A personalised approach to prostate cancer screening based on genotyping of risk founder alleles.

BACKGROUND: To evaluate whether genotyping for 18 prostate cancer founder variants is helpful in identifying high-risk individuals and for determining optimal screening regimens. METHODS: A serum PSA level was measured and a digital rectal examination (DRE) was performed on 2907 unaffected men aged 40-90. Three hundred and twenty-three men with an elevated PSA (≥4 ng ml⁻¹) or an abnormal DRE underwent a prostate biopsy. All men were genotyped for three founder alleles in BRCA1 (5382insC, 4153delA and C61G), for four alleles in CHEK2 (1100delC, IVS2+1G>A, del5395 and I157T), for one allele in NBS1 (657del5), for one allele in HOXB13 (G84E), and for nine low-risk single-nucleotide polymorphisms (SNPs). RESULTS: On the basis of an elevated PSA or an abnormal DRE, prostate cancer was diagnosed in 135 of 2907 men (4.6%). In men with a CHEK2 missense mutation I157T, the cancer detection rate among men with an elevated PSA or an abnormal DRE was much higher (10.2%, P=0.0008). The cancer detection rate rose with the number of SNP risk genotypes observed from 1.2% for men with no variant to 8.6% for men who carried six or more variants (P=0.04). No single variant was helpful on its own in predicting the presence of prostate cancer, however, the combination of all rare mutations and SNPs improved predictive power (area under the curve=0.59; P=0.03). CONCLUSION: These results suggest that testing for germline CHEK2 mutations improves the ability to predict the presence of prostate cancer in screened men, however, the clinical utility of incorporating DNA variants in the screening process is marginal.

Long polymerase chain reaction in detection of germline deletions in the von Hippel-Lindau tumour suppressor gene.

Experimental conditions for detection of germline deletions of the von Hippel-Lindau (VHL) gene by means of long polymerase chain reaction have been established. Primers were designed to analyse the VHL gene in three overlapping fragments: 12.5 kb in length containing promoter and exons 1 and 2; 8.7kb in length containing exons 2 and 3; and 16kb in length containing exons 2 and 3 and the 3' untranslated region. Using the described procedure, it was possible to detect large deletions in four of five cases with such mutations previously detected by Southern blotting and in 5 of 11 unrelated Polish VHL patients in whom constitutional VHL gene mutations were not found by sequencing.

[Hippel-Lindau disease]. / Choroba Hippel-Lindau.

Hippel-Lindau disease is one of inherited tumour susceptibility syndromes. The most common lesions are located in central nervous system, retina and visceral organs. In Poland the disease was rarely diagnosed although the prevalence is much higher than it was supposed and is estimated as 1: 30-50,000. It is inherited in an autosomal dominant manner with age related penetrance reaching almost 98% penetrance at the age of 60 and variable expression. The VHL gene is located near the tip of the short arm of chromosome 3 (3p25-26). Classical lesions in VHL patients are: haemangioblastomas of CNS, retina, cysts and clear cell carcinoma of kidney, cysts and tumours of pancreas, phaeochromocytoma and paraganglioma, papillary cystadenoma of epididymis and endolymphatic sac tumours. Multifocal, often bilateral lesions in form of benign cysts, vascular tumours or carcinomas occur. Management of the lesions often differs from that in sporadic cases of the tumours. Non-symptomatic lesions of CNS need no treatment, neither do non-symptomatic tumours of epididymis and some of phaeochromocytomas. Kidney carcinoma is treated when it reaches a certain size preferably by nephron-sparing surgery. Special care should be provided to pregnant VHL patients. Available DNA testing enables to identify VHL carriers. Although the mean age of death in VHL patients is 41 at the moment a proper prophylactic, diagnostic and treatment management can probably prolong survival of the patients and limit complications of the disease. The coordination between genetic consultants and clinicians is crucial in the management of the patients. The authors coordinate work of Polish VHL Registry and Polish VHL Association.