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It remains unclear if pre‐diagnostic factors influence the developmental pathways of colorectal cancer (CRC) that could enhance tumor aggressiveness. This study used prospective data from 205,489 cancer‐free US health professionals to investigate the associations of 31 known or putative risk factors with the risk of aggressive CRC. Tumor aggressiveness was characterized by three endpoints: aggressive CRC (cancer that causes death within 5 years of diagnosis), fatal CRC, and tumor stage at diagnosis. The data augmentation method was used to assess the difference in the associations between risk factors and endpoints. We documented 3201 CRC cases, of which 899 were aggressive. The protective associations of undergoing lower endoscopy (hazard ratios [HR] 0.43, 95% confidence interval (CI) 0.37, 0.49 for aggressive versus HR 0.61, 95% CI 0.56, 0.67 for non‐aggressive) and regular use of aspirin (HR 0.70, 95% CI 0.61, 0.81 versus HR 0.84, 95% CI 0.77, 0.92) were stronger for aggressive than non‐aggressive CRC (pHeterogeneity <0.05). Lower intake of whole grains or cereal fiber and greater dietary inflammatory potential were associated with a higher risk of aggressive but not non‐aggressive CRC. The remaining risk factors showed comparable associations with aggressive CRC and non‐aggressive CRC. Aggressive cases were more likely to have KRAS‐mutated tumors but less likely to have distal or MSI‐high tumors (p <.007). Similar results were observed for fatal CRC and advanced tumor stages at diagnosis. These findings provide initial evidence for the role of pre‐diagnostic risk factors in the pathogenesis of aggressive CRC and suggest research priorities for preventive interventions. [ABSTRACT FROM AUTHOR]

Background: The mechanisms underlying alcohol‐induced breast carcinogenesis are not fully understood but may involve hormonal changes. Methods: Cross‐sectional associations were investigated between self‐reported alcohol intake and serum or plasma concentrations of estradiol, estrone, progesterone (in premenopausal women only), testosterone, androstenedione, dehydroepiandrosterone sulfate, and sex hormone binding globulin (SHBG) in 45 431 premenopausal and 173 476 postmenopausal women. Multivariable linear regression was performed separately for UK Biobank, European Prospective Investigation into Cancer and Nutrition, and Endogenous Hormones and Breast Cancer Collaborative Group, and meta‐analyzed the results. For testosterone and SHBG, we also conducted Mendelian randomization and colocalization using the ADH1B (alcohol dehydrogenase 1B) variant (rs1229984). Results: Alcohol intake was positively, though weakly, associated with all hormones (except progesterone in premenopausal women), with increments in concentrations per 10 g/day increment in alcohol intake ranging from 1.7% for luteal estradiol to 6.6% for postmenopausal dehydroepiandrosterone sulfate. There was an inverse association of alcohol with SHBG in postmenopausal women but a small positive association in premenopausal women. Two‐sample randomization identified positive associations of alcohol intake with total testosterone (difference per 10 g/day increment: 4.1%; 95% CI, 0.6–7.6) and free testosterone (7.8%; 4.1–11.5), and an inverse association with SHBG (–8.1%; –11.3% to –4.9%). Colocalization suggested a shared causal locus at ADH1B between alcohol intake and higher free testosterone and lower SHBG (posterior probability for H4, 0.81 and 0.97, respectively). Conclusions: Alcohol intake was associated with small increases in sex hormone concentrations, including bioavailable fractions, which may contribute to its effect on breast cancer risk. Alcohol intake was associated with small increases in sex hormone concentrations, including bioavailable fractions. Sex hormones are therefore likely to be part of the mechanism through which alcohol increases breast cancer risk. [ABSTRACT FROM AUTHOR]

Background: Elevated mammographic density (MD) for a woman's age and body mass index (BMI) is an established breast cancer risk factor. The relationship of parity, age at first birth, and breastfeeding with MD is less clear. We examined the associations of these factors with MD within the International Consortium of Mammographic Density (ICMD). Methods: ICMD is a consortium of 27 studies with pooled individual-level epidemiological and MD data from 11,755 women without breast cancer aged 35–85 years from 22 countries, capturing 40 country-& ethnicity-specific population groups. MD was measured using the area-based tool Cumulus. Meta-analyses across population groups and pooled analyses were used to examine linear regression associations of square-root (√) transformed MD measures (percent MD (PMD), dense area (DA), and non-dense area (NDA)) with parity, age at first birth, ever/never breastfed and lifetime breastfeeding duration. Models were adjusted for age at mammogram, age at menarche, BMI, menopausal status, use of hormone replacement therapy, calibration method, mammogram view and reader, and parity and age at first birth when not the association of interest. Results: Among 10,988 women included in these analyses, 90.1% (n = 9,895) were parous, of whom 13% (n = 1,286) had ≥ five births. The mean age at first birth was 24.3 years (Standard deviation = 5.1). Increasing parity (per birth) was inversely associated with √PMD (β: − 0.05, 95% confidence interval (CI): − 0.07, − 0.03) and √DA (β: − 0.08, 95% CI: − 0.12, − 0.05) with this trend evident until at least nine births. Women who were older at first birth (per five-year increase) had higher √PMD (β:0.06, 95% CI:0.03, 0.10) and √DA (β:0.06, 95% CI:0.02, 0.10), and lower √NDA (β: − 0.06, 95% CI: − 0.11, − 0.01). In stratified analyses, this association was only evident in women who were post-menopausal at MD assessment. Among parous women, no associations were found between ever/never breastfed or lifetime breastfeeding duration (per six-month increase) and √MD. Conclusions: Associations with higher parity and older age at first birth with √MD were consistent with the direction of their respective associations with breast cancer risk. Further research is needed to understand reproductive factor-related differences in the composition of breast tissue and their associations with breast cancer risk. [ABSTRACT FROM AUTHOR]

Background: Sexual minority (SM) individuals (e.g., those with same‐sex attractions/partners or who identify as lesbian/gay/bisexual) experience a host of physical and mental health disparities. However, little is known about sexual orientation‐related disparities in gestational diabetes mellitus (GDM) and hypertensive disorders of pregnancy (HDP; gestational hypertension [gHTN] and preeclampsia). Objective: To estimate disparities in GDM, gHTN and preeclampsia by sexual orientation. Methods: We used data from the Nurses' Health Study II—a cohort of nurses across the US enrolled in 1989 at 25–42 years of age—restricted to those with pregnancies ≥20 weeks gestation and non‐missing sexual orientation data (63,518 participants; 146,079 pregnancies). Our primary outcomes were GDM, gHTN and preeclampsia, which participants reported for each of their pregnancies. Participants also reported their sexual orientation identity and same‐sex attractions/partners. We compared the risk of each outcome in pregnancies among heterosexual participants with no same‐sex experience (reference) to those among SM participants overall and within subgroups: (1) heterosexual with same‐sex experience, (2) mostly heterosexual, (3) bisexual and (4) lesbian/gay participants. We used modified Poisson models to estimate risk ratios (RR) and 95% confidence intervals (CI), fit via weighted generalised estimating equations, to account for multiple pregnancies per person over time and informative cluster sizes. Results: The overall prevalence of each outcome was ≤5%. Mostly heterosexual participants had a 31% higher risk of gHTN (RR 1.31, 95% CI 1.03, 1.66), and heterosexual participants with same‐sex experience had a 31% higher risk of GDM (RR 1.31, 95% CI 1.13, 1.50), compared to heterosexual participants with no same‐sex experience. The magnitudes of the risk ratios were high among bisexual participants for gHTN and preeclampsia and among lesbian/gay participants for gHTN. Conclusions: Some SM groups may be disparately burdened by GDM and HDP. Elucidating modifiable mechanisms (e.g., structural barriers, discrimination) for reducing adverse pregnancy outcomes among SM populations is critical. [ABSTRACT FROM AUTHOR]

Background: Evidence on type 2 diabetes onset age and duration on mortality risk has been limited by short follow‐up, inadequate control for confounding, missing repeated measurements, and inability to cover the full range of onset age, duration, and major causes of death. Moreover, scarce data dissect how type 2 diabetes onset age and duration shape life expectancy. Methods: We evaluate prospectively these topics based on 270,075 eligible participants in the Nurses' Health Studies and Health Professionals Follow‐up Study, leveraging repeated measurements throughout up to 40 years of follow‐up. Cox models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: In fully adjusted analyses, incident early onset type 2 diabetes (diagnosed <40 years of age) was associated with significantly higher mortality from all‐causes (HR, 95% CI was 3.16, 2.64–3.79; vs. individuals without type 2 diabetes), cardiovascular disease (6.56, 4.27–10.1), respiratory disease (3.43, 1.38–8.51), neurodegenerative disease (5.13, 2.09–12.6), and kidney disease (8.55, 1.98–36.9). The relative risk elevations declined dramatically with each higher decade of age at diagnosis for deaths from most of these causes, though the absolute risk difference increased continuously. A substantially higher cumulative incidence of mortality and a greater loss in life expectancy were associated with younger age at type 2 diabetes diagnosis. Longer disease duration was associated with generally higher relative and absolute risk of mortality. Conclusion: Early onset of type 2 diabetes and longer disease duration are associated with substantially increased risk of all‐cause and cause‐specific mortality and greater loss in life expectancy. [ABSTRACT FROM AUTHOR]

We aimed to examine the association between the use of metformin and other anti‐diabetic medications and breast cancer incidence within two large prospective cohort studies. We followed 185,181 women who participated in the Nurses' Health Study (NHS; 1994–2016) and the NHSII (1995–2017), with baseline corresponding to the date metformin was approved for type 2 diabetes (T2D) treatment in the US Information on T2D diagnosis, anti‐diabetes medications, and other covariates was self‐reported at baseline and repeatedly assessed by follow‐up questionnaires every 2 years. Breast cancer cases were self‐reported and confirmed by medical record review. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between medication use and breast cancer were estimated using Cox proportional hazards regression models, adjusting for breast cancer risk factors. During 3,324,881 person‐years of follow‐up, we ascertained 9,192 incident invasive breast cancer cases, of which 451 were among women with T2D. Compared with women without T2D (n = 169,263), neither metformin use (HR = 0.97; 95% CI = 0.81–1.15) nor other anti‐diabetic medications use (HR = 1.11; 95% CI = 0.90–1.36) associated with significantly lower breast cancer incidence. Among women with T2D (n = 15,918), compared with metformin never users, metformin ever use was not significantly inversely associated with breast cancer (HR = 0.92; 95% CI = 0.74–1.15). Although we observed that past use of metformin was inversely associated with breast cancer in the T2D population (HR = 0.67; 95% CI = 0.48–0.94), current use (HR = 1.01; 95% CI = 0.80–1.27) and longer duration of metformin use were not associated with breast cancer (each 2‐year interval: HR = 1.01; 95% CI = 0.95–1.07). Overall, metformin use was not associated with the risk of developing breast cancer among the overall cohort population or among women with T2D. [ABSTRACT FROM AUTHOR]

Background: Early menarche is an established risk factor for breast cancer but its molecular contribution to tumor biology and prognosis remains unclear. Methods: We profiled transcriptome-wide gene expression in breast tumors (N = 846) and tumor-adjacent normal tissues (N = 666) from women in the Nurses' Health Studies (NHS) to investigate whether early menarche (age < 12) is associated with tumor molecular and prognostic features in women with breast cancer. Multivariable linear regression and pathway analyses using competitive gene set enrichment analysis were conducted in both tumor and adjacent-normal tissue and externally validated in TCGA (N = 116). Subgroup analyses stratified on ER-status based on the tumor were also performed. PAM50 signatures were used for tumor molecular subtyping and to generate proliferation and risk of recurrence scores. We created a gene expression score using LASSO regression to capture early menarche based on 28 genes from FDR-significant pathways in breast tumor tissue in NHS and tested its association with 10-year disease-free survival in both NHS (N = 836) and METABRIC (N = 952). Results: Early menarche was significantly associated with 369 individual genes in adjacent-normal tissues implicated in extracellular matrix, cell adhesion, and invasion (FDR ≤ 0.1). Early menarche was associated with upregulation of cancer hallmark pathways (18 significant pathways in tumor, 23 in tumor-adjacent normal, FDR ≤ 0.1) related to proliferation (e.g. Myc, PI3K/AKT/mTOR, cell cycle), oxidative stress (e.g. oxidative phosphorylation, unfolded protein response), and inflammation (e.g. pro-inflammatory cytokines IFN α and IFN γ ). Replication in TCGA confirmed these trends. Early menarche was associated with significantly higher PAM50 proliferation scores (β = 0.082 [0.02–0.14]), odds of aggressive molecular tumor subtypes (basal-like, OR = 1.84 [1.18–2.85] and HER2-enriched, OR = 2.32 [1.46–3.69]), and PAM50 risk of recurrence score (β = 4.81 [1.71–7.92]). Our NHS-derived early menarche gene expression signature was significantly associated with worse 10-year disease-free survival in METABRIC (N = 952, HR = 1.58 [1.10–2.25]). Conclusions: Early menarche is associated with more aggressive molecular tumor characteristics and its gene expression signature within tumors is associated with worse 10-year disease-free survival among women with breast cancer. As the age of onset of menarche continues to decline, understanding its relationship to breast tumor characteristics and prognosis may lead to novel secondary prevention strategies. [ABSTRACT FROM AUTHOR]

We aimed to investigate the associations between maternal intake of folate, vitamin B12, B6, B2, methionine, choline, phosphatidylcholine and betaine during the period surrounding pregnancy and offspring weight outcomes from birth to early adulthood. These associations were examined among 2454 mother–child pairs from the Nurses' Health Study II and Growing Up Today Study. Maternal energy-adjusted nutrient intakes were derived from food frequency questionnaires. Birth weight, body size at age 5 and repeated BMI measurements were considered. Overweight/obesity was defined according to the International Obesity Task Force (<18 years) and World Health Organization guidelines (18+ years). Among other estimands, we report relative risks (RRs) for offspring ever being overweight with corresponding 95% confidence intervals across quintiles of dietary factors, with the lowest quintile as the reference. In multivariate-adjusted models, higher maternal intakes of phosphatidylcholine were associated with a higher risk of offspring ever being overweight (RRQ5vsQ1 = 1.16 [1.01–1.33] p-trend: 0.003). The association was stronger among offspring born to mothers with high red meat intake (high red meat RRQ5vsQ1 = 1.50 [1.14–1.98], p-trend: 0.001; low red meat RRQ5vsQ1 = 1.05 [0.87–1.27], p-trend: 0.46; p-interaction = 0.13). Future studies confirming the association between a higher maternal phosphatidylcholine intake during pregnancy and offspring risk of being overweight or obese are needed. [ABSTRACT FROM AUTHOR]

Background To support mammography screening decision making, we developed a competing-risk model to estimate 5-year breast cancer risk and 10-year nonbreast cancer death for women aged 55 years and older using Nurses' Health Study data and examined model performance in the Black Women's Health Study (BWHS). Here, we examine model performance in predicting 10-year outcomes in the BWHS, Women's Health Initiative-Extension Study (WHI-ES), and Multiethnic Cohort (MEC) and compare model performance to existing breast cancer prediction models. Methods We used competing-risk regression and Royston and Altman methods for validating survival models to calculate our model's calibration and discrimination (C index) in BWHS (n = 17 380), WHI-ES (n = 106 894), and MEC (n = 49 668). The Nurses' Health Study development cohort (n = 48 102) regression coefficients were applied to the validation cohorts. We compared our model's performance with breast cancer risk assessment tool (Gail) and International Breast Cancer Intervention Study (IBIS) models by computing breast cancer risk estimates and C statistics. Results When predicting 10-year breast cancer risk, our model's C index was 0.569 in BWHS, 0.572 in WHI-ES, and 0.576 in MEC. The Gail model's C statistic was 0.554 in BWHS, 0.564 in WHI-ES, and 0.551 in MEC; IBIS's C statistic was 0.547 in BWHS, 0.552 in WHI-ES, and 0.562 in MEC. The Gail model underpredicted breast cancer risk in WHI-ES; IBIS underpredicted breast cancer risk in WHI-ES and in MEC but overpredicted breast cancer risk in BWHS. Our model calibrated well. Our model's C index for predicting 10-year nonbreast cancer death was 0.760 in WHI-ES and 0.763 in MEC. Conclusions Our competing-risk model performs as well as existing breast cancer prediction models in diverse cohorts and predicts nonbreast cancer death. We are developing a website to disseminate our model. [ABSTRACT FROM AUTHOR]

Objectives: To better understand whether history of infertility is associated with anti-Müllerian hormone (AMH) levels later in life, outside of reproduction., Methods: Among 1,758 premenopausal women in the Nurses' Health Study II with measured AMH, we used multivariable generalized linear models to compare log-transformed plasma AMH for women with a history of infertility compared with fertile women. We investigated AMH levels by cause of infertility and effect modification by menstrual cycle regularity. Lastly, we investigated AMH levels by history of primary and secondary infertility and age at reported infertility., Results: Mean age at blood collection was 40 years. We observed no association between overall history of infertility and AMH levels (% difference AMH: -8.1% [CI, -19.4 to 4.8]). The association between overall infertility and AMH was strongest among women who first reported infertility at >30 years (-17.7% [CI, -32.1 to -0.3])., Conclusions: Overall, we observed no association between the history of infertility and AMH levels later in life. However, specific subgroups of women with a history of infertility may have lower AMH levels throughout life compared with fertile women. This association was observed among subgroups, such as those who first experienced infertility at >30 years. These findings have implications for mechanisms through which infertility may be associated with premature menopause and chronic disease risk., Competing Interests: Financial disclosure/conflicts of interest: S.A.M. receives ongoing institutional funding from the Department of Defense, Abbvie (grant), and Marriot Family Foundation (grant). She also receives honoraria from University of British Columbia, WERF, Huilun Shanghai, and University of Kansas Medical Center (honoraria). She receives coverage for travel to meetings by SRI, ESHRE, University of Michigan, Massachusetts Institute of Technology, ASRM, LIDEA Registry, Taiwan Endometriosis Society, SEUD, Japan Endometriosis Society, and NASEM. She receives personal fees for advisory board, roundtable, consultant, or editor role from AbbVie, Roche, Frontiers in Reproductive Health, Abbott, and LIDEA Registry. She holds unpaid board or leadership roles at Human Reproduction, SWHR, WERF, WES, ASRM, ESHRE. The other authors have nothing to disclose., (Copyright © 2024 by The Menopause Society.)

Background: Metabolomic profiles may influence colorectal cancer (CRC) development. Few studies have performed pre-diagnostic metabolome-wide analyses with CRC risk., Methods: We conducted a nested case-control study among women (Nurses' Health Study (NHS)) and men (Health Professionals Follow-up Study (HPFS)) who provided blood between 1989 and 1995. Over 22.9 years, 684 (409 NHS, 275 HPFS) incident CRC cases occurred and were matched 1:1 to controls. Liquid chromatography-mass spectrometry (LC-MS) identified 255 plasma metabolites after quality control. Cohort-specific and combined metabolite association analyses were performed using conditional logistic regression. Metabolite set enrichment analysis (MSEA) was used to identify differential abundance in metabolite classes. Weighted Correlation Network Analysis (WGCNA) provided modules of covarying metabolites, which were tested for CRC association., Results: MSEA identified specific acylcarnitines associated with higher CRC risk and triacylglycerols with lower CRC risk among women and men. Further, phosphatidylcholines were associated with a higher risk of CRC among men. In an analysis restricted to CRC cases diagnosed two years after blood draw, myristoleic acid (OR = 1.37; 95%CI = 1.15-1.62; FDR = 0.072) and C60:12 triacylglycerol (OR = 0.75; 95%CI = 0.64-0.88; FDR = 0.072 were associated with CRC risk in women. WGCNA identified amino acids associated with CRC in men, fatty acid esters (carnitines) with distal CRC in men, and triradylcglycerols inversely associated with CRC in women., Conclusions: We identified pre-diagnostic CRC-associated metabolites with distinct sex-specific profiles. These results provide insight into CRC etiopathogenesis and have implications for risk prediction strategies., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Debate persists regarding the potential carcinogenicity of aspartame as suggested by experimental studies. Therefore, we prospectively evaluated whether aspartame consumption is associated with breast cancer risk in the Nurses' Health Study (NHS) and Nurses' Health study II (NHSII). We used Cox models to calculate HRs and 95% CIs. During up to 30 years of follow-up with 4-yearly assessments of intake, we documented 10,814 invasive breast cancer cases. Overall, there was no association between aspartame consumption and invasive breast cancer risk (HR per 200 mg/day [approximately one 12 oz serving of diet soda] = 1.00 (95% CI 0.98, 1.03). We observed similar lack of associations after excluding cases occurring in the first 10 years of follow-up (n = 3,125) (HR per 200 mg/day 1.00, 95% CI 0.97, 1.03). In these cohorts, aspartame consumption did not increase breast cancer risk., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To evaluate whether disparities exist in adverse neonatal outcomes among the offspring of lesbian, gay, bisexual, and other sexually minoritized (LGB+) birthing people., Methods: We used longitudinal data from 1995 to 2017 from the Nurses' Health Study II, a cohort of nurses across the United States. We restricted analyses to those who reported live births (N=70,642) in the 2001 or 2009 lifetime pregnancy questionnaires. Participants were asked about sexual orientation identity (current and past) and same-sex attractions and partners. We examined preterm birth, low birth weight, and macrosomia among 1) completely heterosexual; 2) heterosexual with past same-sex attractions, partners, or identity; 3) mostly heterosexual; 4) bisexual; and 5) lesbian or gay participants. We used log-binomial models to estimate risk ratios for each outcome and weighted generalized estimating equations to account for multiple pregnancies per person over time and informative cluster sizes., Results: Compared with completely heterosexual participants, offspring born to parents in all LGB+ groups combined (groups 2-5) had higher estimated risks of preterm birth (risk ratio 1.22, 95% CI, 1.15-1.30) and low birth weight (1.27, 95% CI, 1.15-1.40) but not macrosomia (0.98, 95% CI, 0.94-1.02). In the subgroup analysis, risk ratios were statistically significant for heterosexual participants with past same-sex attractions, partners, or identity (preterm birth 1.25, 95% CI, 1.13-1.37; low birth weight 1.32, 95% CI, 1.18-1.47). Risk ratios were elevated but not statistically significant for lesbian or gay participants (preterm birth 1.37, 95% CI, 0.98-1.93; low birth weight 1.46, 95% CI, 0.96-2.21) and bisexual participants (preterm birth 1.29, 95% CI, 0.85-1.93; low birth weight 1.24, 95% CI, 0.74-2.08)., Conclusion: The offspring of LGB+ birthing people experience adverse neonatal outcomes, specifically preterm birth and low birth weight. These findings highlight the need to better understand health risks, social inequities, and health care experiences that drive these adverse outcomes., Competing Interests: Financial Disclosure Payal Chakraborty was a research consultant for the Ohio Policy Evaluation Network (OPEN) at The Ohio State University and for the STRIPED research project at Boston Children's Hospital. She received honorariums from the Society of Family Planning for being a grant reviewer. She received travel support from the Take Root 2023 conference. Juno Obedin-Maliver reports receiving payments from Ibis Reproductive Health, Hims, Inc, Folx Inc, and Upstream Inc. The other authors did not report any potential conflicts of interest., (Copyright © 2024 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Clinical genetic testing identifies variants causal for hereditary cancer, information that is used for risk assessment and clinical management. Unfortunately, some variants identified are of uncertain clinical significance (VUS), complicating patient management. Case-control data is one evidence type used to classify VUS, and previous findings indicate that case-control likelihood ratios (LRs) outperform odds ratios for variant classification. As an initiative of the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) Analytical Working Group we analyzed germline sequencing data of BRCA1 and BRCA2 from 96,691 female breast cancer cases and 303,925 unaffected controls from three studies: the BRIDGES study of the Breast Cancer Association Consortium, the Cancer Risk Estimates Related to Susceptibility consortium, and the UK Biobank. We observed 11,227 BRCA1 and BRCA2 variants, with 6,921 being coding, covering 23.4% of BRCA1 and BRCA2 VUS in ClinVar and 19.2% of ClinVar curated (likely) benign or pathogenic variants. Case-control LR evidence was highly consistent with ClinVar assertions for (likely) benign or pathogenic variants; exhibiting 99.1% sensitivity and 95.4% specificity for BRCA1 and 92.2% sensitivity and 86.6% specificity for BRCA2 . This approach provides case-control evidence for 785 unclassified variants, that can serve as a valuable element for clinical classification.

Background: Estradiol and estrone are well-established risk factors for postmenopausal breast cancer (BC). Experimental evidence suggests that specific estrogen metabolites, produced via irreversible hydroxylation of estrone and estradiol at the 2- or 16-position may independently influence carcinogenesis., Methods: We performed a nested case-control study of BC (328 BC cases; 639 controls) among postmenopausal women within the Nurses' Health Study (NHS)to examine the role of estrogens and estrogen metabolites (jointly referred to as EM). Plasma concentrations of each EM (unconjugated+conjugated forms) were measured by liquid chromatography-tandem mass spectrometry. Multivariable conditional logistic regression, adjusting for BC risk factors, estimated relative risks (RR) and 95% confidence intervals (CI) of BC across quintiles of individual EM, EM pathways, and pathway ratios. Associations by estrogen/progesterone receptor (ER/PR) status were analyzed by unconditional logistic regression., Results: Estradiol and estrone were strongly associated with increased BC risk [estradiol: RRQ5v.Q1 (95% CI)=2.64 (1.64-4.26), estrone: 2.78 (1.74-4.45); both p-trends<0.001]. The 2-hydroxylation pathway was strongly associated with risk [RRQ5v.Q1=3.09 (1.81-5.27), p-trend<0.001], and remained so after adjusting for unconjugated estradiol [RRQ5v.Q1=2.23 (1.25-3.96), p-trend=0.01]. While the 16-hydroxylation pathway was modestly associated with risk [RRQ5v.Q1=1.62 (1.03-2.54), p-trend=0.01], the association was attenuated after unconjugated estradiol adjustment [RRQ5v.Q1=1.24 (0.77-1.99), p-trend=0.19]. Similar positive associations with the 2-pathway and 16-pathway were observed for ER+/PR+ and ER-/PR- tumors., Conclusions: In this cohort of postmenopausal women, 2-hydroxylation of estrone and estradiol was associated with increased BC risk, independent of unconjugated estradiol., Impact: These results highlight the need to revisit the role of estrogen metabolism in BC etiology and prevention.

Objective: Our objective was to prospectively investigate prediagnostic population-based metabolome for risk of hospitalized gout (ie, most accurate, severe, and costly cases), accounting for serum urate., Methods: We conducted prediagnostic metabolome-wide analyses among 249,677 UK Biobank participants with nuclear magnetic resonance metabolomic profiling (N = 168 metabolites, including eight amino acids) from baseline blood samples (2006-2010) without a history of gout. We calculated multivariable hazard ratios (HRs) for hospitalized incident gout, before and after adjusting for serum urate levels; we included patients with nonhospitalized incident gout in a sensitivity analysis. Potential causal effects were evaluated with two-sample Mendelian randomization., Results: Correcting for multiple testing, 107 metabolites were associated with incidence of hospitalized gout (n = 2,735) before urate adjustment, including glycine and glutamine (glutamine HR 0.64, 95% confidence interval [CI] 0.54-0.75, P = 8.3 × 10 -8 ; glycine HR 0.69, 95% CI 0.61-0.78, P = 3.3 × 10 -9 between extreme quintiles), and glycoprotein acetyls (HR 2.48, 95% CI 2.15-2.87, P = 1.96 × 10 -34 ). Associations remained significant and directionally consistent following urate adjustment (HR 0.83, 95% CI 0.70-0.98; HR 0.86, 95% CI 0.76-0.98; HR 1.41, 95% CI 1.21-1.63 between extreme quintiles), respectively; corresponding HRs per SD were 0.91 (95% CI 0.86-0.97), 0.94 (95% CI 0.91-0.98), and 1.10 (95% CI 1.06-1.14). Findings persisted when including patients with nonhospitalized incident gout. Mendelian randomization corroborated their potential causal role on hyperuricemia or gout risk; with change in urate levels of -0.05 mg/dL (95% CI -0.08 to -0.01) and -0.12 mg/dL (95% CI -0.22 to -0.03) per SD of glycine and glutamine, respectively, and odds ratios of 0.94 (95% CI 0.88-1.00) and 0.81 (95% CI 0.67-0.97) for gout., Conclusion: These prospective findings with causal implications could lead to biomarker-based risk prediction and potential supplementation-based interventions with glycine or glutamine., (© 2024 American College of Rheumatology.)

Background: Inflammation and metabolic dysregulation are associated with increased risk of colorectal cancer (CRC); the underlying mechanisms are not fully understood. We characterized metabolomic signatures of inflammation and metabolic dysregulation and evaluated the association of the signatures and individual metabolites with CRC risk., Methods: Among 684 incident CRC cases and 684 age-matched controls in the Nurses' Health Study (n = 818 women) and Health Professionals Follow-up Study (n = 550 men), we applied reduced rank and elastic net regression to 277 metabolites for markers of inflammation (C-reactive protein, interleukin 6, tumor necrosis factor receptor superfamily member 1B, and growth differentiation factor 15) or metabolic dysregulation (body mass index, waist circumference, C-peptide, and adiponectin) to derive metabolomic signatures. We evaluated the association of the signatures and individual metabolites with CRC using multivariable conditional logistic regression. All statistical tests were 2-sided., Results: We derived a signature of 100 metabolites that explained 24% of variation in markers of inflammation and a signature of 73 metabolites that explained 27% of variation in markers of metabolic dysregulation. Among men, both signatures were associated with CRC (odds ratio [OR] = 1.34, 95% confidence interval [CI] = 1.07 to 1.68 per 1-standard deviation increase, inflammation; OR = 1.25, 95% CI = 1.00 to 1.55 metabolic dysregulation); neither signature was associated with CRC in women. A total of 11 metabolites were individually associated with CRC and biomarkers of inflammation or metabolic dysregulation among either men or women., Conclusion: We derived metabolomic signatures and identified individual metabolites associated with inflammation, metabolic dysregulation, and CRC, highlighting several metabolites as promising candidates involved in the inflammatory and metabolic dysregulation pathways for CRC incidence., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: To support mammography screening decision making, we developed a competing-risk model to estimate 5-year breast cancer risk and 10-year nonbreast cancer death for women aged 55 years and older using Nurses' Health Study data and examined model performance in the Black Women's Health Study (BWHS). Here, we examine model performance in predicting 10-year outcomes in the BWHS, Women's Health Initiative-Extension Study (WHI-ES), and Multiethnic Cohort (MEC) and compare model performance to existing breast cancer prediction models., Methods: We used competing-risk regression and Royston and Altman methods for validating survival models to calculate our model's calibration and discrimination (C index) in BWHS (n = 17 380), WHI-ES (n = 106 894), and MEC (n = 49 668). The Nurses' Health Study development cohort (n = 48 102) regression coefficients were applied to the validation cohorts. We compared our model's performance with breast cancer risk assessment tool (Gail) and International Breast Cancer Intervention Study (IBIS) models by computing breast cancer risk estimates and C statistics., Results: When predicting 10-year breast cancer risk, our model's C index was 0.569 in BWHS, 0.572 in WHI-ES, and 0.576 in MEC. The Gail model's C statistic was 0.554 in BWHS, 0.564 in WHI-ES, and 0.551 in MEC; IBIS's C statistic was 0.547 in BWHS, 0.552 in WHI-ES, and 0.562 in MEC. The Gail model underpredicted breast cancer risk in WHI-ES; IBIS underpredicted breast cancer risk in WHI-ES and in MEC but overpredicted breast cancer risk in BWHS. Our model calibrated well. Our model's C index for predicting 10-year nonbreast cancer death was 0.760 in WHI-ES and 0.763 in MEC., Conclusions: Our competing-risk model performs as well as existing breast cancer prediction models in diverse cohorts and predicts nonbreast cancer death. We are developing a website to disseminate our model., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)