Breakthrough Generations Research Articles

What Applied Physical Chemistry Can Contribute to Understanding Cancer: Toward the Next Generation of Breakthroughs

What Applied Physical Chemistry Can Contribute to Understanding Cancer: Toward the Next Generation of Breakthroughs

Modeling the Solid Electrolyte Interphase: Machine Learning as a Game Changer?

AbstractThe solid electrolyte interphase (SEI) is a complex passivation layer that forms in situ on many battery electrodes such as lithium‐intercalated graphite or lithium metal anodes. Its essential function is to prevent the electrolyte from continuous electrochemical degradation, while simultaneously allowing ions to pass through, thus constituting an electronically insulating, but ionically conducting material. Its properties crucially affect the overall performance and aging of a battery cell. Despite decades of intense research, understanding the SEI's precise formation mechanism, structure, composition, and evolution remains a conundrum. State‐of‐the‐art computational modeling techniques are powerful tools to gain additional insights, although confronted with a trade‐off between accuracy and accessible time‐ and length scales. In this review, it is discussed how recent advances in data‐driven models, especially the development of fast and accurate surrogate simulators and deep generative models, can work with physics‐based and physics‐informed approaches to enable the next generation of breakthroughs in this field. Machine learning‐enhanced multiscale models can provide new pathways to inverse the design of interphases with desired properties.

Knowledge Development Approaches and Breakthrough Innovations in Technology‐Based New Firms

Compared to large established firms, technology‐based new firms (TBNF) seem well placed to produce breakthrough innovations although questions remain as to their adeptness at subsequent exploitation. Building on the innovation and strategy literatures, the study identifies two different knowledge‐development approaches or modes (business models) in TBNFs—internal versus external—and examines their relation to breakthrough innovation and subsequent progression of the product to market. The internal mode assembles knowledge inside the firm to generate its innovations, whereas the external mode relies heavily on alliances to develop and assemble knowledge among firms embedded in a creative network. The study uses a unique panel dataset of 69 UK new biotechnology firms over an 11‐year period to explore this issue empirically. The findings show that the external knowledge‐development mode is associated with more breakthrough innovations and a faster movement of innovations to market. The externally focused mode is not impeded by its relative lack of internal knowledge; it uses partners to access, assemble, and develop a wide scope of knowledge in a flexible manner. In addition, partners provide deep domain expertise to undertake the requisite deep‐dives. In contrast, the internal mode has the huge challenge of assembling knowledge resources internally and suffers from a quicker onset of path dependence that impedes the generation of breakthroughs. This study provides a choice of business models (internal or external) that is associated with different breakthrough and speed to market performance outcomes. Going forward, policy makers and managers seeking breakthrough innovations, and speedy progression of the innovations to market should consider the potential resource efficiency of the external mode and the vital role played by collaborations—small firm versus large firm and private versus public entities.

Abstract P1-04-01: Epigenome-wide association study for breast cancer risk using whole genome and target captured bisulphite sequencing: A pooled case-control study nested in the breakthrough generations study

Abstract Background: The field of epigenetic epidemiology has rapidly advanced and recent work has discovered epigenetic markers of breast cancer risk in white blood cell (WBC) DNA. Using Epigenome-Wide Association Studies (EWAS) on the Illumina 450k methylation array, we and others have shown epigenome-wide hypomethylation (-0.2%, p<2.2x10-16) in incident breast cancer cases compared with controls in several prospective cohorts. We have proposed a mechanism that involves cancer risk exposures, lifetime and environmental events, that alter the epigenome and stably modifies an individual's cancer risk. However, more work is needed to establish the clinical utility of this observation, the underlying causes of this variation and to determine whether the 1.7% of CpG sites targeted by the 450k array are representative of the remaining 98% of the epigenome that has not yet been interrogated. Our overall aim is to identify epigenetic traits within the epigenome that are associated with the risk of developing breast cancer. Methods: We conducted an EWAS using whole genome bisulphite sequencing (WGBS) of WBC DNA from incident breast cancer cases (n=548) compared to matched controls (n=548) from a prospective cohort (Breakthrough Generations Study) using a DNA pooling approach. Eight DNA pools were prepared in sequencing libraries and sequenced on the Hiseq2500 at PE100bp reads, resulting in ~10-fold coverage per CpG, per library, across ~20 million mappable CpG sites. Each pooled sample was also analysed in triplicate on the Illumina 450k methylation array for validation. We used Agilent target capture bisulphite sequencing (TCBS) for technical validation in a subset of breast cancer cases (n=48) and matched controls (n=48), individually barcoded and sequenced on the MiSeq at PE150bp, aiming for >1000 fold coverage of 425 kb targeted sequence. Results: Interrogation of specific genomic regions showed that gene-body methylation averages tended to be hypomethylated in cases, while CpG island averages identified both hypo- and hypermethylation. We have validated the same direction of change in 40/51 CpG islands that were covered by the Illumina 450K methylation array and have developed a target capture panel for validation of 960 gene body regions and 224 CpG island regions that were identified as significantly different between cases and controls (average -11%, FDR<5%). Analysis of TCBS data is ongoing. Conclusions: Results indicate that epigenome-wide hypomethylation and methylation in specific sites, particularly gene bodies, measured in pre-diagnostic blood samples may be predictive of breast cancer risk, and may thus be useful as a risk biomarker. Citation Format: Flanagan JM, Curry E, Stirling L, Flower K, Orr N, Tomczyk K, Coulson P, Jones M, Ashworth A, Swerdlow A, Brown R, Garcia-Closas M. Epigenome-wide association study for breast cancer risk using whole genome and target captured bisulphite sequencing: A pooled case-control study nested in the breakthrough generations study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-04-01.

Length ofFMR1repeat alleles within the normal range does not substantially affect the risk of early menopause

STUDY QUESTIONIs the length of FMR1 repeat alleles within the normal range associated with the risk of early menopause?SUMMARY ANSWERThe length of repeat alleles within the normal range does not substantially affect risk of early menopause.WHAT IS KNOWN ALREADYThere is a strong, well-established relationship between length of premutation FMR1 alleles and age at menopause, suggesting that this relationship could continue into the normal range. Within the normal range, there is conflicting evidence; differences in ovarian reserve have been identified with FMR1 repeat allele length, but a recent population-based study did not find any association with age at menopause as a quantitative trait.STUDY DESIGN, SIZE, DURATIONWe analysed cross-sectional baseline survey data collected at recruitment from 2004 to 2010 from a population-based, prospective epidemiological cohort study of >110 000 women to investigate whether repeat allele length was associated with early menopause.PARTICIPANTS/MATERIALS, SETTING, METHODWe included 4333 women from the Breakthrough Generations Study (BGS), of whom 2118 were early menopause cases (menopause under 46 years) and 2215 were controls. We analysed the relationship between length of FMR1 alleles and early menopause using logistic regression with allele length as continuous and categorical variables. We also conducted analyses with the outcome age at menopause as a quantitative trait as well as appropriate sensitivity and exploratory analyses.MAIN RESULTS AND THE ROLE OF CHANCEThere was no association of the shorter or longer FMR1 allele or their combined genotype with the clinically relevant end point of early menopause in our main analysis. Likewise, there were no associations with age at menopause as a quantitative trait in our secondary analysis.LIMITATIONS, REASONS FOR CAUTIONWomen with homozygous alleles in the normal range may have undetected FMR1 premutation alleles, although there was no evidence to suggest this. We estimate minor dilution of risk of early menopause from the likely inclusion of some women with menopause at over 45 years in the early menopause cases due to age-rounding bias in self-reports.WIDER IMPLICATIONS OF THE FINDINGSThere is no robust evidence in this large study that variation within the normal range of FMR1 repeat alleles influences timing of menopause in the general population, which contradicts findings from some earlier, mainly smaller studies. The FMR1 CGG repeat polymorphism in the normal range is unlikely to contribute to genetic susceptibility to early menopause.STUDY FUNDING/COMPETING INTEREST(S)We thank Breast Cancer Now and The Institute of Cancer Research for funding the BGS. The Institute of Cancer Research acknowledges NHS funding to the NIHR Biomedical Research Centre. The study was funded by the Wellcome Trust (grant number 085943). There are no competing interests.TRIAL REGISTRATION NUMBERNot applicable.

Epigenome-wide association study reveals decreased average methylation levels years before breast cancer diagnosis.

BackgroundInterest in the potential of DNA methylation in peripheral blood as a biomarker of cancer risk is increasing. We aimed to assess whether epigenome-wide DNA methylation measured in peripheral blood samples obtained before onset of the disease is associated with increased risk of breast cancer. We report on three independent prospective nested case-control studies from the European Prospective Investigation into Cancer and Nutrition (EPIC-Italy; n = 162 matched case-control pairs), the Norwegian Women and Cancer study (NOWAC; n = 168 matched pairs), and the Breakthrough Generations Study (BGS; n = 548 matched pairs). We used the Illumina 450k array to measure methylation in the EPIC and NOWAC cohorts. Whole-genome bisulphite sequencing (WGBS) was performed on the BGS cohort using pooled DNA samples, combined to reach 50× coverage across ~16 million CpG sites in the genome including 450k array CpG sites. Mean β values over all probes were calculated as a measurement for epigenome-wide methylation.ResultsIn EPIC, we found that high epigenome-wide methylation was associated with lower risk of breast cancer (odds ratio (OR) per 1 SD = 0.61, 95 % confidence interval (CI) 0.47–0.80; −0.2 % average difference in epigenome-wide methylation for cases and controls). Specifically, this was observed in gene bodies (OR = 0.51, 95 % CI 0.38–0.69) but not in gene promoters (OR = 0.92, 95 % CI 0.64–1.32). The association was not replicated in NOWAC (OR = 1.03 95 % CI 0.81–1.30). The reasons for heterogeneity across studies are unclear. However, data from the BGS cohort was consistent with epigenome-wide hypomethylation in breast cancer cases across the overlapping 450k probe sites (difference in average epigenome-wide methylation in case and control DNA pools = −0.2 %).ConclusionsWe conclude that epigenome-wide hypomethylation of DNA from pre-diagnostic blood samples may be predictive of breast cancer risk and may thus be useful as a clinical biomarker.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-015-0104-2) contains supplementary material, which is available to authorized users.

Mitochondrial DNA Copy Number in Peripheral Blood Cells and Risk of Developing Breast Cancer.

Increased mitochondrial DNA (mtDNA) copy number in peripheral blood cells (PBC) has been associated with the risk of developing several tumor types. Here we evaluate sources of variation of this biomarker and its association with breast cancer risk in a prospective cohort study. mtDNA copy number was measured using quantitative real-time PCR on PBC DNA samples from participants in the UK-based Breakthrough Generations Study. Temporal and assay variation was evaluated in a serial study of 91 women, with two blood samples collected approximately 6-years apart. Then, associations with breast cancer risk factors and risk were evaluated in 1,108 cases and 1,099 controls using a nested case-control design. In the serial study, mtDNA copy number showed low assay variation but large temporal variation [assay intraclass correlation coefficient (ICC), 79.3%-87.9%; temporal ICC, 38.3%). Higher mtDNA copy number was significantly associated with younger age at blood collection, being premenopausal, having an older age at menopause, and never taking HRT, both in cases and controls. Based on measurements in a single blood sample taken on average 6 years before diagnosis, higher mtDNA copy number was associated with increased breast cancer risk [OR (95% CI) for highest versus lowest quartile, 1.37 (1.02-1.83); P trend = 0.007]. In conclusion, mtDNA copy number is associated with breast cancer risk and represents a promising biomarker for risk assessment. The relatively large temporal variation should be taken into account in future analyses.

Temporal stability and determinants of white blood cell DNA methylation in the breakthrough generations study.

Epigenome-wide association studies (EWAS) using measurements of blood DNA methylation are performed to identify associations of methylation changes with environmental and lifestyle exposures and disease risk. However, little is known about the variation of methylation markers in the population and their stability over time, both important factors in the design and interpretation of EWAS. We aimed to identify stable variable methylated probes (VMP), i.e., markers that are variable in the population, yet stable over time. We estimated the intraclass correlation coefficient (ICC) for each probe on the Illumina 450K methylation array in paired samples collected approximately 6 years apart from 92 participants in the Breakthrough Generations Study. We also evaluated relationships with age, reproductive and hormonal history, weight, alcohol intake, and smoking. Approximately 17% of probes had an ICC > 0.50 and were considered stable VMPs (stable-VMPs). Stable-VMPs were enriched for probes located in "shores" bordering CpG islands, and at approximately 1.3 kb downstream from the transcription start site in the transition between the unmethylated promoter and methylated gene body. Both cross-sectional and longitudinal data analyses provided strong evidence for associations between changes in methylation levels and aging. Smoking-related probes at 2q37.1 and AHRR were stable-VMPs and related to time since quitting. We also observed associations between methylation and weight changes. Our results provide support for the use of white blood cell DNA methylation as a biomarker of exposure in EWAS. Larger studies, preferably with repeated measures over time, will be required to establish associations between specific probes and exposures.

The relationship between obesity and exposure to light at night: cross-sectional analyses of over 100,000 women in the Breakthrough Generations Study.

There has been a worldwide epidemic of obesity in recent decades. In animal studies, there is convincing evidence that light exposure causes weight gain, even when calorie intake and physical activity are held constant. Disruption of sleep and circadian rhythms by exposure to light at night (LAN) might be one mechanism contributing to the rise in obesity, but it has not been well-investigated in humans. Using multinomial logistic regression, we examined the association between exposure to LAN and obesity in questionnaire data from over 100,000 women in the Breakthrough Generations Study, a cohort study of women aged 16 years or older who were living in the United Kingdom and recruited during 2003-2012. The odds of obesity, measured using body mass index, waist:hip ratio, waist:height ratio, and waist circumference, increased with increasing levels of LAN exposure (P < 0.001), even after adjustment for potential confounders such as sleep duration, alcohol intake, physical activity, and current smoking. We found a significant association between LAN exposure and obesity which was not explained by potential confounders we could measure. While the possibility of residual confounding cannot be excluded, the pattern is intriguing, accords with the results of animal experiments, and warrants further investigation.

Reproducibility of Estradiol and Testosterone Levels in Postmenopausal Women Over 5 Years: Results From the Breakthrough Generations Study

Prospective cohort studies examining sex hormones in relation to cancer risk have generally collected blood samples at 1 time point, with an assumption that hormone levels measured in these samples will be reliable markers of true levels at other times. In postmenopausal women, body fat is a major source of estradiol; therefore, changes in adiposity may affect the correlation of single measurements to more relevant long-term averages. To estimate the intraclass correlation coefficient (ICC) for estradiol and testosterone, we collected repeat blood samples from 119 postmenopausal women (average age = 59.4 (standard deviation, 4.7) years) from the United Kingdom during 2004-2005 and again during 2010-2011. The ICCs (adjusted for assay variation) were 0.73 (95% confidence interval: 0.63, 0.82) for total estradiol and 0.59 (95% confidence interval: 0.47, 0.72) for total testosterone. The ICCs were 3%-5% larger after adjustment for change in body mass index (weight (kg)/height (m)(2)) or leptin, which are 2 markers of change in adiposity. There was no increase in ICCs after adjustment for change in age, alcohol consumption, smoking, exercise, time between waking and blood collection, or season. The results suggest that other factors account for within-woman variation in these sex hormones.

Combined effects of endogenous sex hormone levels and mammographic density on postmenopausal breast cancer risk: results from the Breakthrough Generations Study

Background:Mammographic density and sex hormone levels are strong risk factors for breast cancer, but it is unclear whether they represent the same aetiological entity or are independent risk factors.Methods:Within the Breakthrough Generations Study cohort, we conducted a case–control study of 265 postmenopausal breast cancer cases and 343 controls with prediagnostic mammograms and blood samples. Plasma was assayed for oestradiol, testosterone and sex hormone-binding globulin (SHBG) concentrations and mammographic density assessed by Cumulus.Results:Oestradiol and testosterone were negatively and SHBG positively associated with percentage density and absolute dense area, but after adjusting for body mass index the associations remained significant only for SHBG. Breast cancer risk was independently and significantly positively associated with percentage density (P=0.002), oestradiol (P=0.002) and testosterone (P=0.007) levels. Women in the highest tertile of both density and sex hormone level were at greatest risk, with an odds ratio of 7.81 (95% confidence interval (CI): 2.89–21.1) for oestradiol and 4.57 (95% CI: 1.75–11.9) for testosterone and high density compared with those who were in the lowest tertiles. The cumulative risk of breast cancer in the highest oestradiol and density tertiles, representing 8% of controls, was estimated as 12.8% at ages 50–69 years and 19.4% at ages 20–79 years, and in the lowest tertiles was 1.7% and 4.3%, respectively. Associations of breast cancer risk with tertiles of mammographic dense area were less strong than for percentage density.Conclusions:Endogenous sex hormone levels and mammographic density are independent risk factors for postmenopausal breast cancer, which in combination can identify women who might benefit from increased frequency of screening and chemoprophylaxis.

Timing of pubertal stages and breast cancer risk: the Breakthrough Generations Study.

IntroductionBreast development and hormonal changes at puberty might affect breast cancer risk, but epidemiological analyses have focussed largely on age at menarche and not at other pubertal stages.MethodsWe investigated associations between the timing of pubertal stages and breast cancer risk using data from a cohort study of 104,931 women (Breakthrough Generations Study, UK, 2003–2013). Pubertal variables were reported retrospectively at baseline. Breast cancer risk was analysed using Cox regression models with breast cancer diagnosis as the outcome of interest, attained age as the underlying time variable, and adjustment for potentially confounding variables.ResultsDuring follow-up (mean = 4.1 years), 1094 breast cancers (including ductal carcinoma in situ) occurred. An increased breast cancer risk was associated with earlier thelarche (age when breast growth begins; HR [95% CI] = 1.23 [1.02, 1.48], 1 [referent] and 0.80 [0.69, 0.93] for ≤10, 11–12 and ≥13 years respectively), menarche (initiation of menses; 1.06 [0.93, 1.21], 1 [referent] and 0.78 [0.62, 0.99] for ≤12, 13–14 and ≥15 years), regular periods (0.99 [0.83, 1.18], 1 [referent] and 0.74 [0.59, 0.92] for ≤12, 13–14 and ≥15 years) and age reached adult height (1.25 [1.03, 1.52], 1 [referent] and 1.07 [0.87, 1.32] for ≤14, 15–16 and ≥17 years), and with increased time between thelarche and menarche (0.87 [0.65, 1.15], 1 [referent], 1.14 [0.96, 1.34] and 1.27 [1.04, 1.55] for <0, 0, 1 and ≥2 years), and shorter time between menarche and regular periods (1 [referent], 0.87 [0.73, 1.04] and 0.66 [0.50, 0.88] for 0, 1 and ≥2 years). These associations were generally similar when considered separately for premenopausal and postmenopausal breast cancer.ConclusionsBreast duct development may be a time of heightened susceptibility to risk of carcinogenesis, and greater attention needs to be given to the relation of breast cancer risk to the different stages of puberty.

Population-based estimates of the prevalence of FMR1 expansion mutations in women with early menopause and primary ovarian insufficiency

Purpose:Primary ovarian insufficiency before the age of 40 years affects 1% of the female population and is characterized by permanent cessation of menstruation. Genetic causes include FMR1 expansion mutations. Previous studies have estimated mutation prevalence in clinical referrals for primary ovarian insufficiency, but these are likely to be biased as compared with cases in the general population. The prevalence of FMR1 expansion mutations in early menopause (between the ages of 40 and 45 years) has not been published.Methods:We studied FMR1 CGG repeat number in more than 2,000 women from the Breakthrough Generations Study who underwent menopause before the age of 46 years. We determined the prevalence of premutation (55–200 CGG repeats) and intermediate (45–54 CGG repeats) alleles in women with primary ovarian insufficiency (n = 254) and early menopause (n = 1,881).Results:The prevalence of the premutation was 2.0% in primary ovarian insufficiency, 0.7% in early menopause, and 0.4% in controls, corresponding to odds ratios of 5.4 (95% confidence interval = 1.7–17.4; P = 0.004) for primary ovarian insufficiency and 2.0 (95% confidence interval = 0.8–5.1; P = 0.12) for early menopause. Combining primary ovarian insufficiency and early menopause gave an odds ratio of 2.4 (95% confidence interval = 1.02–5.8; P = 0.04). Intermediate alleles were not significant risk factors for either early menopause or primary ovarian insufficiency.Conclusion:FMR1 premutations are not as prevalent in women with ovarian insufficiency as previous estimates have suggested, but they still represent a substantial cause of primary ovarian insufficiency and early menopause.

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Intragenic ATM Methylation in Peripheral Blood DNA as a Biomarker of Breast Cancer Risk

Few studies have evaluated the association between DNA methylation in white blood cells (WBC) and the risk of breast cancer. The evaluation of WBC DNA methylation as a biomarker of cancer risk is of particular importance as peripheral blood is often available in prospective cohorts and easier to obtain than tumor or normal tissues. Here, we used prediagnostic blood samples from three studies to analyze WBC DNA methylation of two ATM intragenic loci (ATMmvp2a and ATMmvp2b) and genome-wide DNA methylation in long interspersed nuclear element-1 (LINE1) repetitive elements. Samples were from a case-control study derived from a cohort of high-risk breast cancer families (KConFab) and nested case-control studies in two prospective cohorts: Breakthrough Generations Study (BGS) and European Prospective Investigation into Cancer and Nutrition (EPIC). Bisulfite pyrosequencing was used to quantify methylation from 640 incident cases of invasive breast cancer and 741 controls. Quintile analyses for ATMmvp2a showed an increased risk of breast cancer limited to women in the highest quintile [OR, 1.89; 95% confidence interval (CI), 1.36-2.64; P = 1.64 × 10(-4)]. We found no significant differences in estimates across studies or in analyses stratified by family history or menopausal status. However, a more consistent association was observed in younger than in older women and individually significant in KConFab and BGS, but not EPIC. We observed no differences in LINE1 or ATMmvp2b methylation between cases and controls. Together, our findings indicate that WBC DNA methylation levels at ATM could be a marker of breast cancer risk and further support the pursuit of epigenome-wide association studies of peripheral blood DNA methylation.

Abstract 4045: Intragenic ATM methylation in peripheral blood DNA as a biomarker of breast cancer risk

Abstract DNA methylation is an important epigenetic modification that could affect cancer risk through direct effects on disease, and/or mediating effects of genetic and environmental factors. Global and gene-specific DNA methylation levels in white blood cells (WBC) have been related to risk of breast and other cancers, however, evidence is generally weak. We analysed WBC DNA methylation of two ATM intragenic loci (ATMmvp2a and ATMmvp2b) and genome-wide DNA methylation in LINE1 repetitive elements in three breast cancer studies with pre-diagnostic blood samples. Studies included a case-control study with cases derived from a prospective cohort of high-risk breast cancer families (KConFab), and nested case-control studies in two prospective cohorts: the Breakthrough Generations Study (BGS) and the European Prospective Investigation into Cancer and Nutrition (EPIC). Total sample size was 640 incident cases of invasive breast cancer and 741 controls. Bisulphite pyrosequencing was used to quantify methylation in WBC DNA. Quintile analyses of the combined data for ATMmvp2a showed an increased risk of breast cancer limited to women in the highest quintile of methylation (OR =1.89 (1.36-2.64), p= 1.64x10-4). We found no significant differences in estimates across studies, however, the largest differences in ATMmvp2a methylation levels were observed for familial cases in KConFab compared to controls. We observed no significant differences in LINE1 or ATMmvp2b methylation levels between cases and controls. These results indicate that WBC DNA methylation levels at ATM could be a marker of breast cancer risk and further support the pursuit of epigenome-wide association studies in peripheral blood DNA methylation. Funding: Breast Cancer Campaign Fellowship and Cancer Research UK Program C536/A6689. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4045. doi:1538-7445.AM2012-4045

Body Mass Index, Exercise, and Other Lifestyle Factors in Relation to Age at Natural Menopause: Analyses From the Breakthrough Generations Study

The authors examined the effect of women's lifestyles on the timing of natural menopause using data from a cross-sectional questionnaire used in the United Kingdom-based Breakthrough Generations Study in 2003-2011. The analyses included 50,678 women (21,511 who had experienced a natural menopause) who were 40-98 years of age at study entry and did not have a history of breast cancer. Cox competing risks proportional hazards models were fitted to examine the relation of age at natural menopause to lifestyle and anthropometric factors. Results were adjusted for age at reporting, smoking status at menopause, parity, and body mass index at age 40 years, as appropriate. All P values were 2-sided. High adult weight (P(trend) < 0.001), high body mass index (P(trend) < 0.001), weight gain between the ages of 20 and 40 years (P(trend) = 0.01), not smoking (P < 0.001), increased alcohol consumption (P(trend) < 0.001), regular strenuous exercise (P < 0.01), and not being a vegetarian (P < 0.001) were associated with older age at menopause. Neither height nor history of an eating disorder was associated with menopausal age. These findings show the importance of lifestyle factors in determining menopausal age.

Interview: An Interview with Pharmacogenomics for the Breast Cancer Special Focus Issue

Alan Ashworth speaks to Sarah Miller, Assistant Commissioning Editor Alan Ashworth joined the Institute of Cancer Research (ICR; London, UK) in 1986 as a postdoctoral scientist in the Section of Cell and Molecular Biology. He is now the Chief Executive of the ICR, a position he has held since January 2011. Prior to this, he was Director of the Breakthrough Breast Cancer Research Centre (London, UK) at the ICR, where he continues to lead the Gene Function teams’ research efforts in breast cancer genetics, genomics and therapeutics. Together with Anthony Swerdlow (ICR), he cofounded and codirects the Breakthrough Generations Study, a large and comprehensive study aimed at unraveling the mysteries of breast cancer causation. In 1995, he played a key role in the team that discovered the BRCA2 risk gene. 10 years later, he was instrumental in discovering the potential of PARP inhibitors as synthetic lethal agents in BRCA-mutated cells. In 2008, Ashworth was elected as a Fellow of the Royal Society in recognition of his work in mammalian genetics and breast cancer susceptibility genes, and he continues to be passionate about developing personalized cancer treatments.

Familial concordance for height and its components: Analyses from the breakthrough generations study

To assess familial resemblance for height, arm span, and components of these, and differences between concordance for short and tall heights. We examined whether female relatives were similar for six anthropometric measurements (height, arm span, leg, trunk and arm length, and leg:trunk length ratio). Subjects were 31,622 related individuals aged 16-102 yr participating in the UK Breakthrough Generations Study. Height and arm span were self-reported, limb and trunk length were measured in a subset (N = 508) by study investigators, and paternal height was reported by the daughter. Data were analyzed using correlations and Poisson regression. Correlation coefficients within families were 0.4 for height, 0.3 for arm span, and 0.5 for leg length, trunk length, leg:trunk ratio, and arm length. Women had a relative risk (RR) of being short (i.e., in the lowest height quintile) of 2.3 (95% confidence interval [CI] = 2.1-2.5) if their mother was short, 2.1 (95% CI = 1.9-2.3) if their father was short, and 3.7 (95% CI = 3.4-4.0) if both parents were short. RRs of being tall (i.e., in the highest height quintile) were 2.3 (95% CI = 2.1-2.5), 2.4 (95% CI = 2.2-2.6), and 4.4 (95% CI = 4.1-4.8) if their mother, father or both were tall, respectively. We have shown, for the first time, that leg:trunk length ratio and arm length aggregate within families. Concordance seemed to be stronger for tall than short heights.

The Breakthrough Generations Study: design of a long-term UK cohort study to investigate breast cancer aetiology

Background:The rationale, design, recruitment and follow-up methods are described for the Breakthrough Generations Study, a UK cohort study started in 2003, targeted at investigation of breast cancer aetiology.Methods:Cohort members have been recruited by a participant referral method intended to assemble economically a large general population cohort from whom detailed questionnaire information and blood samples can be obtained repeatedly over decades, with high completeness of follow-up and inclusion of large numbers of related individuals. ‘First-generation’ recruits were women contacted directly, or who volunteered directly, to join the study. They nominated female friends and family, whom we contacted, and those who joined (‘second generation’) nominated others, reiterated for up to 28 generations.Results:The method has successfully been used during 2003–2011 to recruit 112 049 motivated participants with a broad geographic and socioeconomic distribution, aged 16–102 years, who have completed detailed questionnaires; 92% of the participants gave blood samples at recruitment. When eligible, 2½ years after recruitment, >98% completed the first follow-up questionnaire. Thirty percent are first-degree relatives of other study members.Conclusion:The ‘generational’ recruitment method has enabled recruitment of a large cohort who appear to have the commitment to enable long-term continuing data and sample collection, to investigate the effects of changing endogenous and exogenous factors on cancer risk.