Genetic characterisation of radiation-induced breast cancer in survivors of Hodgkin's lymphoma

Abstract

Hodgkin's lymphoma (HL) accounts for less than one percent of new cancer cases every year in the UK. Although historically HL patients had a poor prognosis, decades of treatments for this hematopoietic neoplasm have led to improved survival rates. However, as with many childhood cancers, the price of success includes adverse treatment-related effects such as cardiovascular disease, neurological disorders, and elevated risk of second cancers in later life. In the case of HL, radiotherapy is thought to be a significant factor that underpins the high rate of second cancers amongst HL survivors relative to the general population. Although it occurs almost exclusively in women, breast cancer (BC) is the most common second cancer in HL survivors, who have a six-fold increased risk compared to the general population. Despite both the high incidence of BC in this setting and rapidly accruing knowledge regarding genetic determinants of sporadic and familial BC, the genetics of radiation-induced BC are largely understudied and it remains unclear whether some women are genetically predisposed to developing BC following radiation exposure. The aim of this thesis is to determine whether germline variation contributes to the aetiology of radiation-induced BC. Firstly, I performed a Genome-Wide Assocation Study (GWAS) of HL survivors who received radiotherapy as part of their HL treatment to identify common polymorphisms associated with radiation-induced BC. This GWAS identified a total of 72 SNPs forming ten independent signlas. Secondly, I investigated whether a BC polygenic risk score (PRS) is associated with risk of radiation-induced BC. This PRS successfully demonstrated a trend of increasing BC risk with increasing PRS scores, thus indicating that a PRS may be a useful method for identifying high risk and low risk individuals. Finally, I performed a targeted sequencing analysis of DNA repair genes in order to investigate whether rare variants in these genes influence predisposition to HLBC. This approach identified a total of 10 rare variants that are associated with radiation-induced BC, thereby providing an indication that DNA repair defects may play a role in the aetiology of radiation-induced BC. In identifying both common and rare variants underlying radiation-induced BC, this project contributes to improving the current understanding of this disease and provides new insights that may help develop new prevention and treatment strategies in the future.