Analysis of cancerous and pre-cancerous skin lesions to generate a repository for studying the mutation burden of UV

Abstract

Exposure of skin to ultraviolet radiation (UVR) can cause DNA mutations in skin and subsequent development of skin cancer, but UVR is also used is as a treatment for skin diseases. However, it is not known how many courses of UVR for skin disease a patient can receive over their lifetime without being at high risk of developing skin cancer. One way to approach this is to identify all the genetic mutations in skin cancers, and to determine which mutated genes are driver genes, i.e. genes in which mutations promote the development of cancer. Following that, one could use this information to look at mutations in the skin before and after a course of UVR treatment for skin disease to assess the amount of mutational damage in driver genes from that UVR course, in order to estimate the number of courses of UVR that patients with skin disease could safely have in their lifetime.
This thesis used a bioinformatics approach to document the genetic mutations in skin cancer, including cutaneous squamous cell cancer (cSCC), basal cell cancer (BCC) and melanoma in order to identify driver genes in these cancers. Along the way, the genetic mutations in squamous cell cancers (SCCs) of four other organs (lung, oesophagus, oropharynx and cervix) were documented to allow comparison of the driver genes in cSCC with SCCs of these other organs.
Whole genome and whole exome sequencing data were identified from online genetic databases and literature searches. Driver genes and mutation signatures were extracted from this data for all the aforementioned cancers. Linux was used for data manipulation and R was used for data analysis. The results of this bioinformatic analysis identified driver genes in each of the three
types of skin cancer and that most of the driver genes in cSCC, BCC and melanoma differed between these cancers. However, some driver genes were common to more than one type of skin cancer, including TP53 as a driver gene in the three different types of skin cancer, CDKN2A as a driver gene in both cSCC and melanoma, PPP6C as a driver gene in BCC and melanoma, and CDC27 and TMEM222 as driver genes in cSCC and BCC. In the comparison of cSCC with SCCs of the other organs, six driver genes (TP53, CDKN2A, FAT1, HRAS, NOTCH1 and NOTCH2) in cSCC were noted as driver genes in one or more of the other cSCC types.
Whole exome sequencing data from precancerous skin lesions and targeted sequencing data from chronically sun exposed skin and chronically sun exposed normal melanocytes were also analysed. This data was used to identify driver genes, that were present in cSCC, BCC and melanoma, in these precancerous skin lesions as well as in the chronically sun exposed skin/melanocytes. This allowed the generation of a repository or “adjunct” to a future pipeline for assessing the carcinogenicity of UVR treatment for skin disease. Specifically, this repository will assist in assessing whether mutated genes in skin after a course of UVR treatment, in comparison with skin prior to that course of UVR, are likely to be driver genes (i.e. promoting skin cancer development). By comparing the number of driver genes mutated in skin after one course of UVR therapy with the number of driver genes mutated in non-cancerous skin of people with skin cancer, it is hoped that one can estimate the number of courses of UVR therapy for skin disease that patients can safely have without significantly increasing their risk of skin cancer development. In this way, the data in this thesis could be used to help inform clinical practice on the maximum number of UVR courses for skin disease that dermatology patients should have in their lifetime.

More information

Identifiers

Catalogue record

Export record