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Keywords: Skin Cancer; Sun protection; Melanoma; Retrotransposons; Gene-Environnement Interaction; Meiomitosis; Genomic Instability; Retionid Resistance

Skin cancer is more common than all other malignancies combined. According to the American Academy of Dermatology, approximately ~5 million skin cancers are treated each year in the United States alone. It is estimated that ~1/4 Canadians will be affected by a skin cancer in their lifetime and the incidence of these malignancies is increasing. Cutaneous melanoma is responsible for 80% of skin cancer deaths and is the 8^th most diagnosed cancer in Canada.

While my lab studies the molecular pathogenesis of skin cancer, a large portion of my team is working on patient public involvement (PPI) research with the goal of instilling safe sun exposure habits in Canadian youth ().

Fair complexion, ultraviolet (UV) exposure and history of sunburns remain critical risk factors for melanoma/skin cancers. Despite extensive knowledge on UVRs detrimental impact, many still fail to implement sun protection/sun avoidance. Hence, promoting sun protection is vital to decrease individual risk of melanoma/skin cancers. We have mapped the incidence of melanoma across Canada by postal code (), described how weather/environment impacts risk of melanoma incidence (), conducted surveys (quantitative) and focus groups (qualitative) to understand risk factors and beliefs/attitudes driving high risk sun exposure behaviors in Canada (; ; ). We also assessed melanoma mortality-to-incidence rate of melanoma across Canada (). We defined the 鈥渟unscreen paradox鈥� whereby increased sunscreen use is correlated with augmented sun exposure and higher rates of skin cancer, leading to a deceptive sense of security (). Our team is using validated patient questionnaires and focus groups to assess melanoma risk, knowledge and protective behavior in select high- vs. low-incidence regions to establish baseline understanding, why certain areas may have higher incidence of this malignancy. We are working with patient partners to develop gender-specific and geographic region-specific recommendations to help change sun exposure practices. We are also actively studying gene-environment interaction to understand how genetic risk in specific regions leads to skin cancer development ().

In the lab we are studying pathogenesis of skin cancers. Genomic instability is a fundamental defining characteristic of cancer that is essential for disease initiation and progression. A critical mechanism that could promote genomic instability is based on the ectopic re-expression of germ cell proteins by cancer cells that could drive cancer meiomitosis, a term describing the clashing of mitosis and meiosis machineries during the cell cycle. Hundreds of proteins expressed by germ and cancer cells have been termed Cancer/Testis antigens (CTAs), which include meiosis-specific CTAs (meiCT). A number of meiCT genes, including HORMAD1, have been shown to be strongly expressed in highly genomically unstable cancers with poor prognoses, suggesting a role in DNA damage/repair processes. MeiCT genes are of particular interest for oncogenesis as they possess chromosome modulating potential due to their inherent activities and may promote genomic instability. Also, in the skin narrow band ultraviolet B (NB-UVB) is has been shown by us and others to trigger LINE-1 reactivation. LINE-1 constitutes ~17% of human genome, has played important evolutionary role. Reactivation of this retrotransposon may result in deleterious effects leading to DNA damage, cellular senescence and photoaging.

Our team is studying the function of ectopically expressed CT genes and reactivation of retrotransposons in these malignancies highlighting the importance of HORMAD1 and LINE-1 in promoting/mediating genomic instability (; ) Our team also defined the function of the ectopically expressed PRAME in KC demonstrating its role in inhibiting retinoid responses and subsequent cell differentiation. We are investigating the molecular mechanism of HORMAD1, PRAME and LINE-1 reactivation and its impact on the carcinogenesis of skin cancers and how HORMAD1 and PRAME pathways could be targeted for clinical benefit.