients were identified with peripheral blood mononuclear cells for genome sequencing (GS). The median age of the early-onset MCC cohort was 45 years. There were 26 of these patients tested for MCPyV, of whom 25 (96%) had tumors that tested positive—which suggested that patients with MCC of younger ages experience increased rates of virus-positive tumors.

Seven of the 37 patients (19%) tested positive for genetic variants that are linked to cancer predisposition. These gene variations were observed in MAGT1, ATM, BRCA1, BRCA2, and TP53. Additional GS was performed to determine the associations between these variants and cancer predisposition. Analysis showed that early-onset MCC was significantly linked to cancer predisposition in these genetic variations (OR, 30.35; 95% CI, 8.89-106.30; P < .03).

DNA repair genes were also affected in 16 patients (43%), who demonstrated variations not observed in the general public, and an additional 3 patients (8%) who were heterozygous carriers of cancer-predisposing variations.

The authors mentioned that they did not find any pathogenic alleles in MAGT1, ATM, BRCA1, BRCA2, or TP53 that were associated with cancer predisposition among the later-onset MCC cohort.

As the authors conclude, they highlight the importance of their study as the first to investigate the inheritable risk factors associated with MCC. “On clinical review, the patients with MCC with these variants all had personal or family histories consistent with the associated genetic syndromes. It is noteworthy that MCC has not been considered to run in families, nor has it been associated with well-studied syndromes,” Mohsin, et al write.

“These findings also suggest that defective DNA repair may potentiate MCPyV integration events to promote virus-positive MCC formation. Indeed, augmented DNA damage has been associated with the integration of other human oncoviruses,” the authors add. “The fact that MCPyV T antigens can inhibit DNA repair may further enhance this process in virus-infected cells. Elucidating the specific mechanisms whereby these genetic variants increase MCC risk will require further investigation.”

Reference

Mohsin N, Hunt D, Yan J, et al. Genetic risk factors for early-onset Merkel cell carcinoma. JAMA Dermatol. Published online January 3, 2024. doi:10.1001/jamadermatol.2023.5362