Family History, Genetic Risk Factors, and Risk of Multiple Primary Cancers

Abstract

Multiple primary cancers (MPC), often called second cancers, occur when more than one tumor arises in a patient from different cellular origins at different sites or presents with different histologies or morphologies [1, 2]. With improvements in the early detection and treatment of cancer over the years, both the population of cancer survivors and the chance of developing a new primary cancer has grown [3-5]. However, the etiology of MPC is not well understood. Established and suspected risk factors for MPC include host-related factors (e.g., primary immune deficiency), medical and lifestyle factors (e.g., immunosuppression, chemotherapy), environmental exposures (e.g., arsenic), and genetic factors (e.g., Lynch syndrome)[1]. However, many of the established factors, such as radiation and chemotherapy, only account for a small fraction of the risk [6]. Most research investigating genetic factors for MPC has focused on known cancer syndromes (e.g., Li-Fraumeni syndrome) and rare genetic variants with little research on the contribution of common variants. To understand the heritable risk of MPC, the first project aimed to understand if a family history of cancer is a risk factor for MPC. I also tested if there was a linear relationship between the number of cancers in the family history and MPC. The second project aimed to find common genetic variants associated with MPC. Molecular factors, such as inflammatory factors, insulin-like growth factor, and telomere length (TL), are also hypothesized to play a role in the development of cancer. Telomeres are DNA-nucleoprotein complex at the termini of eukaryotic chromosomes that protect the chromosome from degradation [7]. Telomeres are important in cell division and senescence and critical for chromosomal stability. Progressive telomere shortening occurs naturally with aging, and telomere attrition has been associated with some age-related diseases [7]; however, the relationship with cancer is complex. Despite the expectation of higher cancer risk with shortened telomere length, studies of measured TL have not always found that to be true. A meta-analysis including 121 studies conducted on blood cells did not find associations between TL and overall cancer risk; however, they found both positive and negative associations when stratified by cancer type [8]. Previous studies focused on certain primary cancers, while the relationship between TL and the risk of MPC is not well understood. Association studies with measured TL may be more susceptible to confounding by environmental and lifestyle factors. TL is highly heritable [9, 10], and 197 common genetic variants have been found associated with the leukocyte TL [11]. The advantage of using genetically predicted TL is that it uses germline genotypes that are present from birth and are uncorrelated with environmental exposures. The third study aimed to understand whether genetically predicted TL is associated with the risk of MPC. In summary, the overall objective of this dissertation is to provide insight into the etiology of MPC. The specific aims of the study are to: 1. To examine the association between a family history of cancers and the risk of MPC 2. To identify common genetic variants associated with the risk of MPC 3. To examine the association between genetically-predicted telomere length and MPC To our knowledge, this dissertation project is one of the first studies to examine the role of family history, genetically predicted telomere length and common genetic variants in relationship to the risk of MPC. The results will contribute to our understanding of the etiology of MPC and may suggest biological mechanisms and potential biomarkers for future studies.