Common Predisposition Alleles For Moderately Common Cancers: Bladder Cancer
Main Category: Urology / Nephrology
Also Included In: Cancer / Oncology; Genetics
Article Date: 21 Jun 2010 - 6:00 PDT
UroToday.com - Whilst the two major risk factors for bladder cancer are smoking and occupational exposure to chemicals, there is also evidence of a genetic component to its aetiology. Candidate gene studies have mostly focussed on genes involved in adduct metabolism and DNA repair, including a recent consortium-based meta-analysis (Stern et al., Cancer Res 2009, 69:6857-64), which included 10 SNPs in seven DNA repair genes in 13 studies. Weak but consistent associations were found for ERCC2 Asp312Asn, NBN Glu185Gln and XPC Ala499Val.
In contrast to candidate gene studies, genome wide association studies (GWAS) adopt a hypothesis-free approach to the detection of genetic variations associated with common diseases, which has resulted in the discovery of previously unsuspected aetiological pathways. Recently, two genome wide association studies in bladder cancer have been published and a third is awaited with interest.
The first genome-wide association study in bladder cancer was published by Kiemeney et al. in September 2008 (Nat Genet 2008 40:991-5) and included 1803 cases and 34336 controls in phase I and 2165 cases and 3800 controls in phase II. In phase I, no single SNP reached the genome-wide significance threshold, but the ten most significant SNPs (all p<5x105) were followed up in seven additional European case-control groups. When discovery and follow-up groups were combined, two SNPs were found to have genome-wide significance, one 30 kb upstream of MYC at 8q24.21 (rs9642880[T])and one on chromosome 3q28, in a region overlapping the TP63 gene (rs710521[A]). The second bladder cancer GWAS was published in August 2009, by the MD Anderson Cancer Centre and collaborators (Wu et al., Nat Genet 2009, 41:991-5). In phase I (969 cases and 957 controls) no SNP reached genome-wide significance. However, rs2294008[T] in exon 1 of the PSCA gene, included in a fast-track replication in three additional US populations (1713 cases and 3871 controls) of the top 50 SNPs and 10 others, was significant in the combined US populations. This SNP was then replicated using the nine European case-control groups from the first GWAS.
MYC may have a role in carcinogenesis, as its deregulation is associated with malignant growth, and TP63 regulates cell cycle arrest and is involved in apoptosis. An association between PSCA and bladder cancer is also biologically plausible as it is involved in cell proliferation and migration, is over-expressed in most bladder cancers, and is an independent predictor of recurrence in superficial tumours. However, it is not clear that the rs2294008[T] allele has a functional effect in vivo.
A large study in 16 different tumour types (Rafnar et al., Nat Genet 2009, 41:221-7), including the European bladder GWAS samples, was made of rs401681[C] on chromosome 5p15.33, previously genome-wide significant in basal cell carcinoma, along with rs27366098[A], also located at the TERT-CLPTM1L locus. These were found to be associated with cancers with strong environmental components to their risk, including bladder cancer.
Most of the common variants identified in GWAS are associated with odds ratios of only 1.2-1.3, so the bulk of the heritable component is not accounted for. This so-called 'missing heritability' includes rare variants and structural variants, such as copy number variants and insertion-deletions, which are incompletely assayed by commercial platforms. It also reflects the lack of power to detect other SNPs of modest effect, so there is a need to perform larger genome wide association studies and meta-analyses, in which such SNPs achieve genome-wide significance and that are powered to detect gene-gene and gene-environment interactions. Resequencing and fine mapping along with functional assays are required to find the functional genetic variants. These approaches in conjunction with assessment of known risk factors, may ultimately lead to personalised medicine becoming a reality in bladder cancer.
Written by Anne Kiltie, MD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations, etc., of their research by referencing the published abstract.
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