| Title: | Increased Frequency of CHEK2 Germline Pathogenic Variants Among Individuals with Dermatofibrosarcoma Protuberans |
| Journal: | Genetics in Medicine Open |
| Published: | 1 Sep 2024 |
| DOI: | https://doi.org/10.1016/j.gimo.2024.101895 |
Publication 13531
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Abstract
Purpose To identify candidate susceptibility genes for dermatofibrosarcoma protuberans (DFSP). Methods All individuals with DFSP from the International Sarcoma Kindred Study (ISKS; n=3,767 individuals with sarcoma diagnoses from Australia, Europe, New Zealand, and United States) and cohorts that were not ascertained based on sarcoma status or other phenotypes (Geisinger MyCode, n=170,503 individuals, United States; UK Biobank, n=469,789 individuals, United Kingdom) were evaluated for germline pathogenic or likely pathogenic (P/LP) variants in 156 cancer genes. Results There were 92 unrelated individuals with DFSP across the three cohorts. The mean age at diagnosis (standard deviation [SD]) in ISKS, Geisinger, and UK Biobank was 40.8 (14.5), 50.3 (9.4), and 49.4 (13.2) years, respectively. Germline P/LP variants were most common in the CHEK2 gene (4/92 [4.3%]). CHEK2-related cases were often associated with early onset disease (age at diagnosis: 30-39 years) and were observed in all three cohorts. Among 640,292 individuals in Geisinger and UK Biobank who were not ascertained based on phenotype, there was a significantly increased frequency of CHEK2 P/LP variants among individuals with DFSP (n=3/65 [4.6%]) compared to those without (n=6,388/640,227 [1.0%]) (Fisher exact, P=.03). Additional genes with P/LP variation (one case for each gene) included ACD, ERCC5, ERCC1, DOCK8, GBA1, ATM, MUTYH, TP53, RECQL4, and COL7A1. Conclusion This study of multiple cohorts identifies CHEK2 as a candidate susceptibility gene for DFSP. Additional epidemiologic and functional studies are needed to further characterize this potential gene-tumor relationship.</p>
10 Authors
- Michael R. Sargen
- Jung Kim
- Jeremy S. Haley
- Hayley P. Barker
- Piyushkumar A. Mundra
- Mandy L. Ballinger
- David M. Thomas
- David J. Carey
- Alisa M. Goldstein
- Douglas R. Stewart
1 Application
| Application ID | Title |
|---|---|
| 54389 | Frequency, phenotypic spectrum, and penetrance of pathogenic variation in cancer susceptibility genes in the general population |
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