Melbourne School of Population and Global Health - Theses
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ItemExploration of sex differences in genetic susceptibility to glioma( 2023-08)Glioma comprises around 80% of all malignant primary adult brain tumours. It consists of a heterogenous group of tumours with the most common types being glioblastoma (GBM), astrocytoma and oligodendroglioma, each having a distinct molecular characteristic and varying rates of survival. GBM has one of the worst median survival times among cancers, less than 15 months. Glioma incidence is around 6.0 per 100,000 people in the USA and Australia with a higher incidence in men than women. This sex difference in incidence exists across all adult age groups and across ethnicities. The only consistently validated environmental risk factor for glioma is high level ionising radiation and a protective association with asthma and eczema. First-degree relatives of an affected individual have a two-fold increase in glioma risk and there are several rare inherited cancer syndromes which increase glioma risk but these account for only 1-2% of adult glioma cases. Previous genome-wide association studies (GWAS) have identified 50 common risk variants in 34 genomic risk regions with some of these risk variants being glioma type-specific, according to current evidence. These known glioma risk variants explain less than 40% of the familial risk leaving much of glioma’s familial risk to be discovered. This thesis examines whether biological sex (having XX versus XY sex chromosomes) influences an individual’s genetic risk of glioma. Sex differences in the incidence and survival of many cancers is well documented with many cancer-related pathways such as DNA repair, cellular metabolism, tumour suppressor activity, cell cycle regulation and immunity having known sex differences. The brain is also noted for sex differences in its structure and function. Many neurological and psychiatric disorders have sex differences in risk, prevalence, and symptoms. Glioma shows sex differences in incidence, survival, therapy responses and tumour molecular characteristics. Gene expression in the brain is known to vary between the sexes, across brain regions and across time, therefore it is possible that some of glioma’s missing heritability may be accounted for by sex-specific or sex-different risk variants. This thesis uses sex-stratified GWAS to identify novel genetic risk variants/regions of glioma. The major contributions of this thesis are: 1) validation of the sex difference in oligodendroglioma risk of the CCDC26 long non-coding RNA region using an Australian glioma case-control study. This GWAS was the first to validate a previous sex-specific study that found women are at higher risk than men for variants within the CCDC26 region (see Chapter 4). 2) Identification of 11 potential novel risk regions of glioma using region-based GWAS methods which analyse genomic regions rather than individual genetic variants. Four of these regions were consistently associated with one sex across multiple studies. Seven of the 11 regions contain genes previously reported as potential regulators of glioma tumour cell proliferation. This study highlights the importance of region-based GWAS analyses for detecting risk regions in existing datasets that are missed by conventional SNP-based analyses and suggests that sex may be an important influence on genetic susceptibility to glioma (see Chapter 5). 3) Identification of ten potential novel risk regions of glioma that are specific to certain brain locations (frontal, temporal or parietal lobes). To the best of my knowledge this is the first glioma GWAS stratified by tumour location. Nine of the ten potential risk regions were identified in sex-specific data. The known glioma risk regions including TERT, EGFR, CCDC26, CDKN2BAS, TP53 and RTEL1 do not appear to be strong drivers of tumour location (see Chapter 6). 4) Identification of candidate gene families and biological pathways that warrant future investigation for their potential association with glioma risk. These include the synapse-related genes, olfactory receptor genes and genes involved in the heparan sulphate/fibroblast growth factor (FGF) biological pathway (see Chapter 8). The validation of CCDC26 as a higher female risk region for oligodendroglioma (Chapter 4), and the discovery of novel glioma risk regions using sex-specific data (Chapter 5 and 6) infers that an individual’s biological sex (XX or XY chromosome) plays a role in their genetic susceptibility to glioma. An individual with glioma has their own unique combination of hundreds, possibly thousands of known and undiscovered glioma genetic risk variants. Some of these variants may place that individual at risk of developing any cancer, other variants may influence the risk of developing a particular glioma type anywhere in the brain (e.g., GBM, astrocytoma or oligodendroglioma) and some may be risk factors for developing a tumour in a particular brain location. Many of these risk variants will be mutual to both sexes, but some may have sex-differences in their effect or be specific for one sex. Acknowledging that sex may influence the assortment of genetic variants that increase an individual’s glioma risk may guide future clinical trials and the development of more effective personalised treatments.