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

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

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.

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.

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.