Introduction:
CDKN2A is the primary familial melanoma gene., Genotype-phenotype studies show increased atypical naevus counts in CDKN2A carriers; but other phenotypic-dermatological variables have been under-explored. There have been no studies exploring correlations between the dermatological phenotype and POT1/POLE/BAP1 genotypes.
Method:
Fifty-two individuals (Australia(n=22), Spain(n=18), and North America(n=11)) with pathogenic variants [CDKN2A(n=19), POT1(n=16), BAP1(n=10)], POLE(n=6)] and diagnosed with primary melanoma, underwent 3D-total-body-imaging (TBI) (VECTRA-WB360). Phenotypic variables investigated included naevus count, size (≥2-5mm diameter and >5mm diameter), location by body site, and severity of UV-damage. An unaffected cohort (n=127 individuals) was used as a comparator.
Results:
TBI revealed that pathogenic variant carriers had significantly greater naevus counts >2mm diameter compared to controls (median n=102 naevi and n=39 naevi respectively, p-value=<0.0001) and most were located on the back and lower limbs. POLE carriers had the highest total naevus counts >2mm diameter (median n=220 naevi), followed by POT1 (median n=101 naevi), then CDKN2A (median n=81). BAP1 naevus counts (median n=60 naevi) were not significantly increased compared to controls. CDKN2A carriers had significantly greater naevus counts on the head and neck (median n=9 naevi >2mm) compared to controls (n=0 naevi). (p-value=<0.0001). Of interest, POLE and POT1 carriers exhibited significantly greater naevus counts >5mm diameter in body sites with absent-mild UV-damage compared to CDKN2A, BAP1 and control groups: lower-back(p-value=<0.0001); abdomen(p-value=≤0.01).
Conclusion:
Carriage of a pathogenic variant in POLE/POT1/CDKN2A increased naevus development generally on the back and lower limbs, and naevi >5mm diameter in POLE and POT1 carriers, independently of or with mild UV-exposure in this cohort.