Oral Presentation ASDR-AWTRS-MEPSA 2018 Joint Meeting

Epidermal clonal expansion upon UV irradiation: implications for carcinogenesis. (#26)

Edwige Roy 1 , Ho Yi Wong 1 , Valentine Murigneux 1 , Lynn Fink 1 , Kiarash Khosrotehrani 1
  1. University of Queensland, Diamantina Institute, Brisbane, QLD, Australia

Oncogenic mutations induce by UV can be found in normal skin suggesting that accumulation of oncogenic mutations is necessary to overcome cell intrinsic mechanisms as well as cell of origin restrictions towards tumour formation. A major determinant for a cell to accumulate mutations relies in its ability to persist long term and to give rise to a large clone of mutant cells. We used multicolour fate tracing (K14Cre/Er::Rainbow3 mice) to evaluate size changes in clones of epidermal cells in response to chronic ultraviolet B radiation injury. Our findings highlight a bimodal progression of epidermal clones. Epidermal clones expanded more if attached to hair follicles (HF) compared to those not attached that remained of smaller size despite months of UV irradiation with proliferating cells concentrated within 60um of HF openings and clones distant from HF harbouring label retaining cells suggesting their relative slow cycling behaviour. Functionally, microdissection of clones attached or not to HF followed by whole exome sequencing did not reveal any difference in mutation load between proliferative and slow-cycling clones. More detailed picture of genomic alterations showed that none of the clones were mutated for Tp53 or Notch genes but classical SCC mutations were identified. Clones harbouring DNA repair gene mutations had higher numbers of clonal mutation per Mbps suggested that mutation load in epidermal clones might be driven by the integrity of the DNA repair machinery. In a UVB inducible murine BCC model (K14Cre/ER::Ptch1lox/+ mice), although keratin17 expressing groups of epidermal cells reflecting hedgehog pathway activation through loss of the second ptch1 allele were evenly distributed across dorsal skin, they were larger in size if attached to HF. Invasive BCCs emanated from HF attached clones. In conclusion, ultraviolet irradiation results in significant stimulation of epidermal proliferation in proximity of hair follicles resulting in susceptibility to skin carcinogenesis.