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 are no studies investigating correlations between the dermatological phenotype and POT1/POLE/BAP1 genotypes.
Method:
An international cohort comprising fifty-two individuals (Australia(n=22), Spain(n=18), and North America(n=11)) carrying a rare, pathogenic variant [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 include total naevus count, naevus size (≥2-5mm and >5mm diameter), naevus count by body site, and severity of UV-damage by body site. An unaffected cohort with no personal or familial history of melanoma (n=127 individuals) was used as a comparator.
Results:
TBI revealed that pathogenic variant carriers had significantly greater naevus counts >2mm diameter (median n=102) compared to controls (n=39 naevi) p-value=<0.0001) and the majority of naevi 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. Of interest, POLE and POT1 carriers exhibited significantly greater total body naevus counts >5mm diameter (median n=40 naevi and n=10 naevi respectively) compared to controls and BAP1 carriers (p-value=<0.01); additionally, >5mm diameter naevus counts were found to be significant on body sites with absent-mild UV-damage in POLE and POT1 carriers compared to CDKN2A, BAP1 and control groups: lower-back (p-value=<0.0001); abdomen (p-value=≤0.01). CDKN2A carriers had significantly greater naevus counts >2mm on the head and neck (median n=9 naevi) compared to controls (n=0 naevi) (p-value=<0.0001).
Conclusion:
Carriage of a pathogenic variant in POLE/POT1/CDKN2A increased naevus development generally, and naevi >5mm diameter in POLE and POT1 carriers, independently of or with mild UV-exposure in this cohort.