Woolmanhill Hospital

IMPORTANCE: Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists. OBJECTIVE: To identify mutation-specific cancer risks for carriers of BRCA1/2. DESIGN, SETTING, AND PARTICIPANTS: Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19,581 carriers of BRCA1 mutations and 11,900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk. EXPOSURES: Mutations of BRCA1 or BRCA2. MAIN OUTCOMES AND MEASURES: Breast and ovarian cancer risks. RESULTS: Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95% CI, 1.22-1.74; P = 2 × 10(-6)), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95% CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95% CI, 1.22-1.55; P = 6 × 10(-9)). We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95% CI, 0.56-0.70; P = 9 × 10(-17)). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95% CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1'; RHR = 1.63; 95% CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95% CI, 1.69-3.16; P = .00002). We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95% CI, 0.44-0.60; P = 6 × 10(-17)). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95% CI, 0.41-0.80; P = .001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers. CONCLUSIONS AND RELEVANCE: Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations.

Succinate dehydrogenase B (SDHB) and D (SDHD) subunit gene mutations predispose to adrenal and extraadrenal pheochromocytomas, head and neck paragangliomas (HNPGL), and other tumor types. We report tumor risks in 358 patients with SDHB (n=295) and SDHD (n=63) mutations. Risks of HNPGL and pheochromocytoma in SDHB mutation carriers were 29% and 52%, respectively, at age 60 years and 71% and 29%, respectively, in SDHD mutation carriers. Risks of malignant pheochromocytoma and renal tumors (14% at age 70 years) were higher in SDHB mutation carriers; 55 different mutations (including a novel recurrent exon 1 deletion) were identified. No clear genotype-phenotype correlations were detected for SDHB mutations. However, SDHD mutations predicted to result in loss of expression or a truncated or unstable protein were associated with a significantly increased risk of pheochromocytoma compared to missense mutations that were not predicted to impair protein stability (most such cases had the common p.Pro81Leu mutation). Analysis of the largest cohort of SDHB/D mutation carriers has enhanced estimates of penetrance and tumor risk and supports in silicon protein structure prediction analysis for functional assessment of mutations. The differing effect of the SDHD p.Pro81Leu on HNPGL and pheochromocytoma risks suggests differing mechanisms of tumorigenesis in SDH-associated HNPGL and pheochromocytoma.

Screening programs using retinal photography for the detection of diabetic eye disease are being introduced in the UK and elsewhere. Automatic grading of the images is being considered by health boards so that the human grading task is reduced. Microaneurysms (MAs) are the earliest sign of this disease and so are very important for classifying whether images show signs of retinopathy. This paper describes automatic methods for MA detection and shows how image contrast normalization can improve the ability to distinguish between MAs and other dots that occur on the retina. Various methods for contrast normalization are compared. Best results were obtained with a method that uses the watershed transform to derive a region that contains no vessels or other lesions. Dots within vessels are handled successfully using a local vessel detection technique. Results are presented for detection of individual MAs and for detection of images containing MAs. Images containing MAs are detected with sensitivity 85.4% and specificity 83.1%.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist.

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CONTEXT: Observational studies show an association between low vitamin D status assessed by circulating 25-hydroxyvitamin D and cardiovascular events and mortality. Data from randomized controlled trials are limited. OBJECTIVE: The aim of this study was to test whether daily doses of vitamin D(3) at 400 or 1000 IU/d for 1 yr affected conventional markers of cardiovascular disease (CVD) risk. DESIGN: We conducted a parallel-group, double-blind, placebo-controlled randomized controlled trial. Randomization was computer generated. Participants and study investigators were blinded to intervention groupings throughout the trial. SETTING: The study was conducted at the Clinical Research Facility, University of Aberdeen, United Kingdom. PARTICIPANTS: A total of 305 healthy postmenopausal women aged 60-70 yr were recruited for the study. INTERVENTION: Each woman received a daily capsule of 400 or 1000 IU vitamin D(3) or placebo randomly allocated. MAIN OUTCOME MEASURES: Primary outcomes were serum lipid profile [total, high-density lipoprotein, and low-density lipoprotein cholesterol; triglycerides; and apolipoproteins A-1 and B100], insulin resistance (homeostatic model assessment), inflammatory biomarkers (high-sensitivity C-reactive protein, IL-6, soluble intracellular adhesion molecule-1), and blood pressure. RESULTS: A total of 265 (87%) participants completed all study visits. Small differences between groups for serum apolipoprotein B100 change [repeated measures ANOVA, P=0.04; mean (sd), -1.0 (10.0) mg/dl (400 IU); -1.0 (10.0) mg/dl (1000 IU); and +0.02 (10.0) mg/dl (placebo)] were not considered clinically significant. Other systemic markers for CVD risk remained unchanged. There was significant seasonal variation in systolic and diastolic blood pressure independent of vitamin D dose (P<0.001, linear mixed model). Mean (sd) reduction in systolic blood pressure from winter to summer was -6.6 (10.8) mm Hg. CONCLUSIONS: Improving vitamin D status through dietary supplementation is unlikely to reduce CVD risk factors. Confounding of seasonality should be recognized and addressed in future studies of vitamin D.

Screening programmes for diabetic retinopathy are being introduced in the United Kingdom and elsewhere. These require large numbers of retinal images to be manually graded for the presence of disease. Automation of image grading would have a number of benefits. However, an important prerequisite for automation is the accurate location of the main anatomical features in the image, notably the optic disc and the fovea. The locations of these features are necessary so that lesion significance, image field of view and image clarity can be assessed. This paper describes methods for the robust location of the optic disc and fovea. The elliptical form of the major retinal blood vessels is used to obtain approximate locations, which are refined based on the circular edge of the optic disc and the local darkening at the fovea. The methods have been tested on 1056 sequential images from a retinal screening programme. Positional accuracy was better than 0.5 of a disc diameter in 98.4% of cases for optic disc location, and in 96.5% of cases for fovea location. The methods are sufficiently accurate to form an important and effective component of an automated image grading system for diabetic retinopathy screening.

AIMS/HYPOTHESIS: Current drug labels for thiazolidinediones (TZDs) warn of increased fractures, predominantly for distal fractures in women. We examined whether exposure to TZDs affects hip fracture in women and men and compared the risk to that found with other drugs used in diabetes. METHODS: Using a nationwide database of prescriptions, hospital admissions and deaths in those with type 2 diabetes in Scotland we calculated TZD exposure among 206,672 individuals. Discrete-time failure analysis was used to model the effect of cumulative drug exposure on hip fracture during 1999-2008. RESULTS: There were 176 hip fractures among 37,479 exposed individuals. Hip fracture risk increased with cumulative exposure to TZD: OR per year of exposure 1.18 (95% CI 1.09, 1.28; p = 3 × 10(-5)), adjusted for age, sex and calendar month. Hip fracture increased with cumulative exposure in both men (OR 1.20; 95% CI 1.03, 1.41) and women (OR 1.18; 95% CI 1.07, 1.29) and risks were similar for pioglitazone (OR 1.18) and rosiglitazone (OR 1.16). The association was similar when adjusted for exposure to other drugs for diabetes and for other potential confounders. There was no association of hip fracture with cumulative exposure to sulfonylureas, metformin or insulin in this analysis. The 90-day mortality associated with hip fractures was similar in ever-users of TZD (15%) and in never-users (13%). CONCLUSIONS/INTERPRETATION: Hip fracture is a severe adverse effect with TZDs, affecting both sexes; labels should be changed to warn of this. The excess mortality is at least as much as expected from the reported association of pioglitazone with bladder cancer.

Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p<0.05 in the combined analysis. Four of the five genes for which strongest evidence of association was observed were DNA glycosylases. The strongest evidence was for rs1466785 in the NEIL2 (endonuclease VIII-like 2) gene (HR: 1.09, 95% CI (1.03-1.16), p = 2.7 × 10(-3)) for association with breast cancer risk in BRCA2 mutation carriers, and rs2304277 in the OGG1 (8-guanine DNA glycosylase) gene, with ovarian cancer risk in BRCA1 mutation carriers (HR: 1.12 95%CI: 1.03-1.21, p = 4.8 × 10(-3)). DNA glycosylases involved in the first steps of the BER pathway may be associated with cancer risk in BRCA1/2 mutation carriers and should be more comprehensively studied.

INTRODUCTION: Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour. METHODS: We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach. RESULTS: The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, single nucleotide polymorphism (SNP) rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, P-heterogeneity = 6.5 × 10-6). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and 1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status. CONCLUSIONS: The associations of the 12 SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models may improve clinical management for mutation carriers.

The inverse relation between osteoporosis and osteoarthritis has long been considered in the literature. This review looks at current evidence to support this relation, concentrating on studies published since 1998. The review also summarizes previous large studies investigating this relation. Recent studies indicate higher bone mineral density as measured by dual energy x-ray absorptiometry in subjects with osteoarthritis at a distant site, but suggest less association with hand osteoarthritis. Genetic work has sought to explain this association and this too is discussed. There is some indication that a higher bone density may not protect against fracture in these subjects, due to the increased risk of falls.

OBJECTIVE: Periarticular osteoporosis is one of the first radiological signs of rheumatoid arthritis (RA). Osteoporosis is now quantified using dual-energy X-ray absorptiometry (DXA), although it was originally assessed by radiogrammetry. A new updated system of radiogrammetry has been developed: digitized X-ray radiogrammetry (DXR). We used this DXR system to identify whether changes seen in hand X-rays of RA patients can predict those who subsequently develop erosions. METHODS: We enrolled 24 patients with early RA and they attended for hand radiographs at baseline, 12, 24 and 48 months. The hand radiographs were analysed using a Pronosco X-Posure system which measures bone mineral density, and other parameters using DXR. DXA of the hand was also performed to measure bone mineral density. Sharp and Larsen radiographic scores were calculated and other disease activity markers were measured. RESULTS: DXR bone mineral density fell significantly throughout the study. The group of RA subjects were divided according to the change in erosive status. Change in DXR bone mineral density after 1 yr was very specific (100%) and highly sensitive (63%) in predicting those who either became erosive or whose erosions significantly worsened. In contrast, of the other disease activity markers, only baseline ESR (sensitivity 67%, specificity 80%) significantly predicted the erosive status of subjects at 4 yr. CONCLUSION: Computerized radiogrammetry from digitized images can predict at 1 yr those patients with RA who will become erosive at 4 yr. A larger prospective study is required to confirm these findings; however, these results show some promise as a method of targeting those patients who require more aggressive, expensive therapy.

INTRODUCTION: Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 (ZNF365), rs704010 (ZMIZ1), rs2380205 (10p15), rs614367 (11q13), rs1292011 (12q24), rs10771399 (12p11 near PTHLH) and rs865686 (9q31.2). METHODS: To evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12,599 BRCA1 and 7,132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework. RESULTS: Only SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele hazard ratio (HR) = 0.87, 95% CI: 0.81 to 0.94, P-trend = 3 × 10-4). The association was restricted to mutations proven or predicted to lead to absence of protein expression (HR = 0.82, 95% CI: 0.74 to 0.90, P-trend = 3.1 × 10-5, P-difference = 0.03). Four SNPs were associated with the risk of breast cancer for BRCA2 mutation carriers: rs10995190, P-trend = 0.015; rs1011970, P-trend = 0.048; rs865686, 2df-P = 0.007; rs1292011 2df-P = 0.03. rs10771399 (PTHLH) was predominantly associated with estrogen receptor (ER)-negative breast cancer for BRCA1 mutation carriers (HR = 0.81, 95% CI: 0.74 to 0.90, P-trend = 4 × 10-5) and there was marginal evidence of association with ER-negative breast cancer for BRCA2 mutation carriers (HR = 0.78, 95% CI: 0.62 to 1.00, P-trend = 0.049). CONCLUSIONS: The present findings, in combination with previously identified modifiers of risk, will ultimately lead to more accurate risk prediction and an improved understanding of the disease etiology in BRCA1 and BRCA2 mutation carriers.

Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide association study in Europeans identified two further breast cancer susceptibility variants: rs11249433 at 1p11.2 and rs999737 in RAD51L1 at 14q24.1. Although previously identified breast cancer susceptibility variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers, the involvement of these SNPs to breast cancer susceptibility in mutation carriers is currently unknown. To address this, we genotyped these SNPs in BRCA1 and BRCA2 mutation carriers from 42 studies from the Consortium of Investigators of Modifiers of BRCA1/2. In the analysis of 14 123 BRCA1 and 8053 BRCA2 mutation carriers of European ancestry, the 6q25.1 SNPs (r(2) = 0.14) were independently associated with the risk of breast cancer for BRCA1 mutation carriers [hazard ratio (HR) = 1.17, 95% confidence interval (CI): 1.11-1.23, P-trend = 4.5 × 10(-9) for rs2046210; HR = 1.28, 95% CI: 1.18-1.40, P-trend = 1.3 × 10(-8) for rs9397435], but only rs9397435 was associated with the risk for BRCA2 carriers (HR = 1.14, 95% CI: 1.01-1.28, P-trend = 0.031). SNP rs11249433 (1p11.2) was associated with the risk of breast cancer for BRCA2 mutation carriers (HR = 1.09, 95% CI: 1.02-1.17, P-trend = 0.015), but was not associated with breast cancer risk for BRCA1 mutation carriers (HR = 0.97, 95% CI: 0.92-1.02, P-trend = 0.20). SNP rs999737 (RAD51L1) was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers (P-trend = 0.27 and 0.30, respectively). The identification of SNPs at 6q25.1 associated with breast cancer risk for BRCA1 mutation carriers will lead to a better understanding of the biology of tumour development in these women.

AIMS: To assess compliance with Department of Health guidelines on weaning practice in a representative sample of 127 infants from Glasgow, and to identify factors influencing timing of weaning. METHODS: Questionnaires on feeding and weaning were completed during home visits. Ninety eight mothers completed a further questionnaire on attitudes to weaning. RESULTS: Median age at introduction of solid food was 11 weeks (range 4-35 weeks); only 7% of infants had not been weaned before age 4 months. There was no difference in timing of weaning between boys and girls. Younger mothers (< 20 years old), those of lower socioeconomic status, and those who formula fed their infants tended to introduce solids earlier. Infants who were heaviest before weaning were weaned earlier. Seventy three of 98 mothers reported that they weaned their babies because they felt that they required more food. Sources of information influencing time of weaning were previous experience (53/98), books and leaflets (43/98), advice from the health visitor (31/98), and family and friends (15/98). Sixty five of 98 mothers reported receiving formal information on weaning, in most cases (54) this was from the health visitor. Mothers who received formal information tended to wean their infants later. Two per cent of infants had been given cow's milk as a main drink by age 6 months, 17% by 9 months, and 45% by the end of the first year. CONCLUSION: Compliance with recommendations on timing of weaning (not before 4 months), weaning foods, and cow's milk consumption in Glasgow is poor, although no poorer than in many other areas of the UK as found by Office of Population, Censuses and Surveys. Public health messages in relation to weaning may not be reaching their target audience.

BACKGROUND: Increasing prevalence of diabetes worldwide is projected to lead to an increase in patients with end-stage renal disease (ESRD) requiring renal replacement therapy (RRT). AIM: To provide contemporary estimates of the prevalence of ESRD and requirement for RRT among people with diabetes in a nationwide study and to report associated survival. METHODS: Data were extracted and linked from three national databases: Scottish Renal Registry, Scottish Care Initiative-Diabetes Collaboration and National Records of Scotland death data. Survival analyses were modelled with Cox regression. RESULTS: Point prevalence of chronic kidney disease (CKD)5 in 2008 was 1.63% of 19 414 people with type 1 diabetes (T1DM) compared with 0.58% of 167 871 people with type 2 diabetes (T2DM) (odds ratio for DM type 0.97, P = 0.77, on adjustment for duration. Although 83% of those with T1DM and CKD5 and 61% of those with T2DM and CKD5 were receiving RRT, there was no difference when adjusted for age, sex and DM duration (odds ratio for DM type 0.83, P = 0.432). Diabetic nephropathy was the primary renal diagnosis in 91% of people with T1DM and 58% of people with T2DM on RRT. Median survival time from initiation of RRT was 3.84 years (95% CI 2.77, 4.62) in T1DM and 2.16 years (95% CI: 1.92, 2.38) in T2DM. CONCLUSION: Considerable numbers of patients with diabetes continue to progress to CKD5 and RRT. Almost half of all RRT cases in T2DM are considered to be due to conditions other than diabetic nephropathy. Median survival time for people with diabetes from initiation of RRT remains poor. These prevalence data are important for future resource planning.

Few year-long vitamin D supplementation trials exist that match seasonal changes. The aim of this study was to determine whether daily oral vitamin D3 at 400 IU or 1000 IU compared with placebo affects annual bone mineral density (BMD) change in postmenopausal women in a 1-year double-blind placebo controlled trial in Scotland. White women aged 60 to 70 years (n = 305) were randomized to one of two doses of vitamin D or placebo. All participants started simultaneously in January/February 2009, attending visits at bimonthly intervals with 265 (87%) women attending the final visit and an additional visit 1 month after treatment cessation. BMD (Lunar iDXA) and 1,25-dihydroxyvitamin D[1,25(OH)2 D], N-terminal propeptide of type 1 collagen [P1NP], C-terminal telopeptide of type I collagen [CTX], and fibroblast growth factor-23 [FGF23] were measured by immunoassay at the start and end of treatment. Circulating PTH, serum Ca, and total 25-hydroxyvitamin D [25(OH)D] (latter by tandem mass spectrometry) were measured at each visit. Mean BMD loss at the hip was significantly less for the 1000 IU vitamin D group (0.05% ± 1.46%) compared with the 400 IU vitamin D or placebo groups (0.57% ± 1.33% and 0.60% ± 1.67%, respectively) (p < 0.05). Mean (± SD) baseline 25(OH)D was 33.8 ± 14.6 nmol/L; comparative 25(OH)D change for the placebo, 400 IU, and 1000 IU vitamin D groups was -4.1 ± 11.5 nmol/L, +31.6 ± 19.8 nmol/L, and +42.6 ± 18.9 nmol/L, respectively. Treatment did not change markers of bone metabolism, except for a small reduction in PTH and an increase in serum calcium (latter with 1000 IU dose only). The discordance between the incremental increase in 25(OH)D between the 400 IU and 1000 IU vitamin D and effect on BMD suggests that 25(OH)D may not accurately reflect clinical outcome, nor how much vitamin D is being stored.

A pencil beam Hologic QDR 1000W scanner (1000), a fan beam QDR 4500A scanner (4500) and a fan beam Lunar Expert scanner (Expert) were compared for bone mineral and body composition measurement accuracy. Phantoms were scanned with each instrument to assess magnification effects and to compare calibrations for bone mineral and fat proportion. 41 volunteers were scanned with both the 1000 and the 4500, and 21 patients with both the 4500 and the Expert. The height of a bone within the body affected the measured bone mineral content (BMC) and, to a lesser extent, the bone mineral density (BMD). There were differences in calibration against recognized standards for fat proportion between the three instruments. The 1000 underestimated low fat proportions and the 4500 underestimated high fat proportions. Fat results for the Expert were closer to nominal values. Comparisons on volunteers showed that measured mean total body BMD was 4% higher and BMC was 7% higher with the 1000 compared with the 4500; some regional differences were greater. Mean values of per cent fat were equal, but the total and regional regression coefficients were well above unity. Mean BMD was 3% higher and mean BMC was 10% higher with the Expert compared with the 4500, but most regression coefficients for these comparisons were less than unity. Mean values of per cent fat were equal, but regression coefficients were above unity. Errors due to magnification are acceptable. Differences between the instruments are appreciable, but can be accommodated by cross-calibration.

INTRODUCTION: More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers. METHODS: We used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement. RESULTS: The estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive associations in the general population (intraclass correlation (ICC) = 0.61, 95% confidence interval (CI): 0.45 to 0.74), and the same was true when considering ER-negative associations in both groups (ICC = 0.59, 95% CI: 0.42 to 0.72). Similarly, there was strong correlation between the ER-positive associations for BRCA1 and BRCA2 carriers (ICC = 0.67, 95% CI: 0.52 to 0.78), whereas ER-positive associations in any one of the groups were generally inconsistent with ER-negative associations in any of the others. After stratifying by ER status in mutation carriers, additional significant associations were observed. Several previously unreported variants exhibited associations at P <10(-6) in the analyses by PR status, HER2 status, TN phenotype, morphologic subtypes, histological grade and nodal involvement. CONCLUSIONS: Differences in associations of common BC susceptibility alleles between BRCA1 and BRCA2 carriers and the general population are explained to a large extent by differences in the prevalence of ER-positive and ER-negative tumors. Estimates of the risks associated with these variants based on population-based studies are likely to be applicable to mutation carriers after taking ER status into account, which has implications for risk prediction.

Infantile juvenile polyposis is a rare disease with severe gastrointestinal symptoms and a grave clinical course. Recently, 10q23 microdeletions involving the PTEN and BMPR1A genes were found in four patients with infantile juvenile polyposis. It was hypothesized that a combined and synergistic effect of the deletion of both genes would explain the condition. Subsequently, however, a patient with a larger 10q23 deletion including the same genes but with a mild clinical phenotype was identified. Here, we present four additional patients with 10q23 microdeletions involving the PTEN and BMPR1A genes. The sizes of the deletions were analyzed using single nucleotide polymorphism array analysis. All patients had macrocephaly, dysmorphic features, retardation and congenital abnormalities. One patient developed colorectal cancer. However, only one case had disease onset before 2 years of age and severe symptoms requiring colectomy. No clear correlation was found between ages at onset or severity of gastrointestinal symptoms and the sizes of the deletions. We conclude that patients with 10q23 microdeletions involving the PTEN and BMPR1A genes have variable clinical phenotypes, which cannot be explained merely by the deletion sizes. The phenotypes are not restricted to severe infantile juvenile polyposis but include childhood-onset cases with macrocephaly, retardation, mild gastrointestinal symptoms and possibly early-onset colorectal cancer.