eP047: Germline cancer predisposition variants in a cohort of early-onset Merkel cell carcinoma patients


      Merkel cell carcinoma (MCC) is a rare and highly aggressive skin cancer that is associated with advanced age and immunosuppression. Most patients diagnosed with MCC are older than 70 years of age, with incidence below age 50 being rare. To date, no cases of familial MCC have been reported. To identify possible predisposition alleles in a cohort of 37 early-onset MCC patients, ages 18-49 (median age = 45 years, females = 17, males =27), we performed genome sequencing and subsequent clinical-grade analysis. We report findings from this cohort and discuss the benefits of genome sequencing in detecting germline variants in known cancer predisposition and DNA repair genes.


      We performed genome sequencing on peripheral blood DNA from patients diagnosed with MCC prior to age 50. Analysis was carried out using the custom-enhanced analysis tool, SEQR, developed for the NIAID Centralized Sequencing Program. First-tier analysis focused on rare pathogenic and likely pathogenic variants in known cancer predisposition genes. Additionally, we identified rare variants of unknown clinical significance in the same group of genes.


      Our analysis identified variants in known cancer predisposition genes in 16/37 (43%) early-onset MCC patients across 14 autosomal genes. Notably, 5/37 (14%) of these patients were heterozygous for previously well-described pathogenic variants in cancer predisposition genes (ATM = 2, BRCA1 = 2, and BRCA2). Furthermore, 4/37 (11%) patients had likely pathogenic variants in other known cancer predisposition genes (FANCA, RAD54L, SMARCAD1, and TP53). Additionally, 8/37 (22%) patients had very rare (minor allele frequency ≤ 3.5E-05) variants of uncertain clinical significance in cancer predisposition genes (APC, ATM, ERCC4, FANCA, FGFR3, PTCH1, TSC1, WT1). Genome-based copy number variant (CNV) analysis did not detect any underlying CNVs in BRCA1 and BRCA2.


      Our study demonstrates the clinical value of genomic workup in early-onset MCC patients and suggests that heritable cancer predisposition variants can increase the risk for MCC. As 6 (16%) patients carried variants strongly associated with familial cancer syndromes (ATM, BRCA1, BRCA2, and TP53), including inherited risk for breast and other malignancies, the genomic sequencing resulted in a high frequency of personal and familial benefit. Genetic counseling and cascade testing are indicated for patients and their families to ascertain the familial risk for inherited cancer predisposition. Further investigation of the genetic risk of identified variants toward the development of MCC is warranted. Future studies will include similar workup and analysis in older MCC patients to determine the relative contribution of variants in known cancer predisposition genes to more typical presentations of MCC.