Smoking causes most bladder cancer, and blood in the urine is the symptom that matters. The variant here is unusual in a small way: it destroys a start codon, so what it does to the protein can be seen rather than guessed.
Bladder cancer is strongly linked to smoking and to certain occupational chemical exposures, and its most important symptom is blood in the urine — often painless, often intermittent, and never something to wait out.
Most common cancer variants sit in non-coding DNA and nobody can say exactly what they do. rs2294008 is different. It is a missense variant in PSCA — prostate stem cell antigen, despite the name, expressed in bladder tissue too — and it alters the start codon, predicted to truncate nine amino acids from the N-terminal signal sequence of the protein. A laboratory reporter assay showed the variant allele significantly reduced promoter activity, and resequencing found it to be the only common missense change in the gene.
So the chain from position to protein is visible here, which is rare enough on this site to be the reason the page exists.
Ordinary. The discovery scan compared 969 cases and 957 controls in Texas, validation followed in three further US populations and nine European ones, and across 6,667 cases and 39,590 controls the allelic odds ratio was 1.15 (95% CI 1.10–1.20, P = 2.14 x 10-10).
Fifteen per cent higher odds, in a disease whose dominant risk factor is smoking. That comparison is the useful one: no common variant here comes close to what tobacco does.
Not smoking, and taking blood in the urine seriously. Visible blood in urine warrants investigation even once, even if it clears up, and even if there is an easier explanation available. Occupational exposure to aromatic amines — historically in dye, rubber and leather work — matters too, and is worth mentioning to a doctor if it applies.
There is no screening programme and no role for this genotype in one.
The variant. Wu et al. conducted a GWAS in 969 bladder cancer cases and 957 controls from Texas, evaluated 60 SNPs in three additional US populations, and validated the top signal in nine European populations. Across all subjects (6,667 cases, 39,590 controls) rs2294008 gave an allelic odds ratio of 1.15 (95% CI 1.10–1.20, P = 2.14 x 10-10). The variant alters the start codon of PSCA and is predicted to truncate nine amino acids from the N-terminal signal sequence of the primary translation product; an in vitro reporter assay showed the variant allele significantly reduced promoter activity, and resequencing of the region established it as the only common missense SNP in the gene.
Context. Other established bladder cancer susceptibility loci include NAT2 slow-acetylator genotypes and the GSTM1 null genotype, both carcinogen-metabolism genes whose effects interact with smoking — a cleaner gene-environment story than most, and one where the environmental term dominates. Tobacco smoking accounts for a large share of cases; occupational exposure to aromatic amines is the classic non-smoking cause.
Clinical position. Visible haematuria is investigated with imaging and cystoscopy; management depends on whether disease is non-muscle-invasive or muscle-invasive, and surveillance after treatment is intensive because recurrence is common. No genotype enters diagnosis, staging, treatment or surveillance.
What a 23andMe/AncestryDNA export or raw VCF can and can't tell you about Bladder Cancer comes down to these specific, well-studied positions — not a diagnosis.
Its mechanism is visible. It changes the start codon of PSCA, is predicted to shorten the protein's signal sequence, and reduced promoter activity in a laboratory assay. Most common cancer variants sit in non-coding DNA where nobody can say what they do.
It is not close. This variant carries about 15% higher odds; smoking is the dominant cause of bladder cancer. The genetics here is interesting; the cigarette is the risk factor.
Blood in the urine — even once, even painless, even if it goes away. It has many causes, most of them not cancer, and all of them are better found than assumed.
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