Kate Walker

Novel Breast Cancer Susceptibility Locus at 9q31.2: Results of a Genome-Wide Association Study

BACKGROUND Genome-wide association studies have identified several common genetic variants associated with breast cancer risk. It is likely, however, that a substantial proportion of such loci have not yet been discovered. METHODS We compared 296,114 tagging single-nucleotide polymorphisms in 1694 breast cancer case subjects (92% with two primary cancers or at least two affected first-degree relatives) and 2365 control subjects, with validation in three independent series totaling 11,880 case subjects and 12,487 control subjects. Odds ratios (ORs) and associated 95% confidence intervals (CIs) in each stage and all stages combined were calculated using unconditional logistic regression. Heterogeneity was evaluated with Cochran Q and I(2) statistics. All statistical tests were two-sided. RESULTS We identified a novel risk locus for breast cancer at 9q31.2 (rs865686: OR = 0.89, 95% CI = 0.85 to 0.92, P = 1.75 × 10(-10)). This single-nucleotide polymorphism maps to a gene desert, the nearest genes being Kruppel-like factor 4 (KLF4, 636 kb centromeric), RAD23 homolog B (RAD23B, 794 kb centromeric), and actin-like 7A (ACTL7A, 736 kb telomeric). We also identified two variants (rs3734805 and rs9383938) mapping to 6q25.1 estrogen receptor 1 (ESR1), which were associated with breast cancer in subjects of northern European ancestry (rs3734805: OR = 1.19, 95% CI = 1.11 to 1.27, P = 1.35 × 10(-7); rs9383938: OR = 1.18, 95% CI = 1.11 to 1.26, P = 1.41 × 10(-7)). A variant mapping to 10q26.13, approximately 300 kb telomeric to the established risk locus within the second intron of FGFR2, was also associated with breast cancer risk, although not at genome-wide statistical significance (rs10510102: OR = 1.12, 95% CI = 1.07 to 1.17, P = 1.58 × 10(-6)). CONCLUSIONS These findings provide further evidence on the role of genetic variation in the etiology of breast cancer. Fine mapping will be needed to identify causal variants and to determine their functional effects.

The maternal age-specific live birth prevalence of trisomies 13 and 18 compared to trisomy 21 (Down syndrome).

To estimate the maternal age‐specific live birth prevalence (in the absence of prenatal diagnosis and selective termination) of trisomy 13 (Patau syndrome) and trisomy 18 (Edwards syndrome) and compare it with that of trisomy 21 (Down syndrome).

Premenopausal Mammographic Density in Relation to Cyclic Variations in Endogenous Sex Hormone Levels, Prolactin, and Insulin-like Growth Factors

Mammographic density is strongly associated with breast cancer risk, and endogenous hormones, which are risk factors for breast cancer, may be involved in the mechanism. This cross-sectional study of 494 premenopausal women is the first to account for cyclic variations in estrogen levels, by measuring urinary estrone glucuronide (E1G) in the periovulatory and luteal phases of the menstrual cycle, and to assess the role of androgens. Computer-assisted density readings were obtained from digitized mammograms. Mean ovulatory E1G level and daily E1G load were both positively associated with percent density before adjustment for body mass index (BMI), with women in the top fourth having 10.2% (95% CI: 2.9%, 18.1%) and 8.9% (1.7%, 16.7%), respectively, higher density than those in the bottom fourth (Ptrend before/after BMI adjustment=0.006/0.11 and 0.01/0.13, respectively). Neither the peak nor luteal E1G levels were predictive of density after adjustment for E1G levels at other points in the cycle. The plasma androgens testosterone, androstenedione, and dehydroepiandrosterone sulfate were negatively associated with density. In mutually adjusted analyses, density was positively associated with insulin-like growth factor (IGF)-I and negatively with IGF-II (Ptrend=0.006 for both) but not with IGF binding protein-3. There was also weak evidence of a positive association of prolactin with density. The study supports the hypothesis that endogenous hormones affect density in premenopausal women; in particular, it shows a positive association between estrogen levels and density and suggests that the mean level throughout the cycle is the most biologically relevant measure. Most of these hormone-density associations were attenuated with further adjustment for BMI.

Prenatal screening for serious congenital heart defects using nuchal translucency: a meta-analysis.

To assess the performance of nuchal translucency (NT) measurements in screening for congenital heart defects (CHD) which would benefit from prenatal detection.

CYP3A Variation, Premenopausal Estrone Levels, and Breast Cancer Risk

BACKGROUND Epidemiological studies have provided strong evidence for a role of endogenous sex steroids in the etiology of breast cancer. Our aim was to identify common variants in genes involved in sex steroid synthesis or metabolism that are associated with hormone levels and the risk of breast cancer in premenopausal women. METHODS We measured urinary levels of estrone glucuronide (E1G) using a protocol specifically developed to account for cyclic variation in hormone levels during the menstrual cycle in 729 healthy premenopausal women. We genotyped 642 single-nucleotide polymorphisms (SNPs) in these women; a single SNP, rs10273424, was further tested for association with the risk of breast cancer using data from 10 551 breast cancer case patients and 17 535 control subjects. All statistical tests were two-sided. RESULTS rs10273424, which maps approximately 50 kb centromeric to the cytochrome P450 3A (CYP3A) gene cluster at chromosome 7q22.1, was associated with a 21.8% reduction in E1G levels (95% confidence interval [CI] = 27.8% to 15.3% reduction; P = 2.7 × 10(-9)) and a modest reduction in the risk of breast cancer in case patients who were diagnosed at or before age 50 years (odds ratio [OR] = 0.91, 95% CI = 0.83 to 0.99; P = .03) but not in those diagnosed after age 50 years (OR = 1.01, 95% CI = 0.93 to 1.10; P = .82). CONCLUSIONS Genetic variation in noncoding sequences flanking the CYP3A locus contributes to variance in premenopausal E1G levels and is associated with the risk of breast cancer in younger patients. This association may have wider implications given that the most predominantly expressed CYP3A gene, CYP3A4, is responsible for metabolism of endogenous and exogenous hormones and hormonal agents used in the treatment of breast cancer.

Mammographic density and markers of socioeconomic status: a cross-sectional study

BackgroundSocioeconomic status (SES) is known to be positively associated with breast cancer risk but its relationship with mammographic density, a marker of susceptibility to breast cancer, is unclear. This study aims to investigate whether mammographic density varies by SES and to identify the underlying anthropometric, lifestyle and reproductive factors leading to such variation.MethodsIn a cross-sectional study of mammographic density in 487 pre-menopausal women, SES was assessed from questionnaire data using highest achieved level of formal education, quintiles of Census-derived Townsend scores and urban/rural classification of place of residence. Mammographic density was measured on digitised films using a computer-assisted method. Linear regression models were fitted to assess the association between SES variables and mammographic density, adjusting for correlated variables.ResultsIn unadjusted models, percent density was positively associated with SES, with an absolute difference in percent density of 6.3% (95% CI 1.6%, 10.5%) between highest and lowest educational categories, and of 6.6% (95% CI -0.7%, 12.9%) between highest and lowest Townsend quintiles. These associations were mainly driven by strong negative associations between these SES variables and lucent area and were attenuated upon adjustment for body mass index (BMI). There was little evidence that reproductive factors explained this association. SES was not associated with the amount of dense tissue in the breast before or after BMI adjustment. The effect of education on percent density persisted after adjustment for Townsend score. Mammographic measures did not vary according to urban/rural place of residence.ConclusionsThe observed SES gradients in percent density paralleled known SES gradients in breast cancer risk. Although consistent with the hypothesis that percent density may be a mediator of the SES differentials in breast cancer risk, the SES gradients in percent density were mainly driven by the negative association between SES and BMI. Nevertheless, as density affects the sensitivity of screen-film mammography, the higher percent density found among high SES women would imply that these women have a higher risk of developing cancer but a lower likelihood of having it detected earlier.

The H(2) S test versus standard indicator bacteria tests for faecal contamination of water: systematic review and meta-analysis.

Objectives  To assess the diagnostic accuracy of the H2S test for microbiological contamination of domestic water across different settings, as a basis for providing guidance on its use.

Identifying patients at risk of emergency admission for colorectal cancer.

Background:Patients whose colorectal cancer is treated after an emergency admission tend to have late-stage cancer and a poor prognosis. We identified risk factors for an emergency admission by linking data from the National Bowel Cancer Audit (NBCA) and the English Hospital Episode Statistics (HES), an administrative database of all admissions to English National Health Service hospitals, which includes data on mode of admission.Methods:We identified all adults included in the NBCA with a primary diagnosis of bowel cancer, excluding cancer of the appendix, between August 2007 and July 2011 whose record could be linked to HES. Multivariable logistic regression was used to estimate adjusted odds ratios (OR) for an emergency admission for colorectal cancer. All risk factors were adjusted for cancer site and calendar year.Results:97 909 adults were identified with a primary diagnosis of bowel cancer and 82 777 patients could be linked to HES. Patients who were older, female, of a non-white ethnic background, and more socioeconomically deprived, and those with dementia or cardiac, neurologic and liver disease had an increased risk of presenting as an emergency admission. The strongest risk factors were age (90 compared with 70 years: OR 2.99, 95% CI 2.84 to 3.15), dementia (OR 2.46, 2.18 to 2.79), and liver disease (OR 1.87, 1.69 to 2.08).Conclusions:Our study identifies risk factors that may impair health-seeking behaviour and access to healthcare. An earlier recognition of symptoms in patients with these risk factors may contribute to better outcomes.

Model for risk adjustment of postoperative mortality in patients with colorectal cancer

A model was developed for risk adjustment of postoperative mortality in patients with colorectal cancer in order to make fair comparisons between healthcare providers. Previous models were derived in relatively small studies with the use of suboptimal modelling techniques.

A synthesis of convenience survey and other data to estimate undiagnosed HIV infection among men who have sex with men in England and Wales

BACKGROUND Hard-to-reach population subgroups are typically investigated using convenience sampling, which may give biased estimates. Combining information from such surveys, a probability survey and clinic surveillance, can potentially minimize the bias. We developed a methodology to estimate the prevalence of undiagnosed HIV infection among men who have sex with men (MSM) in England and Wales aged 16-44 years in 2003, making fuller use of the available data than earlier work. METHODS We performed a synthesis of three data sources: genitourinary medicine clinic surveillance (11 380 tests), a venue-based convenience survey including anonymous HIV testing (3702 MSM) and a general population sexual behaviour survey (134 MSM). A logistic regression model to predict undiagnosed infection was fitted to the convenience survey data and then applied to the MSMs in the population survey to estimate the prevalence of undiagnosed infection in the general MSM population. This estimate was corrected for selection biases in the convenience survey using clinic surveillance data. A sensitivity analysis addressed uncertainty in our assumptions. RESULTS The estimated prevalence of undiagnosed HIV in MSM was 2.4% [95% confidence interval (95% CI 1.7-3.0%)], and between 1.6% (95% CI 1.1-2.0%) and 3.3% (95% CI 2.4-4.1%) depending on assumptions; corresponding to 5500 (3390-7180), 3610 (2180-4740) and 7570 (4790-9840) men, and undiagnosed fractions of 33, 24 and 40%, respectively. CONCLUSIONS Our estimates are consistent with earlier work that did not make full use of data sources. Reconciling data from multiple sources, including probability-, clinic- and venue-based convenience samples can reduce bias in estimates. This methodology could be applied in other settings to take full advantage of multiple imperfect data sources.