Discussion
In this convenience cohort, 13% of children and young adults with melanoma who underwent germline testing harbored an underlying pathogenic or likely pathogenic GV in a cancer predisposing gene, comparable to the previously reported 9-12% of pediatric cancer patients who have germline cancer predisposition syndromes.7-10 Interestingly, most of the affected genes are not currently associated with increased melanoma risk. Among the five patients harboring GVs, only one (Patient 5) would have been routinely screened based on current surveillance recommendations for LFS. 11 LFS has increased risk of sarcoma, early onset breast cancer, brain tumors, ACC, and leukemia, among others, including melanoma.12 PMS2 is associated with autosomal dominant Lynch syndrome and autosomal recessive CMMRD.13 Patients with CMMRD have an increased risk of developing many different cancers and tumors, often presenting at exceptionally early ages.13 Koolen-de Vries syndrome is characterized by variable developmental delay, hypotonia, seizures, distinct facies, cardiac, kidney and skeletal anomalies and multiple benign nevi.14 Due to benign skin findings, patients with Koolen-de Vries syndrome and CMMRD may be seen by a dermatologist, but melanoma has not yet been reported in these populations to prompt surveillance.14,15 Monoallelic ATM GVs are associated with a moderately increased risk to develop breast cancer, pancreatic cancer, or ovarian cancer in adulthood.4Data have shown ATM heterozygotes have a low to moderate risk for melanoma, but this is not deemed high enough to warrant routine dermatologic screenings.3-4,16 Heterozygous pathogenicBRIP1 GVs are associated with an increased risk to develop ovarian cancer in adulthood.5 One study identified a germline BRIP1 GV in 5 relatives, 3 of which developed melanoma in adulthood.17 The phenotypes for each of these cancer predispositions are evolving with expanded germline testing. Our data provide support for further investigation of the utility of regular dermatology screenings for the early detection of melanoma in individuals with these conditions.
In adults, hereditary melanomas are most commonly associated with pathogenic GVs affecting CDKN2A (22%).1 Other reported genes with increased melanoma risk include CDK4, TERT, POT1, ACD, TERF2IP, MITF, MC1R and BAP1.1,2 Recently, 123 pediatric patients with melanoma were investigated for GVs affecting CDKN2A , CDK4, POT1, MITF, andMC1R .18 In this study, investigators identified a low frequency of CDKN2A (9%) and MITF (3%) variants in all cases but a higher rate of MC1R variants (68%).18 Seventy-four percent of our patients had testing which included all five genes in the aforementioned study. Interestingly, we did not identify any patients harboring a pathogenic variant in one of these genes.
In conclusion, our data reveal that the genes affected in children and adolescents with melanocytic tumors differ from those reported in adults. Broader non-biased germline genetic testing for these patients will further elucidate the genetic underpinnings of this rare cancer type, which will refine the phenotypes and surveillance of known cancer predisposition syndromes.