Publications by authors named "Laura Baglietto"

185 Publications

Association between telomere length and mitochondrial copy number and cancer risk in humans: a meta-analysis on more than 300,000 individuals.

Crit Rev Oncol Hematol 2021 Oct 22:103510. Epub 2021 Oct 22.

Department of Biology, University of Pisa, 56126, Pisa, Italy. Electronic address:

In the last decades the association of leukocyte telomere length (LTL) and mitochondrial copy number (mtDNAcn) with cancer risk has been the focus of many reports, however the relation is not yet completely understood. A meta-analysis of 112 studies including 64,184 cancer cases and 278,641 controls that analysed LTL and mtDNAcn in relation to cancer risk has been conducted to further our understanding of the topic. Stratified analyses for tumor type were also performed. Overall, no association was observed for all cancer combined neither for LTL nor mtDNAcn. Significant associations were detected for these biomarkers and specific cancer type; however, a large degree of heterogeneity was present, even within the same tumor type. Alternatives approaches based on polymorphic variants, such as polygenic risk scores and mendelian randomization, could be adopted to unravel the causal correlation of telomere length and mitochondrial copy number with cancer risk.
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http://dx.doi.org/10.1016/j.critrevonc.2021.103510DOI Listing
October 2021

Telomere Length and Male Fertility.

Int J Mol Sci 2021 Apr 12;22(8). Epub 2021 Apr 12.

Department of Biology, University of Pisa, 56126 Pisa, Italy.

Over the past decade, telomeres have attracted increasing attention due to the role they play in human fertility. However, conflicting results have been reported on the possible association between sperm telomere length (STL) and leukocyte telomere length (LTL) and the quality of the sperm parameters. The aim of this study was to run a comprehensive study to investigate the role of STL and LTL in male spermatogenesis and infertility. Moreover, the association between the sperm parameters and 11 candidate single nucleotide polymorphisms (SNPs), identified in the literature for their association with telomere length (TL), was investigated. We observed no associations between sperm parameters and STL nor LTL. For the individual SNPs, we observed five statistically significant associations with sperm parameters: considering a < 0.05. Namely, -rs11125529 and decreased sperm motility ( = 0.03); -rs6772228 with a lower sperm count ( = 0.02); -rs7675998 with increased probability of having abnormal acrosomes ( = 0.03) and abnormal flagellum ( = 0.04); -rs8105767 and reduction of sperms with normal heads ( = 0.009). This study suggests a moderate involvement of telomere length in male fertility; however, in our analyses four SNPs were weakly associated with sperm variables, suggesting the SNPs to be pleiotropic and involved in other regulatory mechanisms independent of telomere homeostasis, but involved in the spermatogenic process.
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http://dx.doi.org/10.3390/ijms22083959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069448PMC
April 2021

Investigation of circulating metabolites associated with breast cancer risk by untargeted metabolomics: a case-control study nested within the French E3N cohort.

Br J Cancer 2021 May 15;124(10):1734-1743. Epub 2021 Mar 15.

Université Paris-Saclay, UVSQ, Univ. Paris-Sud, Inserm, Gustave Roussy, Exposome and Heredity Team, Centre for Epidemiology and Population Health, Villejuif, France.

Background: Perturbations in circulating metabolites prior to a breast cancer diagnosis are not well characterised. We aimed to gain more detailed knowledge to help understand and prevent the disease.

Methods: Baseline plasma samples from 791 breast cancer cases and 791 matched controls from the E3N (EPIC-France) cohort were profiled by nuclear magnetic resonance (NMR)-based untargeted metabolomics. Partial least-squares discriminant analysis (PLS-DA) models were built from NMR profiles to predict disease outcome, and odds ratios and false discovery rate (FDR)-adjusted CIs were calculated for 43 identified metabolites by conditional logistic regression.

Results: Breast cancer onset was predicted in the premenopausal subgroup with modest accuracy (AUC 0.61, 95% CI: 0.49-0.73), and 10 metabolites associated with risk, particularly histidine (OR = 1.70 per SD increase, FDR-adjusted CI 1.19-2.41), N-acetyl glycoproteins (OR = 1.53, FDR-adjusted CI 1.18-1.97), glycerol (OR = 1.55, FDR-adjusted CI 1.11-2.18) and ethanol (OR = 1.44, FDR-adjusted CI 1.05-1.97). No predictive capacity or significant metabolites were found overall or for postmenopausal women.

Conclusions: Perturbed metabolism compared to controls was observed in premenopausal but not postmenopausal cases. Histidine and NAC have known involvement in inflammatory pathways, and the robust association of ethanol with risk suggests the involvement of alcohol intake.
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http://dx.doi.org/10.1038/s41416-021-01304-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110540PMC
May 2021

Use of antiseizure medications and safety of branded versus generic formulations: A comparative study on Tuscan administrative databases.

Epilepsy Behav 2021 04 11;117:107876. Epub 2021 Mar 11.

Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy. Electronic address:

Purpose: To assess patterns of use of antiseizure medications (ASMs) and to compare the safety of generic versus branded formulations in terms of admission to hospital or to emergency department (ED).

Methods: We conducted a drug utilization study with a propensity score-matched design using the administrative databases of the Italian Tuscany region. New users of ASMs during 2015 with no history of neoplasia were considered and their first prescription was classified as: available only as branded (only-B-ASM); branded with generic available (B-ASM); and generic (G-ASM). Patients with G-ASM first prescription were matched with four patients with B-ASM prescription. Participants were followed up for one year or until the date of death or diagnosis of neoplasia. Cox regression models were fitted to estimate the risk of admission to hospital or ED.

Results: We identified 36,601 ASM new-users, including 2094 (6.4%) with only-B-ASM as first prescription, 24,588 (74.9%) with B-ASM, and 5788 (17.6%) with G-ASM. We found no differences in the risk of admission to hospital or ED (Hazard Ratio (HR), 0.92; 95% Confidence Interval (CI), 0.85-1.02) among users of generic ASMs compared to those using branded ASMs.

Conclusions: In our study population, generic ASMs were used less than branded ones. The similarity in the safety of branded and generic formulations suggests that generic ASMs could be the preferred formulation in current clinical practice resulting in a substantial decrease in the cost of treatment.
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http://dx.doi.org/10.1016/j.yebeh.2021.107876DOI Listing
April 2021

Psychological distress in the academic population and its association with socio-demographic and lifestyle characteristics during COVID-19 pandemic lockdown: Results from a large multicenter Italian study.

PLoS One 2021 10;16(3):e0248370. Epub 2021 Mar 10.

Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

Measures implemented in many countries to contain the COVID-19 pandemic resulted in a change in lifestyle with unpredictable consequences on physical and mental health. We aimed at identifying the variables associated with psychological distress during the lockdown between April and May 2020 in the Italian academic population. We conducted a multicenter cross-sectional online survey (IO CONTO 2020) within five Italian universities. Among about 240,000 individuals invited to participate through institutional communications, 18 120 filled the questionnaire. Psychological distress was measured by the self-administered Hospital Anxiety and Depression Scale (HADS). The covariates collected included demographic and lifestyle characteristics, trust in government, doctors and scientists. Associations of covariates with influenza-like symptoms or positive COVID-19 test and with psychological distress were assessed by multiple regression models at the local level; a meta-analysis of the results was then performed. Severe levels of anxiety or depression were reported by 20% of the sample and were associated with being a student or having a lower income, irrespective of their health condition and worries about contracting the virus. The probability of being severely anxious or depressed also depended on physical activity: compared to those never exercising, the highest OR being for those who stopped during lockdown (1.53; 95% CI, 1.28 to 1.84) and the lowest for those who continued (0.78; 95% CI, 0.64 to 0.95). Up to 21% of severe cases of anxiety or depression might have been avoided if during lockdown participants had continued to exercise as before. Socioeconomic insecurity contributes to increase mental problems related to the COVID-19 pandemic and to the measures to contain it. Maintaining or introducing an adequate level of physical activity is likely to mitigate such detrimental effects. Promoting safe practice of physical activity should remain a public health priority to reduce health risks during the pandemic.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0248370PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946293PMC
April 2021

Myeloid neoplasms and autoimmune diseases: markers of association.

Clin Exp Rheumatol 2021 Jan 6. Epub 2021 Jan 6.

Department of Clinical and Experimental Medicine, University of Pisa, Italy.

Objectives: To investigate the prognostic significance of concomitant autoimmune diseases (ADs) in myeloproliferative neoplasms (MPNs).

Methods: 435 subjects with a diagnosis of MPNs were included in this observational single institution longitudinal study. Of them, 34 patients presented an overt AD at diagnosis of MPN. Clinical presenting features, progression-free and overall survival were compared between MPN subgroups in relation to co-existence of AD at diagnosis of MPN.

Results: Compared to cases without ADs, the subjects with ADs were significantly younger, had lower haemoglobin and haematocrit levels and more frequently presented with splenomegaly. The clinical and biological features associated to progression-free and overall survival were: age, presence of splenomegaly, histotype (MF vs. PV vs. ET), anaemia, high platelet count and presence of any AD at diagnosis of MPN. The age-adjusted hazard ratio (HR) of progression for the presence of AD at diagnosis of MPN was 2.76. Overall survival was not significantly associated to AD at diagnosis, but the HR of progression for the presence of AD at diagnosis of MPN was 2.18.

Conclusions: A possible common genetic predisposition, the inflammatory bone marrow microenvironment and the activation of theJAK/STAT pathway could be considered as responsible for the observed association between MPNs and ADs.
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January 2021

The impact of lifecourse socio-economic position and individual social mobility on breast cancer risk.

BMC Cancer 2020 Nov 23;20(1):1138. Epub 2020 Nov 23.

UMR LEASP, Université de Toulouse III, UPS, Inserm, Toulouse, France.

Background: Women with an advantaged socioeconomic position (SEP) have a higher risk of developing breast cancer (BC). The reasons for this association do not seem to be limited to reproductive factors and remain to be understood. We aimed to investigate the impact of lifecourse SEP from childhood and social mobility on the risk of BC considering a broad set of potential mediators.

Methods: We used a discovery-replication strategy in two European prospective cohorts, E3N (N = 83,436) and EPIC-Italy (N = 20,530). In E3N, 7877 women were diagnosed with BC during a median 24.4 years of follow-up, while in EPIC-Italy, 893 BC cases were diagnosed within 15.1 years. Hazard ratios (HR) were estimated using Cox proportional hazard models on imputed data.

Results: In E3N, women with higher education had a higher risk of BC (HR [95%CI] = 1.21 [1.12, 1.30]). This association was attenuated by adjusting for reproductive factors, in particular age at first childbirth (HR[95%CI] = 1.13 [1.04, 1.22]). Health behaviours, anthropometric variables, and BC screening had a weaker effect on the association. Women who remained in a stable advantaged SEP had a higher risk of BC (HR [95%CI] = 1.24 [1.07; 1.43]) attenuated after adjustment for potential mediators (HR [95%CI] = 1.13 [0.98; 1.31]). These results were replicated in EPIC-Italy.

Conclusions: These results confirm the important role of reproductive factors in the social gradient in BC risk, which does not appear to be fully explained by the large set of potential mediators, including cancer screening, suggesting that further research is needed to identify additional mechanisms.
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http://dx.doi.org/10.1186/s12885-020-07648-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7684912PMC
November 2020

Novel mammogram-based measures improve breast cancer risk prediction beyond an established mammographic density measure.

Int J Cancer 2021 05 4;148(9):2193-2202. Epub 2020 Dec 4.

Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Parkville, Victoria, Australia.

Mammograms contain information that predicts breast cancer risk. We developed two novel mammogram-based breast cancer risk measures based on image brightness (Cirrocumulus) and texture (Cirrus). Their risk prediction when fitted together, and with an established measure of conventional mammographic density (Cumulus), is not known. We used three studies consisting of: 168 interval cases and 498 matched controls; 422 screen-detected cases and 1197 matched controls; and 354 younger-diagnosis cases and 944 controls frequency-matched for age at mammogram. We conducted conditional and unconditional logistic regression analyses of individually- and frequency-matched studies, respectively. We estimated measure-specific risk gradients as the change in odds per standard deviation of controls after adjusting for age and body mass index (OPERA) and calculated the area under the receiver operating characteristic curve (AUC). For interval, screen-detected and younger-diagnosis cancer risks, the best fitting models (OPERAs [95% confidence intervals]) involved: Cumulus (1.81 [1.41-2.31]) and Cirrus (1.72 [1.38-2.14]); Cirrus (1.49 [1.32-1.67]) and Cirrocumulus (1.16 [1.03 to 1.31]); and Cirrus (1.70 [1.48 to 1.94]) and Cirrocumulus (1.46 [1.27-1.68]), respectively. The AUCs were: 0.73 [0.68-0.77], 0.63 [0.60-0.66], and 0.72 [0.69-0.75], respectively. Combined, our new mammogram-based measures have twice the risk gradient for screen-detected and younger-diagnosis breast cancer (P ≤ 10 ), have at least the same discriminatory power as the current polygenic risk score, and are more correlated with causal factors than conventional mammographic density. Discovering more information about breast cancer risk from mammograms could help enable risk-based personalised breast screening.
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http://dx.doi.org/10.1002/ijc.33396DOI Listing
May 2021

Thymoma-associated myasthenia gravis: Clinical features and predictive value of antiacetylcholine receptor antibodies in the risk of recurrence of thymoma.

Thorac Cancer 2021 01 3;12(1):106-113. Epub 2020 Nov 3.

Department of Clinical and Experimental Medicine, Neurology Unit, University of Pisa, Pisa, Italy.

Background: Thymoma-associated myasthenia gravis (TAMG) is one of the subtypes of myasthenia gravis with autoantibodies against the acetylcholine receptor (AChR-Ab). We analyzed the clinical features of our cohort of TAMG patients and the changes in AChR-Ab titer before and after thymectomy in order to identify factors predicting thymoma relapses.

Methods: We retrospectively assessed: age of MG onset, MG clinical status according to MGFA (Myasthenia Gravis Foundation of America), epoch of thymectomy, post-thymectomy status, oncological features and surgical approach. AChR-Ab dosages were measured both before and after thymectomy. Linear regression models were applied to identify clinical determinants of AChR-Ab titers and the Cox regression model was fitted to estimate the factors associated with the risk of thymoma recurrence.

Results: The study sample included 239 MG patients, 27 of whom experienced one or more recurrences (median follow-up time: 4.8 years). The AChR-Ab titers decreased after first thymectomy (P < 0.001); the decrease was more pronounced in female patients (P = 0.05), in patients diagnosed with MG at an older age (P = 0.003), and in those who had lower MG stage before surgery (P = 0.02) or higher Masaoka-Koga stage (P = 0.005). The risk of relapse was closely linked with the age of the patient, the Masaoka-Koga stage and the surgical approach.

Conclusions: Presurgery levels of AChR-Ab or their change after surgery were not associated with thymoma recurrence. The reduction of AChR-Ab titers after thymectomy confirms an immunological role of thymoma in the pathogenesis of MG.

Key Points: Significant findings of the study: Young MG patients with an advanced Masaoka staging score of the primary tumor who underwent thymectomy with approaches different from sternotomy and VATS should be monitored for high risk of recurrence.

What This Study Adds: No other study has ever investigated the changes in AChR-Ab titers before and after thymectomy in a large cohort of TAMG patients. The reduction of AChR-Ab titers after thymectomy suggests an immunological role of thymoma in the pathogenesis of MG.
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http://dx.doi.org/10.1111/1759-7714.13724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779191PMC
January 2021

Invasive Pneumococcal Disease in Tuscany Region, Italy, 2016-2017: Integrating Multiple Data Sources to Investigate Underreporting.

Int J Environ Res Public Health 2020 10 19;17(20). Epub 2020 Oct 19.

Department of Translational Research and New Surgical and Medical Technologies, University of Pisa, 56126 Pisa, Italy.

Invasive pneumococcal disease (IPD) is a vaccine-preventable disease characterized by the presence of in normally sterile sites. Since 2007, Italy has implemented an IPD national surveillance system (IPD-NSS). This system suffers from high rates of underreporting. To estimate the level of underreporting of IPD in 2016-2017 in Tuscany (Italy), we integrated data from IPD-NSS and two other regional data sources, i.e., Tuscany regional microbiological surveillance (Microbiological Surveillance and Antibiotic Resistance in Tuscany, SMART) and hospitalization discharge records (HDRs). We collected (1) notifications to IPD-NSS, (2) SMART records positive for from normally sterile sites, and (3) hospitalization records with IPD-related International Classification of Diseases, Ninth Revision, Clinical Modification (ICD9) codes in discharge diagnoses. We performed data linkage of the three sources to obtain a combined surveillance system (CSS). Using the CSS, we calculated the completeness of the three sources and performed a three-source log-linear capture-recapture analysis to estimate total IPD underreporting. In total, 127 IPD cases were identified from IPD-NSS, 320 were identified from SMART, and 658 were identified from HDRs. After data linkage, a total of 904 unique cases were detected. The average yearly CSS notification rate was 12.1/100,000 inhabitants. Completeness was 14.0% for IPD-NSS, 35.4% for SMART, and 72.8% for HDRs. The capture-recapture analysis suggested a total estimate of 3419 cases of IPD (95% confidence interval (CI): 1364-5474), corresponding to an underreporting rate of 73.7% (95% CI: 34.0-83.6) for CSS. This study shows substantial underreporting in the Tuscany IPD surveillance system. Integration of available data sources may be a useful approach to complement notification-based surveillance and provide decision-makers with better information to plan effective control strategies against IPD.
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http://dx.doi.org/10.3390/ijerph17207581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589942PMC
October 2020

Tyrosine Kinase Inhibitors Play an Antiviral Action in Patients Affected by Chronic Myeloid Leukemia: A Possible Model Supporting Their Use in the Fight Against SARS-CoV-2.

Front Oncol 2020 2;10:1428. Epub 2020 Sep 2.

Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.

SARS-CoV-2 is the viral agent responsible for the pandemic that in the first months of 2020 caused about 400,000 deaths. Among compounds proposed to fight the SARS-CoV-2-related disease (COVID-19), tyrosine kinase inhibitors (TKIs), already effective in Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) and chronic myeloid leukemia (CML), have been proposed on the basis of their antiviral action already demonstrated against SARS-CoV-1. Very few cases of COVID-19 have been reported in Ph+ ALL and in CML Italian cohorts; authors suggested that this low rate of infections might depend on the use of TKIs, but the biological causes of this phenomenon remain unknown. In this study, the CML model was used to test if TKIs would sustain or not the viral replication and if they could damage patient immunity. Firstly, the infection and replication rate of torquetenovirus (TTV), whose load is inversely proportional to the host immunological control, have been measured in CML patients receiving nilotinib. A very low percentage of subjects were infected at baseline, and TTV did not replicate or at least showed a low replication rate during the follow-up, with a mean load comparable to the measured one in healthy subjects. Then, after gene expression profiling experiments, we found that several "antiviral" genes, such as and , were upregulated, while genes with "proviral" action, such as , and , were less expressed during treatment with imatinib, thus demonstrating that TKIs are not detrimental from the immunological point of view. To sum up, our data could offer some biological explanations to the low COVID-19 occurrence in Ph+ ALL and CML patients and sustain the use of TKIs in COVID-19, as already proposed by several international ongoing studies.
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http://dx.doi.org/10.3389/fonc.2020.01428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493657PMC
September 2020

Causal mediation analysis in presence of multiple mediators uncausally related.

Int J Biostat 2020 Oct 7. Epub 2020 Oct 7.

Laboratoire MAP5 (UMR CNRS 8145), Université de Paris, Paris, Île-de-France, France.

Mediation analysis aims at disentangling the effects of a treatment on an outcome through alternative causal mechanisms and has become a popular practice in biomedical and social science applications. The causal framework based on counterfactuals is currently the standard approach to mediation, with important methodological advances introduced in the literature in the last decade, especially for simple mediation, that is with one mediator at the time. Among a variety of alternative approaches, Imai et al. showed theoretical results and developed an R package to deal with simple mediation as well as with multiple mediation involving multiple mediators conditionally independent given the treatment and baseline covariates. This approach does not allow to consider the often encountered situation in which an unobserved common cause induces a spurious correlation between the mediators. In this context, which we refer to as mediation with uncausally related mediators, we show that, under appropriate hypothesis, the natural direct and joint indirect effects are non-parametrically identifiable. Moreover, we adopt the quasi-Bayesian algorithm developed by Imai et al. and propose a procedure based on the simulation of counterfactual distributions to estimate not only the direct and joint indirect effects but also the indirect effects through individual mediators. We study the properties of the proposed estimators through simulations. As an illustration, we apply our method on a real data set from a large cohort to assess the effect of hormone replacement treatment on breast cancer risk through three mediators, namely dense mammographic area, nondense area and body mass index.
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http://dx.doi.org/10.1515/ijb-2019-0088DOI Listing
October 2020

HCV micro-elimination in two prisons in Milan, Italy: A model of care.

J Viral Hepat 2020 12 14;27(12):1444-1454. Epub 2020 Sep 14.

Infectious Diseases Service, Penitentiary Health System, San Paolo University Hospital, Milano, Italy.

People in prison represent a high-risk population for HCV infection control. With the advent of new direct antiviral agents (DAAs) HCV micro-elimination in prison setting became a feasible strategy. We assessed the impact of an intervention for HCV testing and treatment in 2017 and 2018 in a jail (San Vittore,SV) and a prison for sentenced individuals (Opera,OP). A dedicated protocol was applied and implemented over the two years. We collected data on demographics, HCV testing and treatment on all inmates present on 31 October 2017 and 2018. In the two facilities, there were 2,366 and 2,369 inmates in 2017 and 2018 respectively; the majority were men (95.6%; 96.4%) and Italians (57.0%; 61.9%) with a median age of 41 years. Prevalence of lifetime reported drug use remained high (46.5%; 44.2%). HCV screening coverage was 89% in both years, while HCV RNA test coverage increased (90.6%; 99.0%). HCV seroprevalence remained stable (10.1%; 9.2%). In 2017 among inmates with HCV chronic infection 90 (42.4%) individuals had started DAAs treatment and 106 (54.6%) in 2018; of whom 38 (17.9%) and 74 (38.1%) achieved the SVR. The viremic pool decreased significantly over time (SV,24.4%; 15.4%;OP, 16.1%; <1%). Among inmates with HCV-positive serology in 2018, 121 (81.0%) were never linked to care before incarceration. Our study showed how a targeted and well-implemented HCV test-and-treat intervention in prison was feasible and effective in achieving micro-elimination. Viral hepatitis elimination agenda may help drawing interest onto this neglected population and bringing prison health higher up in the global public health agenda.
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http://dx.doi.org/10.1111/jvh.13376DOI Listing
December 2020

Stochastic Epigenetic Mutations Are Associated with Risk of Breast Cancer, Lung Cancer, and Mature B-cell Neoplasms.

Cancer Epidemiol Biomarkers Prev 2020 10 11;29(10):2026-2037. Epub 2020 Aug 11.

MRC Centre for Environment and Health, School of Public Health, Imperial College London, London, United Kingdom.

Background: Age-related epigenetic dysregulations are associated with several diseases, including cancer. The number of stochastic epigenetic mutations (SEM) has been suggested as a biomarker of life-course accumulation of exposure-related DNA damage; however, the predictive role of SEMs in cancer has seldom been investigated.

Methods: A SEM, at a given CpG site, was defined as an extreme outlier of DNA methylation value distribution across individuals. We investigated the association of the total number of SEMs with the risk of eight cancers in 4,497 case-control pairs nested in three prospective cohorts. Furthermore, we investigated whether SEMs were randomly distributed across the genome or enriched in functional genomic regions.

Results: In the three-study meta-analysis, the estimated ORs per one-unit increase in log(SEM) from logistic regression models adjusted for age and cancer risk factors were 1.25; 95% confidence interval (CI), 1.11-1.41 for breast cancer, and 1.23; 95% CI, 1.07-1.42 for lung cancer. In the Melbourne Collaborative Cohort Study, the OR for mature B-cell neoplasm was 1.46; 95% CI, 1.25-1.71. Enrichment analyses indicated that SEMs frequently occur in silenced genomic regions and in transcription factor binding sites regulated by EZH2 and SUZ12 ( < 0.0001 and = 0.0005, respectively): two components of the polycomb repressive complex 2 (PCR2). Finally, we showed that PCR2-specific SEMs are generally more stable over time compared with SEMs occurring in the whole genome.

Conclusions: The number of SEMs is associated with a higher risk of different cancers in prediagnostic blood samples.

Impact: We identified a candidate biomarker for cancer early detection, and we described a carcinogenesis mechanism involving PCR2 complex proteins worthy of further investigations.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0451DOI Listing
October 2020

Serum oncostatin M at baseline predicts mucosal healing in Crohn's disease patients treated with infliximab.

Aliment Pharmacol Ther 2020 07 7;52(2):284-291. Epub 2020 Jun 7.

Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

Background: Oncostatin M is upregulated in Crohn's disease inflamed intestinal mucosa, and has been suggested as a promising biomarker to predict responsiveness to anti-TNF therapy in patients with inflammatory bowel diseases.

Aim: To evaluate the suitability of serum oncostatin M as a predictive marker of response to infliximab in Crohn's disease.

Methods: We included patients treated with infliximab monotherapy. All patients underwent colonoscopy at week 54 to evaluate mucosal healing. Serum oncostatin M and faecal calprotectin were measured at baseline and after 14 weeks of treatment. Mann-Whitney test was used to evaluate correlation of oncostatin M and faecal calprotectin at baseline and week 14 with mucosal healing at week 54. Their accuracy in predicting mucosal healing was assessed by area under the curve (AUC).

Results: In a cohort of 45 included patients, 27 displayed mucosal healing. At both baseline and week 14, oncostatin M levels were significantly lower in patients with mucosal healing than in patients not achieving this endpoint (P < 0.001). Faecal calprotectin levels at week 14 were lower also in responders than nonresponders (P < 0.001). Oncostatin M values at baseline and week 14 were significantly associated (Spearman correlation = 0.92, P < 0.001). The diagnostic accuracy of oncostatin M at baseline in predicting mucosal healing (AUC = 0.91) was greater than faecal calprotectin (AUC = 0.51, P < 0.001).

Conclusion: These results suggest that oncostatin M can predict the outcome of infliximab treatment. Compared with faecal calprotectin, the predictive capability of oncostatin M was appreciable at baseline, thus indicating oncostatin M as a promising biomarker for driving therapeutic choices in Crohn's disease.
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http://dx.doi.org/10.1111/apt.15870DOI Listing
July 2020

The CoV-2 outbreak: how hematologists could help to fight Covid-19.

Pharmacol Res 2020 07 6;157:104866. Epub 2020 May 6.

Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

COVID-19 is a medical emergency, with 20 % of patients presenting with severe clinical manifestations. From the pathogenetic point of view, COVID-19 mimics two other well-known diseases characterized by cytokine storm and hyper-activation of the immune response, with consequent organ damage: acute graft-versus-host disease (aGVHD) and macrophage activation syndrome (MAS). Hematologists are confident with these situations requiring a prompt therapeutic approach for switching off the uncontrolled cytokine release; here, we discuss pros and cons of drugs that are already employed in hematology in the light of their possible application in COVID-19. The most promising drugs might be: Ruxolitinib, a JAK1/2 inhibitor, with a rapid and powerful anti-cytokine effect, tyrosine kinase inhibitors (TKIs), with their good anti-inflammatory properties, and perhaps the anti-Cd26 antibody Begelomab. We also present immunological data from gene expression experiments where TKIs resulted effective anti-inflammatory and pro-immune drugs. A possible combined treatment algorithm for COVID-19 is here proposed.
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http://dx.doi.org/10.1016/j.phrs.2020.104866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202852PMC
July 2020

Assessment of serum cytokines predicts clinical and endoscopic outcomes to vedolizumab in ulcerative colitis patients.

Br J Clin Pharmacol 2020 07 18;86(7):1296-1305. Epub 2020 Feb 18.

Department of General Surgery and Gastroenterology, IBD Unit, Pisa University Hospital, Pisa, Italy.

Aims: Vedolizumab (VDZ) prevents migration of activated leucocytes into inflamed mucosa. This study aimed to assess the patterns of serum cytokines in ulcerative colitis (UC) patients at baseline and during VDZ treatment, and to investigate their association with mucosal healing and clinical remission.

Methods: We enrolled consecutive UC patients eligible for treatment with VDZ. A panel of serum cytokines were measured by fluorescence assay at weeks 0, 6 and 22. Colonoscopy was performed at baseline and week 54, to evaluate mucosal healing. The time trends of serum cytokines were analysed by log-linear mixed effect models, and their prognostic accuracy was evaluated by logistic regression.

Results: Out of 27 patients included in the analysis, at week 54 mucosal healing was achieved in 12 (44%) and clinical remission in 17 (63%). Mucosal healing was associated with higher interleukin (IL)-8 values at baseline and with significant decrease in IL-6 and IL-8 levels over the first 6 weeks. A significant reduction of IL-6 and IL-8 levels over the first 6 weeks of treatment was associated also with clinical remission. Logistic models including, among the predictors, IL-6 and IL-8 at baseline and their changes over the first 6 weeks of treatment had 83% sensitivity and 87% specificity to predict mucosal healing, and 82% sensitivity and 90% specificity to predict clinical remission.

Conclusion: In UC patients, the serum patterns of IL-6 and IL-8 at baseline and over the first 6 weeks of treatment with VDZ could be useful to predict therapeutic outcome.
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http://dx.doi.org/10.1111/bcp.14235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319004PMC
July 2020

Adult weight change and premenopausal breast cancer risk: A prospective pooled analysis of data from 628,463 women.

Int J Cancer 2020 09 15;147(5):1306-1314. Epub 2020 Feb 15.

Albert Einstein College of Medicine, Bronx, NY.

Early-adulthood body size is strongly inversely associated with risk of premenopausal breast cancer. It is unclear whether subsequent changes in weight affect risk. We pooled individual-level data from 17 prospective studies to investigate the association of weight change with premenopausal breast cancer risk, considering strata of initial weight, timing of weight change, other breast cancer risk factors and breast cancer subtype. Hazard ratios (HR) and 95% confidence intervals (CI) were obtained using Cox regression. Among 628,463 women, 10,886 were diagnosed with breast cancer before menopause. Models adjusted for initial weight at ages 18-24 years and other breast cancer risk factors showed that weight gain from ages 18-24 to 35-44 or to 45-54 years was inversely associated with breast cancer overall (e.g., HR per 5 kg to ages 45-54: 0.96, 95% CI: 0.95-0.98) and with oestrogen-receptor(ER)-positive breast cancer (HR per 5 kg to ages 45-54: 0.96, 95% CI: 0.94-0.98). Weight gain from ages 25-34 was inversely associated with ER-positive breast cancer only and weight gain from ages 35-44 was not associated with risk. None of these weight gains were associated with ER-negative breast cancer. Weight loss was not consistently associated with overall or ER-specific risk after adjusting for initial weight. Weight increase from early-adulthood to ages 45-54 years is associated with a reduced premenopausal breast cancer risk independently of early-adulthood weight. Biological explanations are needed to account for these two separate factors.
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http://dx.doi.org/10.1002/ijc.32892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365745PMC
September 2020

Alcohol consumption is associated with widespread changes in blood DNA methylation: Analysis of cross-sectional and longitudinal data.

Addict Biol 2021 01 2;26(1):e12855. Epub 2019 Dec 2.

Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia.

DNA methylation may be one of the mechanisms by which alcohol consumption is associated with the risk of disease. We conducted a large-scale, cross-sectional, genome-wide DNA methylation association study of alcohol consumption and a longitudinal analysis of repeated measurements taken several years apart. Using the Illumina HumanMethylation450 BeadChip, DNA methylation was measured in blood samples from 5606 Melbourne Collaborative Cohort Study (MCCS) participants. For 1088 of them, these measures were repeated using blood samples collected a median of 11 years later. Associations between alcohol intake and blood DNA methylation were assessed using linear mixed-effects regression models. Independent data from the London Life Sciences Prospective Population (LOLIPOP) (N = 4042) and Cooperative Health Research in the Augsburg Region (KORA) (N = 1662) cohorts were used to replicate associations discovered in the MCCS. Cross-sectional analyses identified 1414 CpGs associated with alcohol intake at P < 10 , 1243 of which had not been reported previously. Of these novel associations, 1078 were replicated (P < .05) using LOLIPOP and KORA data. Using the MCCS data, we also replicated 403 of 518 previously reported associations. Interaction analyses suggested that associations were stronger for women, non-smokers, and participants genetically predisposed to consume less alcohol. Of the 1414 CpGs, 530 were differentially methylated (P < .05) in former compared with current drinkers. Longitudinal associations between the change in alcohol intake and the change in methylation were observed for 513 of the 1414 cross-sectional associations. Our study indicates that alcohol intake is associated with widespread changes in DNA methylation across the genome. Longitudinal analyses showed that the methylation status of alcohol-associated CpGs may change with alcohol consumption changes in adulthood.
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http://dx.doi.org/10.1111/adb.12855DOI Listing
January 2021

Interval breast cancer risk associations with breast density, family history and breast tissue aging.

Int J Cancer 2020 07 12;147(2):375-382. Epub 2019 Nov 12.

Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Parkville, VIC, Australia.

Interval breast cancers (those diagnosed between recommended mammography screens) generally have poorer outcomes and are more common among women with dense breasts. We aimed to develop a risk model for interval breast cancer. We conducted a nested case-control study within the Melbourne Collaborative Cohort Study involving 168 interval breast cancer patients and 498 matched control subjects. We measured breast density using the CUMULUS software. We recorded first-degree family history by questionnaire, measured body mass index (BMI) and calculated age-adjusted breast tissue aging, a novel measure of exposure to estrogen and progesterone based on the Pike model. We fitted conditional logistic regression to estimate odds ratio (OR) or odds ratio per adjusted standard deviation (OPERA) and calculated the area under the receiver operating characteristic curve (AUC). The stronger risk associations were for unadjusted percent breast density (OPERA = 1.99; AUC = 0.66), more so after adjusting for age and BMI (OPERA = 2.26; AUC = 0.70), and for family history (OR = 2.70; AUC = 0.56). When the latter two factors and their multiplicative interactions with age-adjusted breast tissue aging (p = 0.01 and 0.02, respectively) were fitted, the AUC was 0.73 (95% CI 0.69-0.77), equivalent to a ninefold interquartile risk ratio. In summary, compared with using dense breasts alone, risk discrimination for interval breast cancers could be doubled by instead using breast density, BMI, family history and hormonal exposure. This would also give women with dense breasts, and their physicians, more information about the major consequence of having dense breasts-an increased risk of developing an interval breast cancer.
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http://dx.doi.org/10.1002/ijc.32731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318124PMC
July 2020

Smoking and blood DNA methylation: an epigenome-wide association study and assessment of reversibility.

Epigenetics 2020 04 25;15(4):358-368. Epub 2019 Sep 25.

Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia.

We conducted a genome-wide association study of blood DNA methylation and smoking, attempted replication of previously discovered associations, and assessed the reversibility of smoking-associated methylation changes. DNA methylation was measured in baseline peripheral blood samples for 5,044 participants in the Melbourne Collaborative Cohort Study. For 1,032 participants, these measures were repeated using blood samples collected at follow-up, a median of 11 years later. A cross-sectional analysis of the association between smoking and DNA methylation and a longitudinal analysis of changes in smoking status and changes in DNA methylation were conducted. We used our cross-sectional analysis to replicate previously reported associations for current (N = 3,327) and former (N = 172) smoking. A comprehensive smoking index accounting for the biological half-life of smoking compounds and several aspects of smoking history was constructed to assess the reversibility of smoking-induced methylation changes. This measure of lifetime exposure to smoking allowed us to detect more associations than comparing current with never smokers. We identified 4,496 cross-sectional associations at P < 10, including 3,296 annotated to 1,326 genes that were not previously implicated in smoking-associated DNA methylation changes at this significance threshold. We replicated the majority of previously reported associations (P < 10) for current and former smokers. In our data, we observed for former smokers a substantial degree of return to the methylation levels of never smokers, compared with current smokers (median: 74%, IQR = 63-86%), corresponding to small values (median: 2.75, IQR = 1.5-5.25) for the half-life parameter of the comprehensive smoking index. Longitudinal analyses identified 368 sites at which methylation changed upon smoking cessation. Our study demonstrates the usefulness of the comprehensive smoking index to detect associations between smoking and DNA methylation at CpGs across the genome, replicates the vast majority of previously reported associations, and quantifies the reversibility of smoking-induced methylation changes.
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http://dx.doi.org/10.1080/15592294.2019.1668739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7153547PMC
April 2020

Appraising the causal relevance of DNA methylation for risk of lung cancer.

Int J Epidemiol 2019 10;48(5):1493-1504

MRC Integrative Epidemiology Unit.

Background: DNA methylation changes in peripheral blood have recently been identified in relation to lung cancer risk. Some of these changes have been suggested to mediate part of the effect of smoking on lung cancer. However, limitations with conventional mediation analyses mean that the causal nature of these methylation changes has yet to be fully elucidated.

Methods: We first performed a meta-analysis of four epigenome-wide association studies (EWAS) of lung cancer (918 cases, 918 controls). Next, we conducted a two-sample Mendelian randomization analysis, using genetic instruments for methylation at CpG sites identified in the EWAS meta-analysis, and 29 863 cases and 55 586 controls from the TRICL-ILCCO lung cancer consortium, to appraise the possible causal role of methylation at these sites on lung cancer.

Results: Sixteen CpG sites were identified from the EWAS meta-analysis [false discovery rate (FDR) < 0.05], for 14 of which we could identify genetic instruments. Mendelian randomization provided little evidence that DNA methylation in peripheral blood at the 14 CpG sites plays a causal role in lung cancer development (FDR > 0.05), including for cg05575921-AHRR where methylation is strongly associated with both smoke exposure and lung cancer risk.

Conclusions: The results contrast with previous observational and mediation analysis, which have made strong claims regarding the causal role of DNA methylation. Thus, previous suggestions of a mediating role of methylation at sites identified in peripheral blood, such as cg05575921-AHRR, could be unfounded. However, this study does not preclude the possibility that differential DNA methylation at other sites is causally involved in lung cancer development, especially within lung tissue.
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http://dx.doi.org/10.1093/ije/dyz190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857764PMC
October 2019

Cirrus: An Automated Mammography-Based Measure of Breast Cancer Risk Based on Textural Features.

JNCI Cancer Spectr 2018 Oct 7;2(4):pky057. Epub 2018 Dec 7.

Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia.

Background: We applied machine learning to find a novel breast cancer predictor based on information in a mammogram.

Methods: Using image-processing techniques, we automatically processed 46 158 analog mammograms for 1345 cases and 4235 controls from a cohort and case-control study of Australian women, and a cohort study of Japanese American women, extracting 20 textural features not based on pixel brightness threshold. We used Bayesian lasso regression to create individual- and mammogram-specific measures of breast cancer risk, Cirrus. We trained and tested measures across studies. We fitted Cirrus with conventional mammographic density measures using logistic regression, and computed odds ratios (OR) per standard deviation adjusted for age and body mass index.

Results: Combining studies, almost all textural features were associated with case-control status. The ORs for Cirrus measures trained on one study and tested on another study ranged from 1.56 to 1.78 (all <10). For the Cirrus measure derived from combining studies, the OR was 1.90 (95% confidence interval [CI] = 1.73 to 2.09), equivalent to a fourfold interquartile risk ratio, and was little attenuated after adjusting for conventional measures. In contrast, the OR for the conventional measure was 1.34 (95% CI = 1.25 to 1.43), and after adjusting for Cirrus it became 1.16 (95% CI = 1.08 to 1.24; =4 × 10).

Conclusions: A fully automated personal risk measure created from combining textural image features performs better at predicting breast cancer risk than conventional mammographic density risk measures, capturing half the risk-predicting ability of the latter measures. In terms of differentiating affected and unaffected women on a population basis, Cirrus could be one of the strongest known risk factors for breast cancer.
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http://dx.doi.org/10.1093/jncics/pky057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6649799PMC
October 2018

Adiposity and estrogen receptor-positive, postmenopausal breast cancer risk: Quantification of the mediating effects of fasting insulin and free estradiol.

Int J Cancer 2020 03 26;146(6):1541-1552. Epub 2019 Jun 26.

Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia.

Adiposity increases estrogen receptor (ER)-positive postmenopausal breast cancer risk. While mechanisms underlying this relationship are uncertain, dysregulated sex-steroid hormone production and insulin signaling are likely pathways. Our aim was to quantify mediating effects of fasting insulin and free estradiol in the adiposity and ER-positive postmenopausal breast cancer association. We used data from a case-cohort study of sex hormones and insulin signaling nested within the Melbourne Collaborative Cohort Study. Eligible women, at baseline, were not diagnosed with cancer, were postmenopausal, did not use hormone therapy and had no history of diabetes or diabetes medication use. Women with ER-negative disease or breast cancer diagnosis within the first follow-up year were excluded. We analyzed the study as a cumulative sampling case-control study with 149 cases and 1,029 controls. Missing values for insulin and free estradiol were multiply imputed with chained equations. Interventional direct (IDE) and indirect (IIE) effects were estimated using regression-based multiple-mediator approach. For women with body mass index (BMI) >30 kg/m compared to women with BMI 18.5-25 kg/m , the risk ratio (RR) of breast cancer was 1.75 (95% confidence interval [CI] 1.05-2.91). The estimated IDE (RR) not through the mediators was 1.03 (95% CI 0.43-2.48). Percentage mediated effect through free estradiol was 72% (IIE-RR 1.56; 95% CI 1.11-2.19). There was no evidence for an indirect effect through insulin (IIE-RR 1.12; 95% CI 0.68-1.84; 28% mediated). Our results suggest that circulating free estradiol plays an important mediating role in the adiposity-breast cancer relationship but does not explain all of the association.
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http://dx.doi.org/10.1002/ijc.32504DOI Listing
March 2020

Joint association of mammographic density adjusted for age and body mass index and polygenic risk score with breast cancer risk.

Breast Cancer Res 2019 05 22;21(1):68. Epub 2019 May 22.

Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.

Background: Mammographic breast density, adjusted for age and body mass index, and a polygenic risk score (PRS), comprised of common genetic variation, are both strong risk factors for breast cancer and increase discrimination of risk models. Understanding their joint contribution will be important to more accurately predict risk.

Methods: Using 3628 breast cancer cases and 5126 controls of European ancestry from eight case-control studies, we evaluated joint associations of a 77-single nucleotide polymorphism (SNP) PRS and quantitative mammographic density measures with breast cancer. Mammographic percent density and absolute dense area were evaluated using thresholding software and examined as residuals after adjusting for age, 1/BMI, and study. PRS and adjusted density phenotypes were modeled both continuously (per 1 standard deviation, SD) and categorically. We fit logistic regression models and tested the null hypothesis of multiplicative joint associations for PRS and adjusted density measures using likelihood ratio and global and tail-based goodness of fit tests within the subset of six cohort or population-based studies.

Results: Adjusted percent density (odds ratio (OR) = 1.45 per SD, 95% CI 1.38-1.52), adjusted absolute dense area (OR = 1.34 per SD, 95% CI 1.28-1.41), and the 77-SNP PRS (OR = 1.52 per SD, 95% CI 1.45-1.59) were associated with breast cancer risk. There was no evidence of interaction of the PRS with adjusted percent density or dense area on risk of breast cancer by either the likelihood ratio (P > 0.21) or goodness of fit tests (P > 0.09), whether assessed continuously or categorically. The joint association (OR) was 2.60 in the highest categories of adjusted PD and PRS and 0.34 in the lowest categories, relative to women in the second density quartile and middle PRS quintile.

Conclusions: The combined associations of the 77-SNP PRS and adjusted density measures are generally well described by multiplicative models, and both risk factors provide independent information on breast cancer risk.
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http://dx.doi.org/10.1186/s13058-019-1138-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6532188PMC
May 2019

Blood DNA methylation and breast cancer risk: a meta-analysis of four prospective cohort studies.

Breast Cancer Res 2019 05 17;21(1):62. Epub 2019 May 17.

Divison of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, USA.

Background: Environmental and genetic factors play an important role in the etiology of breast cancer. Several small blood-based DNA methylation studies have reported risk associations with methylation at individual CpGs and average methylation levels; however, these findings require validation in larger prospective cohort studies. To investigate the role of blood DNA methylation on breast cancer risk, we conducted a meta-analysis of four prospective cohort studies, including a total of 1663 incident cases and 1885 controls, the largest study of blood DNA methylation and breast cancer risk to date.

Methods: We assessed associations with methylation at 365,145 CpGs present in the HumanMethylation450 (HM450K) Beadchip, after excluding CpGs that did not pass quality controls in all studies. Each of the four cohorts estimated odds ratios (ORs) and 95% confidence intervals (CI) for the association between each individual CpG and breast cancer risk. In addition, each study assessed the association between average methylation measures and breast cancer risk, adjusted and unadjusted for cell-type composition. Study-specific ORs were combined using fixed-effect meta-analysis with inverse variance weights. Stratified analyses were conducted by age at diagnosis (< 50, ≥ 50), estrogen receptor (ER) status (+/-), and time since blood collection (< 5, 5-10, > 10 years). The false discovery rate (q value) was used to account for multiple testing.

Results: The average age at blood draw ranged from 52.2 to 62.2 years across the four cohorts. Median follow-up time ranged from 6.6 to 8.4 years. The methylation measured at individual CpGs was not associated with breast cancer risk (q value > 0.59). In addition, higher average methylation level was not associated with risk of breast cancer (OR = 0.94, 95% CI = 0.85, 1.05; P = 0.26; P for study heterogeneity = 0.86). We found no evidence of modification of this association by age at diagnosis (P = 0.17), ER status (P = 0.88), time since blood collection (P = 0.98), or CpG location (P = 0.98).

Conclusions: Our data indicate that DNA methylation measured in the blood prior to breast cancer diagnosis in predominantly postmenopausal women is unlikely to be associated with substantial breast cancer risk on the HM450K array. Larger studies or with greater methylation coverage are needed to determine if associations exist between blood DNA methylation and breast cancer risk.
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http://dx.doi.org/10.1186/s13058-019-1145-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6525390PMC
May 2019

Epigenome-wide association study for lifetime estrogen exposure identifies an epigenetic signature associated with breast cancer risk.

Clin Epigenetics 2019 04 30;11(1):66. Epub 2019 Apr 30.

International Agency for Research on Cancer (IARC), Lyon, France.

Background: It is well established that estrogens and other hormonal factors influence breast cancer susceptibility. We hypothesized that a woman's total lifetime estrogen exposure accumulates changes in DNA methylation, detectable in the blood, which could be used in risk assessment for breast cancer.

Methods: An estimated lifetime estrogen exposure (ELEE) model was defined using epidemiological data from EPIC-Italy (n = 31,864). An epigenome-wide association study (EWAS) of ELEE was performed using existing Illumina HumanMethylation450K Beadchip (HM450K) methylation data obtained from EPIC-Italy blood DNA samples (n = 216). A methylation index (MI) of ELEE based on 31 CpG sites was developed using HM450K data from EPIC-Italy and the Generations Study and evaluated for association with breast cancer risk in an independent dataset from the Generations Study (n = 440 incident breast cancer cases matched to 440 healthy controls) using targeted bisulfite sequencing. Lastly, a meta-analysis was conducted including three additional cohorts, consisting of 1187 case-control pairs.

Results: We observed an estimated 5% increase in breast cancer risk per 1-year longer ELEE (OR = 1.05, 95% CI 1.04-1.07, P = 3 × 10) in EPIC-Italy. The EWAS identified 694 CpG sites associated with ELEE (FDR Q < 0.05). We report a DNA methylation index (MI) associated with breast cancer risk that is validated in the Generations Study targeted bisulfite sequencing data (OR = 1.77, 95% CI 1.07-2.93, P = 0.027) and in the meta-analysis (OR = 1.43, 95% CI 1.05-2.00, P = 0.024); however, the correlation between the MI and ELEE was not validated across study cohorts.

Conclusion: We have identified a blood DNA methylation signature associated with breast cancer risk in this study. Further investigation is required to confirm the interaction between estrogen exposure and DNA methylation in the blood.
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http://dx.doi.org/10.1186/s13148-019-0664-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6492393PMC
April 2019

Genome-wide association study of peripheral blood DNA methylation and conventional mammographic density measures.

Int J Cancer 2019 10 12;145(7):1768-1773. Epub 2019 Feb 12.

Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, VIC, Australia.

Age- and body mass index (BMI)-adjusted mammographic density is one of the strongest breast cancer risk factors. DNA methylation is a molecular mechanism that could underlie inter-individual variation in mammographic density. We aimed to investigate the association between breast cancer risk-predicting mammographic density measures and blood DNA methylation. For 436 women from the Australian Mammographic Density Twins and Sisters Study and 591 women from the Melbourne Collaborative Cohort Study, mammographic density (dense area, nondense area and percentage dense area) defined by the conventional brightness threshold was measured using the CUMULUS software, and peripheral blood DNA methylation was measured using the HumanMethylation450 (HM450) BeadChip assay. Associations between DNA methylation at >400,000 sites and mammographic density measures adjusted for age and BMI were assessed within each cohort and pooled using fixed-effect meta-analysis. Associations with methylation at genetic loci known to be associated with mammographic density were also examined. We found no genome-wide significant (p < 10 ) association for any mammographic density measure from the meta-analysis, or from the cohort-specific analyses. None of the 299 methylation sites located at genetic loci associated with mammographic density was associated with any mammographic density measure after adjusting for multiple testing (all p > 0.05/299 = 1.7 × 10 ). In summary, our study did not find evidence for associations between blood DNA methylation, as measured by the HM450 assay, and conventional mammographic density measures that predict breast cancer risk.
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http://dx.doi.org/10.1002/ijc.32171DOI Listing
October 2019

Predicting interval and screen-detected breast cancers from mammographic density defined by different brightness thresholds.

Breast Cancer Res 2018 12 13;20(1):152. Epub 2018 Dec 13.

Centre for Epidemiology and Biostatistics, The University of Melbourne, Level 3/207 Bouverie Street, Carlton, VIC, 3053, Australia.

Background: Case-control studies show that mammographic density is a better risk factor when defined at higher than conventional pixel-brightness thresholds. We asked if this applied to interval and/or screen-detected cancers.

Method: We conducted a nested case-control study within the prospective Melbourne Collaborative Cohort Study including 168 women with interval and 422 with screen-detected breast cancers, and 498 and 1197 matched controls, respectively. We measured absolute and percent mammographic density using the Cumulus software at the conventional threshold (Cumulus) and two increasingly higher thresholds (Altocumulus and Cirrocumulus, respectively). Measures were transformed and adjusted for age and body mass index (BMI). Using conditional logistic regression and adjusting for BMI by age at mammogram, we estimated risk discrimination by the odds ratio per adjusted standard deviation (OPERA), calculated the area under the receiver operating characteristic curve (AUC) and compared nested models using the likelihood ratio criterion and models with the same number of parameters using the difference in Bayesian information criterion (ΔBIC).

Results: For interval cancer, there was very strong evidence that the association was best predicted by Cumulus as a percentage (OPERA = 2.33 (95% confidence interval (CI) 1.85-2.92); all ΔBIC > 14), and the association with BMI was independent of age at mammogram. After adjusting for percent Cumulus, no other measure was associated with risk (all P > 0.1). For screen-detected cancer, however, the associations were strongest for the absolute and percent Cirrocumulus measures (all ΔBIC > 6), and after adjusting for Cirrocumulus, no other measure was associated with risk (all P > 0.07).

Conclusion: The amount of brighter areas is the best mammogram-based measure of screen-detected breast cancer risk, while the percentage of the breast covered by white or bright areas is the best mammogram-based measure of interval breast cancer risk, irrespective of BMI. Therefore, there are different features of mammographic images that give clinically important information about different outcomes.
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http://dx.doi.org/10.1186/s13058-018-1081-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6293866PMC
December 2018

Breast Cancer Risk After Recent Childbirth: A Pooled Analysis of 15 Prospective Studies.

Ann Intern Med 2019 01 11;170(1):22-30. Epub 2018 Dec 11.

School of Public Health, Imperial College London, London, United Kingdom (M.A.M., E.R.).

Background: Parity is widely recognized as protective for breast cancer, but breast cancer risk may be increased shortly after childbirth. Whether this risk varies with breastfeeding, family history of breast cancer, or specific tumor subtype has rarely been evaluated.

Objective: To characterize breast cancer risk in relation to recent childbirth.

Design: Pooled analysis of individual-level data from 15 prospective cohort studies.

Setting: The international Premenopausal Breast Cancer Collaborative Group.

Participants: Women younger than 55 years.

Measurements: During 9.6 million person-years of follow-up, 18 826 incident cases of breast cancer were diagnosed. Hazard ratios (HRs) and 95% CIs for breast cancer were calculated using Cox proportional hazards regression.

Results: Compared with nulliparous women, parous women had an HR for breast cancer that peaked about 5 years after birth (HR, 1.80 [95% CI, 1.63 to 1.99]) before decreasing to 0.77 (CI, 0.67 to 0.88) after 34 years. The association crossed over from positive to negative about 24 years after birth. The overall pattern was driven by estrogen receptor (ER)-positive breast cancer; no crossover was seen for ER-negative cancer. Increases in breast cancer risk after childbirth were pronounced when combined with a family history of breast cancer and were greater for women who were older at first birth or who had more births. Breastfeeding did not modify overall risk patterns.

Limitations: Breast cancer diagnoses during pregnancy were not uniformly distinguishable from early postpartum diagnoses. Data on human epidermal growth factor receptor 2 (HER2) oncogene overexpression were limited.

Conclusion: Compared with nulliparous women, parous women have an increased risk for breast cancer for more than 20 years after childbirth. Health care providers should consider recent childbirth a risk factor for breast cancer in young women.

Primary Funding Source: The Avon Foundation, the National Institute of Environmental Health Sciences, Breast Cancer Now and the UK National Health Service, and the Institute of Cancer Research.
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http://dx.doi.org/10.7326/M18-1323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6760671PMC
January 2019
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