Increased frequency of CHEK2 germline pathogenic variants among individuals with dermatofibrosarcoma protuberans

Purpose: To identify candidate susceptibility genes for dermatofibrosarcoma protuberans (DFSP).

Methods: All individuals with DFSP from the International Sarcoma Kindred Study (n = 3767 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 3 cohorts. The mean age at diagnosis (standard deviation) in the International Sarcoma Kindred Study, 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 3 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 = 6388/640,227 [1.0%]) (Fisher exact, P = .03). Additional genes with P/LP variation (1 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.