Oral Presentation Australasian Society for Dermatology Research Annual Scientific Meeting 2024

3D total-body-imaging reveals genotype-dermatological phenotype correlations in hereditary melanoma genes: POT1, POLE, BAP1 and CDKN2A (#36)

Ellie Maas 1 , Brigid Betz-Stablein 1 , Maura Gillis 2 , Clare Primiero 1 , Miriam Potrony 3 , Adam Mothershaw 1 , Thi Pham 2 , Vanessa Weir 2 , Nicholas Kurtansky 2 , Josep Malvehy 3 4 , Susana Puig 3 4 , Veronika Rotemberg 2 , Peter Soyer 1 5 , Aideen M McInerney-Leo 1
  1. Dermatology Research Centre, Frazer Institute, The University of Queensland, Brisbane, QLD, Australia
  2. Department of Dermatology, Memorial Sloan Kettering Cancer Center, New York , NY, United States of America
  3. Dermatology Department, Melanoma Unit, Hospital Clínic de Barcelona, IDIBAPS, Universitat de Barcelona, Barcelona, Spain
  4. Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), Valencia , Spain
  5. Department of Dermatology , Princess Alexandra Hospital, Brisbane, Queensland, Australia

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.