Abstract
To identify protein-altering variants (PAVs) for glioma, we analysed Illumina HumanExome BeadChip exome-array data on 1882 glioma cases and 8079 controls from three independent European populations. In addition to single-variant tests we incorporated information on the predicted functional consequences of PAVs and analysed sets of genes with a higher likelihood of having a role in glioma on the basis of the profile of somatic mutations documented by large-scale sequencing initiatives. Globally there was a strong relationship between effect size and PAVs predicted to be damaging (P=2.29 × 10−49); however, these variants which are most likely to impact on risk, are rare (MAF<5%). Although no single variant showed an association which was statistically significant at the genome-wide threshold a number represented promising associations – BRCA2:c.9976A>T, p.(Lys3326Ter), which has been shown to influence breast and lung cancer risk (odds ratio (OR)=2.3, P=4.00 × 10−4 for glioblastoma (GBM)) and IDH2:c.782G>A, p.(Arg261His) (OR=3.21, P=7.67 × 10−3, for non-GBM). Additionally, gene burden tests revealed a statistically significant association for HARS2 and risk of GBM (P=2.20 × 10−6). Genome scans of low-frequency PAVs represent a complementary strategy to identify disease-causing variants compared with scans based on tagSNPs. Strategies to lessen the multiple testing burden by restricting analysis to PAVs with higher priors affords an opportunity to maximise study power.
Highlights
Gliomas account for ~ 40% of all primary brain tumours and are diagnosed in around 26 000 individuals in Europe each year.1,2 Gliomas are typically classified as being either glioblastoma (GBM) or non-GBM tumours.3 Most gliomas carry a poor prognosis, with the most common type, GBM, typically having a median survival of 15 months.2 The only environmental factor consistently shown to influence glioma risk is exposure to ionising radiation,2 which accounts for only a very small number of cases.Evidence for genetic predisposition to glioma is provided by rare inherited cancer syndromes including Turcot's and Li–Fraumeni syndromes, and neurofibromatosis.2,4 Collectively they account for little of the 2-fold increased risk of glioma seen in relatives of patients
They account for little of the 2-fold increased risk of glioma seen in relatives of patients
To assess the fidelity of genotyping we examined the concordance in 493 individuals from the 1958 Birth Cohort (1958BC),15 which had been sequenced18 using TruSeq capture in conjunction with Illumina HiSeq2000 technology, and a GATK2ref. 19 pipeline according to best practices
Summary
Gliomas account for ~ 40% of all primary brain tumours and are diagnosed in around 26 000 individuals in Europe each year. Gliomas are typically classified as being either glioblastoma (GBM) or non-GBM tumours (diffuse ‘low-grade’ glioma WHO grade I/II and anaplastic glioma WHO grade III tumours). Most gliomas carry a poor prognosis, with the most common type, GBM, typically having a median survival of 15 months. The only environmental factor consistently shown to influence glioma risk is exposure to ionising radiation, which accounts for only a very small number of cases.Evidence for genetic predisposition to glioma is provided by rare inherited cancer syndromes including Turcot's and Li–Fraumeni syndromes, and neurofibromatosis. Collectively they account for little of the 2-fold increased risk of glioma seen in relatives of patients.. Gliomas account for ~ 40% of all primary brain tumours and are diagnosed in around 26 000 individuals in Europe each year.. Most gliomas carry a poor prognosis, with the most common type, GBM, typically having a median survival of 15 months.. The only environmental factor consistently shown to influence glioma risk is exposure to ionising radiation, which accounts for only a very small number of cases. Evidence for genetic predisposition to glioma is provided by rare inherited cancer syndromes including Turcot's and Li–Fraumeni syndromes, and neurofibromatosis.. Evidence for genetic predisposition to glioma is provided by rare inherited cancer syndromes including Turcot's and Li–Fraumeni syndromes, and neurofibromatosis.2,4 They account for little of the 2-fold increased risk of glioma seen in relatives of patients.
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