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.