The BARCODE1 Pilot: a feasibility study of using germline single nucleotide polymorphisms to target prostate cancer screening.

OBJECTIVES: To assess the feasibility and uptake of a community-based prostate cancer (PCa) screening programme selecting men according to their genetic risk of PCa. To assess the uptake of PCa screening investigations by men invited for screening. The uptake of the pilot study would guide the opening of the larger BARCODE1 study recruiting 5000 men. SUBJECTS AND METHODS: Healthy males aged 55-69 years were invited to participate via their general practitioners (GPs). Saliva samples were collected via mailed collection kits. After DNA extraction, genotyping was conducted using a study specific assay. Genetic risk was based on genotyping 130 germline PCa risk single nucleotide polymorphisms (SNPs). A polygenic risk score (PRS) was calculated for each participant using the sum of weighted alleles for 130 SNPs. Study participants with a PRS lying above the 90th centile value were invited for PCa screening by prostate magnetic resonance imaging (MRI) and biopsy. RESULTS: Invitation letters were sent to 1434 men. The overall study uptake was 26% (375/1436) and 87% of responders were eligible for study entry. DNA genotyping data were available for 297 men and 25 were invited for screening. After exclusions due to medical comorbidity/invitations declined, 18 of 25 men (72%) underwent MRI and biopsy of the prostate. There were seven diagnoses of PCa (38.9%). All cancers were low-risk and were managed with active surveillance. CONCLUSION: The BARCODE1 Pilot has shown this community study in the UK to be feasible, with an overall uptake of 26%. The main BARCODE1 study is now open and will recruit 5000 men. The results of BARCODE1 will be important in defining the role of genetic profiling in targeted PCa population screening. Patient Summary What is the paper about? Very few prostate cancer screening programmes currently exist anywhere in the world. Our pilot study investigated if men in the UK would find it acceptable to have a genetic test based on a saliva sample to examine their risk of prostate cancer development. This test would guide whether men are offered prostate cancer screening tests. What does it mean for patients? We found that the study design was acceptable: 26% of men invited to take part agreed to have the test. The majority of men who were found to have an increased genetic risk of prostate cancer underwent further tests offered (prostate MRI scan and biopsy). We have now expanded the study to enrol 5000 men. The BARCODE1 study will be important in examining whether this approach could be used for large-scale population prostate cancer screening.

Detection of low-molecular-weight proteins in urine by dipsticks.

BACKGROUND: Testing of urines with dipsticks for proteinuria, glycosuria, etc., is common practice. A deficiency with currently available dipsticks is their lack of chemical sensitivity and underestimation of low-molecular-weight proteins such as light chains. METHODS: We experimented with a number of dyes that gave an easily recognized color change on dipsticks for various low-molecular-weight proteins such as alpha-1-glycoprotein, alpha-1- and beta-2-microglobulin, and kappa and lambda light chains. We were successful in formulating a dye for impregnating dipsticks that gave a color change with low-molecular-weight proteins. RESULTS: Most dipsticks will measure proteins down to about 1 g/l. Our composite of two dyes (described here as the "TPR" dipsticks) gave reproducible results for protein concentrations of >/=300 mg/l, and detected low-molecular proteins. The TPR reagent is resistant to interferences from many compounds; also, the protein results are not altered in a given urine at a pH between 5 and 8. CONCLUSIONS: We have developed a dipstick that detects low-molecular-weight proteins. The dipsticks are easy to use and are suitable for outpatient or point-of-care testing. The precision of the dipsticks is satisfactory and is only marginally lower than quantitative spectrophotometric methods using pyrogallol red (PYR).

Implications for cancer genetics practice of pro-actively assessing family history in a General Practice cohort in North West London.

At present cancer genetics referrals are reactive to individuals asking for a referral and providing a family history thereafter. A previous pilot study in a single General Practice (GP) catchment area in North London showed a 1.5-fold increase in breast cancer risk in the Ashkenazi Jewish population compared with the non-Ashkenazi mixed population. The breast cancer incidence was equal in the Ashkenazim in both pre- and postmenopausal groups. We wanted to investigate the effect of proactively seeking family history data from the entire female population of the practice to determine the effect on cancer genetics referral. Objectives To determine the need for cancer genetics intervention for women in a single GP catchment area. (1) to determine the incidence and strength of family history of cancer in women aged over 18 in the practice, (2) to offer cancer genetics advice and determine the uptake of counselling in those with a positive family history, (3) to identify potential BRCA1/BRCA2 gene mutation carriers who can be offered clinical follow up with appropriate translational research studies. Design Population-based cohort study of one General Practice female population. Participants Three hundred and eighty-three women over the age of 18 from one General Practice who responded to a questionnaire about family history of cancer. The whole female adult GP population was the target and the total number sampled was 3,820. Results 10% of patients completed the questionnaire (n = 383). A family history of cancer was present in 338 cases, 95 went on to have genetic counselling or had previously had counselling and 47 were genetically tested. We identified three carriers of an Ashkenazi Jewish founder mutation in BRCA1. Conclusions Response rate to a family history questionnaire such as that used in genetics centres was low (10%) and other approaches will be needed to proactively assess family history. Although the Ashkenazim are present in 39% of the GP catchment area, 62% of those who returned a family history questionnaire were from this ethnic group and of those returned, 44% warranted referral to a cancer genetics unit. In the non Ashkenazim, the questionnaire return rate was 38% and 18% of those warranted referral to cancer genetics.