Genetics of Skin Cancer

Abstract

Three major types of skin cancers (melanoma, basal cell carcinoma (BCC) and squamous cellcarcinoma (SCC)) are a significant health burden mainly for the fair-skinned population.Melanoma is the most lethal form of skin cancer while BCC is the commonest form of skincancer. Cutaneous squamous cell carcinoma is more frequent than melanoma and moreaggressive than BCC. Ultraviolet radiation, pigmentation phenotypes and genetic factorsplay a role in skin cancer etiology. The objective of this work is to expand the currentunderstanding of genetic architecture of skin cancer. Furthermore, finding the causalassociation of various risk factors and skin cancer may strengthen preventive efforts. Thus, Ihave used genetic data to help evaluate the causal association of polyunsaturated fattyacids (PUFAs), vitamin D and melanoma and overall-cancer risk and mortality.In Chapter 1, I have included an introduction to skin cancer and its various risk factors aswell as a general overview of the statistical and computational methods used in the studiesincluded in the thesis.In Chapter 2, I performed Mendelian randomisation (MR) of melanoma on PUFAs. The studysample comprised 12,874 melanoma cases and 23,203 controls. PUFA Instrumentalvariables were derived from publicly available CHARGE consortium data. By using theinverse variance weighted method, I identified that even with a large change of fatty acidlevels (Docosapentaenoic acid (DPA- moving a person from the 17 th percentile to themedian)) there is no causal association between PUFAs and risk of melanoma odds ratio[OR] = 1.03 (95% confidence interval [CI] = 0.96-1.10). Other PUFAs yielded similar results.In Chapter 3, I used the same instruments of PUFAs to determine the causal association ofoverall cancer risk and mortality (46,155 cases for risk, 6,998 cases for morality and 270,342controls from UK Biobank). I further performed individual cancer analysis for 6 cancer types.I identified that there is no causal association between PUFAs and overall cancer risk andmortality except arachidonic acid (AA) overall cancer risk (OR = 1.02, 95% CI = 1.00 – 1.03).Colorectal cancer risk was increased with higher AA levels (OR = 1.05, 95% CI =1.03 – 1.07).In Chapter 4, I present MR analysis of vitamin D on melanoma risk. Observational studieshave shown many health benefits of vitamin D. To determine the causality of melanoma andvitamin D, I used melanoma meta-analysis consortium data with vitamin D instruments fromprevious publications. I found that changing vitamin D levels by a large amount (20nmol/Ldecrease), did not change the melanoma risk, OR =1.06 (95% CI = 0.95 – 1.19).In Chapter 5, I present the multi-trait analysis of GWAS (MTAG) of keratinocyte cancer (KC)which revealed 29 novel loci for KC risk. From individual cancer meta-analysis of either BCCor SCC, I further identified 12 loci and 1 locus, respectively. I used data from UKBB, QSkin,23andMe and eMERGE (47,742 cases, 634,413 controls) for KC MTAG analysis. I identifiedseveral drug targets; these included the important immune regulation locus CTLA4, which isa target of immunotherapy in melanoma treatment.In Chapter 6, I present the MTAG analysis of melanoma and correlated traits (biochemicaltraits, autoimmune traits) which revealed 74 loci. 18 of them are novel for melanoma risk.New loci included NDUFC2 is a drug target for diabetes mellitus, CTLA4 which is already adrug target for melanoma immunotherapy. My studies may provide future avenues formelanoma and KC treatments. Finally, in Chapter 7 I provide a general discussion withfuture directions for genetic epidemiology, particularly about GWAS, MR and MTAG and theusage of polygenic risk scores.In conclusion, I identified new genetic variants associated with KC and melanoma risk whichwill be potentially useful for future MR and polygenic risk score construction. My causalinference on overall cancer risk and melanoma may inform public health policies. Thesefindings may provide insight for future personalised treatments for skin cancer.