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Abstract Estrogens regulate numerous physiological and pathological processes, including wide-ranging effects in wound healing. The effects of estrogens are mediated through multiple estrogen receptors (ERs), including the classical nuclear ERs (ERα and ER $${\upbeta }$$ β ), that typically regulate gene expression, and the 7-transmembrane G protein-coupled estrogen receptor (GPER), that predominantly mediates rapid “non-genomic” signaling. Estrogen modulates the expression of various genes involved in epidermal function and regeneration, inflammation, matrix production, and protease inhibition, all critical to wound healing. Our previous work demonstrated improved myocutaneous wound healing in female mice compared to male mice. In the current study, we employed male and female GPER knockout mice to investigate the role of this estrogen receptor in wound revascularization and tissue viability. Using a murine myocutaneous flap model of graded ischemia, we measured real-time flap perfusion via laser speckle perfusion imaging. We conducted histologic and immunohistochemical analyses to assess skin and muscle viability, microvascular density and vessel morphology. Our results demonstrate that GPER is crucial in wound healing, mediating effects that are both dependent and independent of sex. Lack of GPER expression is associated with increased skin necrosis, reduced flap perfusion and altered vessel morphology. These findings contribute to understanding GPER signaling in wound healing and suggest possible therapeutic opportunities by targeting GPER.

Abstract CLARITY-AD is an 18-month, double-blinded, placebo-controlled, phase 3 trial which examined the safety and efficacy of the anti-amyloid agent, lecanemab, in mild cognitive impairment and mild dementia due to Alzheimer disease (AD). Lecanemab effectively reduced mean brain amyloid burden and was associated with statistically significant favorable effects, reflected by moderately less decline in the primary and secondary clinical outcomes, at 18 months compared to placebo. However, there is controversy within the AD community regarding the clinical significance of these results and whether they translate into clinically meaningful and tangible benefits on cognition or daily functions. We here review the primary and secondary clinical outcomes of CLARITY-AD and present our interpretation of the potential clinical meaningfulness of the group-level differences in study outcomes in the context of the 18-month study duration. We propose that the validation of stage-appropriate group-level thresholds for clinical meaningfulness of AD trial outcomes in biologically confirmed cohorts will allow objective interpretation of trial results and guide clinical decision-making. Further, in accordance with FDA guidance which emphasizes patient-focused drug development, the contextualization of AD clinical trial outcomes can be facilitated by supplementary individual-level data analyses which measure the risk of disease progression or summarize intraindividual change, using prespecified thresholds of clinically meaningful change, in each of the study groups over the trial period. The concepts of “time-saved” and “time-based” slowing in disease progression can be used to communicate clinical outcomes associated with emerging disease-modifying AD therapies to various stakeholders. We also describe several factors that need to be considered when evaluating outcomes of emerging AD therapies, including disease stage, the neuropathologic complexity of AD, time-based effects of disease-modifying therapies, and the possible influence of individual factors on treatment response and/or risk for adverse events. The consideration of these factors in the design and reporting of future trials of emerging AD therapies will guide clinicians regarding their appropriateness for use in various patient populations. Finally, we emphasize that data from clinical cohorts with longer durations of treatment and follow-up, including extension studies and patient registries, is needed to evaluate the long-term safety and efficacy of lecanemab in early symptomatic AD.

Abstract Background When a Zuni elder sustains a fall-related injury, the closest tribal skilled nursing facility is 100 miles from the Pueblo and no physical therapy services are available. Thus, fall prevention strategies as a primary intervention to avert injurious falls and preserve aging in place are needed. The objective of the study is to compare the effectiveness of a community health representative (CHR)-delivered, culturally-adapted Otago Exercise Program (OEP) fall prevention program compared to the standard of care education-based fall risk management. Methods “Standing Strong in Tribal Communities: Assessing Elder Falls Disparity” is mixed-methods research with a randomized controlled trial. The CHRs will be trained to deliver the culturally-adapted OEP trial and offer advantages of speaking “Shiwi” (Zuni tribal language) and understanding Zuni traditions, family structures, and elders’ preferences for receiving health information. Focus groups will be conducted to assure all materials are culturally appropriate, and adapted. A physical therapist will train CHRs to screen elders for falls risk and to deliver the OEP to the intervention group and education to the control group. Up to 400 Zuni elders will be screened by the CHRs for falls risk and 200 elders will be enrolled into the study (1:1 random allocation by household). The intervention is 6 months with measurements at baseline, 3, 6 and 12 months. The primary outcome is improved strength and balance (timed up and go, sit to stand and 4 stage balance test), secondary outcomes include falls incidence, self-efficacy using Attitudes to Falls-Related Interventions Scale, Medical Outcomes Study Short Form 12 (SF-12v2) and Self-Efficacy for Managing Daily Activities. Discussion Fall prevention for Zuni elders was identified as a tribal priority and this trial is built upon longstanding collaborations between the investigative team, Zuni tribal leaders, and multiple tribal health programs. Delivery by the CHRs make this model more acceptable, and thus, more sustainable long term. This study has the potential to change best practice for elder care in tribal and rural areas with limited access to physical therapist-delivered fall prevention interventions and aligns with tribal goals to avert fall-related injury, reduce healthcare disparity, and preserve elder’s independence. Trial registration NCT04876729

Background: Elevated urine albumin to creatinine ratio (UACR) is associated with cerebrovascular disease and cognitive impairment in older adults, though few studies have evaluated these relationships in midlife. This is particularly important to assess in American Indian populations, which are disproportionately impacted by diabetes and kidney disease. Additionally, evidence suggests that biomarkers may perform differently in underrepresented groups, thus, it is crucial to validate biomarkers in this unique population. Methods: Twenty-five participants from the Zuni Pueblo underwent neuropsychological assessment and an MRI that included fluid attenuated inversion recovery (FLAIR) and diffusion imaging to calculate recently developed MRI markers of cerebrovascular small vessel disease (Peak width of Skeletonized Mean Diffusivity (PSMD), mean free-water fraction (mFW), white matter hyperintensity (WMH)). Results: Regression analyses indicated no significant associations between UACR, MRI biomarkers and cognitive outcomes. Analyses of covariance indicated that the Zuni Indian cohort exhibited reduced white matter damage relative to an existing cohort of older adults with vascular cognitive impairment when accounting for age, sex, and education. Slower processing speed was associated with greater white matter disease across all measures examined. Conclusions: Our pilot study validated the use of MRI biomarkers of cerebrovascular disease in this unique cohort of American Indians.

Introduction Survival following colorectal cancer (CRC) has improved in the US since 1975, but there is limited information on stage-specific survival trends among racial and ethnic subgroups. Objectives The purpose of this study was to estimate and compare trends in 1- and 5-year CRC cause-specific survival in the United States by both stage and race/ethnicity. Methods We performed a retrospective cohort study of individuals diagnosed with CRC using the 1992-2018 Surveillance, Epidemiology and End Results (SEER) database. We estimated and compared time trends in 1- and 5-year survival for CRC stage by race/ethnicity. Results Data from 399 220 individuals diagnosed with CRC were available. There were significant differences in stage-specific 1-year survival trends by race and ethnicity. Differences were most notable for distant stage CRC: survival probabilities increased most consistently for non-Hispanic American Indian/Alaska Native (AIAN) and Black (NHB) persons, but their trend lines were lower than those of Hispanic, and non-Hispanic Asian/Pacific Islander (API) and White (NHW) persons, whose initially greater gains appear to be slowing. Although the data do not support significant racial/ethnic differences in 5-year CRC survival trends by stage, AIAN and NHB persons have the lowest average survival probabilities for multiple CRC stages, and no racial/ethnic group has 5-year survival probabilities above 20% for distant-stage CRC. Conclusion Although there has been an overall improvement in adjusted CRC-specific survival probabilities since 1992, AIAN and NHB persons continue to experience worse prognosis than those of other races/ethnicities. This highlights the importance of reinvigorating efforts to understand the causes of mortality in CRC, including those which may differ according to an individual’s race or ethnicity.

Abstract Background Chronic kidney disease (CKD) is an increasing epidemic globally that is associated with adverse health outcomes including end stage kidney disease (ESKD), cardiovascular disease (CVD), and death. American Indians (AIs) have a higher prevalence of CKD than most other racial/ethnic groups, due in part to a high prevalence of type 2 diabetes. Other genetic and environmental factors not yet identified may also contribute to the disproportionate burden of CKD in AIs. Method We will establish 3 clinical centers to recruit AIs from the Southwest United States (US) to expand the Chronic Renal Insufficiency Cohort (CRIC) study. We will follow the current CRIC protocol for kidney and cardiovascular measures and outcomes, which include ambulatory monitoring of kidney function and the use of mobile health technologies for CVD sub-phenotyping, and compare the outcomes in AIs with those in other racial/ethnic groups in CRIC. Discussion AI-CRIC will identify the role of various risk factors for rapid loss of kidney function among AIs of the Southwest US. In addition, to better understand the natural history of CKD and CVD in this high-risk population, we will identify unique risk factors for CKD and CVD progression in AIs. We will also compare event rates and risk factors for kidney and cardiovascular events in AIs with the other populations represented in CRIC.

Purpose: To examine potential factors associated with maintaining or improving self-reported physical function (PF) among older cancer survivors participating in a gardening intervention impacted by the Coronavirus 2019 (COVID-19) pandemic. Methods: Thirty cancer survivors completed a home-based gardening intervention to encourage a healthier diet and a more active lifestyle. Device-based measures of physical activity (PA) and surveys to evaluate quality of life (QOL; PROMIS-57 questionnaire) were administered at baseline, mid-intervention (6 months), and post-intervention (9 months). Results: Depression, fatigue, and sleeplessness at baseline were significantly associated with worse average PF scores across follow-up (2.3 to 4.9 points lower for every decrease of 5 points in the QOL score; p-values < 0.02). Worsening of these QOL domains during the intervention was also associated with an additional decrease of 2.1 to 2.9 points in PF over follow-up (p values < 0.01). Better social participation and PA at baseline were significantly associated with better average PF scores during the intervention (2.8 to 5.2 points higher for every 5-point increase in social participation or 30 min more of PA; p values < 0.05). Every 5-point increase in pain at baseline, or increases in pain during the intervention, was associated with decreases of 4.9 and 3.0 points, respectively, in PF. Conclusions: Worse QOL scores before and during the intervention were significantly associated with worse PF over follow-up. Encouraging social participation and PA through interventions such as home-based gardening may improve long-term health among older cancer survivors.

Abstract Background Over 40% of women undergoing breast screening have mammographically dense breasts. Elevated mammographic breast density (MBD) is an established breast cancer risk factor and is known to mask tumors within the dense tissue. However, the association of MBD with high risk benign breast disease (BBD) is unknown. Method We analyzed data for 3400 women diagnosed with pathologically confirmed BBD in the Mayo Clinic BBD cohort from 1985–2001, with a clinical MBD measure (either parenchymal pattern (PP) or Breast Imaging Reporting and Data Systems (BI-RADS) density) and expert pathology review. Risk factor information was collected from medical records and questionnaires. MBD was dichotomized as dense (PP classification P2 or DY, or BI-RADS classification c or d) or non-dense (PP classification N1 or P1, or BI-RADS classification a or b). Associations of clinical and histologic characteristics with MBD were examined using logistic regression analysis to estimate odds ratios (ORs) with 95% confidence intervals (CIs). Results Of 3400 women in the study, 2163 (64%) had dense breasts. Adjusting for age and body mass index (BMI), there were positive associations of dense breasts with use of hormone therapy (HT), lack of lobular involution, presence of atypical lobular hyperplasia (ALH), histologic fibrosis, columnar cell hyperplasia/flat epithelia atypia (CCH/FEA), sclerosing adenosis (SA), cyst, usual ductal hyperplasia, and calcifications. In fully adjusted multivariate models, HT (1.3, 95% CI 1.1–1.5), ALH (1.5, 95% CI 1.0–2.2), lack of lobular involution (OR 1.6, 95% CI 1.2–2.1, compared to complete involution), fibrosis (OR 2.2, 95% CI 1.9–2.6) and CCH/FEA (OR 1.3, 95% CI 1.0–1.6) remained significantly associated with high MBD. Conclusion Our findings support an association between high risk BBD and high MBD, suggesting that risks associated with the latter may act early in breast carcinogenesis.

Research Highlights: When biotic interactions such as disease alter both the seed production capacity of stands, and seedling survivorship, the relative importance of seed availability versus substrate specificity may alter future regeneration opportunities for plant populations. Background and Objectives: We investigated the importance of disease severity, seed availability, and substrate limitation to the regeneration dynamics of the endangered limber pine, Pinus flexilis, in two ecosystems with varying forest composition, and different histories of white pine blister rust infection (WPBR; Cronartium ribicola). Materials and Methods: A total of 17 stands from the montane ecoregion (Alberta, Canada) were sampled for seed production between 2007⁻2010, seedling density, and age structure. Model selection using an information theoretic approach compared a series of a priori models and their combinations, based on our hypotheses on the role biotic variables play in the regeneration process. Results: Despite higher rates of WPBR infection, 2.3 times more seed was available for avian dispersers in the southern ecosystem. Recent seedling regeneration did not correspond to seed production (83 versus 251 seedlings/ha, in southern versus northern ecosystems, respectively), resulting in a seven-fold difference in seed to seedling ratios between ecosystems. Models suggest that disease and vegetation cover were important factors explaining the absence of regeneration in 79.4% of the plots sampled, while basal area (BA) of live limber pine, rocky substrates, ecosystem, South aspects, and slope enhanced limber pine regeneration. Seedling age structures suggest that recent regeneration is less likely in more diseased landscapes, than it was historically (40% versus 72.8% of seedlings < 20 years old, respectively, in southern versus northern ecosystems). Conclusions: At the northern limits of limber pine’s range, seed availability does not ensure regeneration, suggesting that other environmental or biotic factors hinder regeneration. Regeneration was consistently predicted to be lower in the southern ecosystem than in the northern ecosystem, suggesting that natural regeneration and the potential for population recovery are ecosystem dependent. We recommend that monitoring recent seedlings will aid the identification of biotic and abiotic factors affecting regeneration.

While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04-1.15, p = 1.9 x 10(-4) (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03-1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted pinteraction values > 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients' survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers.

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 × 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 × 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 × 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.

Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9 × 10(-8)). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer.

The role of fathers in elementary education has shifted drastically in recent years. In particular, stay-at-home dads (SAHDs) have become more relevant in the lives of children. Despite these changes, there remains a paucity of research on SAHDs' experiences with their children's schools. This qualitative study examined SAHDs' perceptions of and experiences with their children's schools. The research identified three themes: (a) involvement, (b) interactions, and (c) communication. The researchers discuss implications for elementary school counseling practice as well as future areas of research.

OBJECTIVE. Our previous work showed that variation measures, which represent breast architecture derived from mammograms, were significantly associated with breast cancer. For replication purposes, we examined the association of three variation measures (variation [V], which is measured in the image domain, and P1 and p1 [a normalized version of P1], which are derived from restricted regions in the Fourier domain) with breast cancer risk in an independent population. We also compared these measures to volumetric density measures (volumetric percent density [VPD] and dense volume [DV]) from a commercial product. MATERIALS AND METHODS. We examined 514 patients with breast cancer and 1377 control patients from a screening practice who were matched for age, date of examination, mammography unit, facility, and state of residence. Spearman rank-order correlation was used to evaluate the monotonic association between measures. Breast cancer associations were estimated using conditional logistic regression, after adjustment for age and body mass index. Odds ratios were calculated per SD increment in mammographic measure. RESULTS. These variation measures were strongly correlated with VPD (correlation, 0.68-0.80) but not with DV (correlation, 0.31-0.48). Similar to previous findings, all variation measures were significantly associated with breast cancer (odds ratio per SD: 1.30 [95% CI, 1.16-1.46] for V, 1.55 [95% CI, 1.35-1.77] for P1, and 1.51 [95% CI, 1.33-1.72] for p1). Associations of volumetric density measures with breast cancer were similar (odds ratio per SD: 1.54 [95% CI, 1.33-1.78] for VPD and 1.34 [95% CI, 1.20-1.50] for DV). When DV was included with each variation measure in the same model, all measures retained significance. CONCLUSION. Variation measures were significantly associated with breast cancer risk (comparable to the volumetric density measures) but were independent of the DV.

High alcohol intake and breast density increase breast cancer (BC) risk, but their interrelationship is unknown. We examined whether volumetric density modifies and/or mediates the alcohol-BC association. BC cases (n = 2233) diagnosed from 2006 to 2013 in the San Francisco Bay area had screening mammograms 6 or more months before diagnosis; controls (n = 4562) were matched on age, mammogram date, race or ethnicity, facility, and mammography machine. Logistic regression was used to estimate alcohol-BC associations adjusted for age, body mass index, and menopause; interaction terms assessed modification. Percent mediation was quantified as the ratio of log (odds ratios [ORs]) from models with and without density measures. Alcohol consumption was associated with increased BC risk (2-sided Ptrend = .004), as were volumetric percent density (OR = 1.45 per SD, 95% confidence interval [CI] = 1.36 to 1.56) and dense volume (OR = 1.30, 95% CI = 1.24 to 1.37). Breast density did not modify the alcohol-BC association (2-sided P > .10 for all). Dense volume mediated 25.0% (95% CI = 5.5% to 44.4%) of the alcohol-BC association (2-sided P = .01), suggesting alcohol may partially increase BC risk by increasing fibroglandular tissue.

Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.

Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.

BackgroundThe rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study.MethodsWe genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant.ResultsFor European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10-5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10-8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants.ConclusionsThis report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.

While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04-1.15, p = 1.9 x 10(-4) (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03-1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted pinteraction values > 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients' survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers.

IntroductionWe have previously shown that a tag single nucleotide polymorphism (rs10235235), which maps to the CYP3A locus (7q22.1), was associated with a reduction in premenopausal urinary estrone glucuronide levels and a modest reduction in risk of breast cancer in women age ≤50 years.MethodsWe further investigated the association of rs10235235 with breast cancer risk in a large case control study of 47,346 cases and 47,570 controls from 52 studies participating in the Breast Cancer Association Consortium. Genotyping of rs10235235 was conducted using a custom Illumina Infinium array. Stratified analyses were conducted to determine whether this association was modified by age at diagnosis, ethnicity, age at menarche or tumor characteristics.ResultsWe confirmed the association of rs10235235 with breast cancer risk for women of European ancestry but found no evidence that this association differed with age at diagnosis. Heterozygote and homozygote odds ratios (ORs) were OR = 0.98 (95% CI 0.94, 1.01; P = 0.2) and OR = 0.80 (95% CI 0.69, 0.93; P = 0.004), respectively (P(trend) = 0.02). There was no evidence of effect modification by tumor characteristics. rs10235235 was, however, associated with age at menarche in controls (P(trend) = 0.005) but not cases (P(trend) = 0.97). Consequently the association between rs10235235 and breast cancer risk differed according to age at menarche (P(het) = 0.02); the rare allele of rs10235235 was associated with a reduction in breast cancer risk for women who had their menarche age ≥15 years (OR(het) = 0.84, 95% CI 0.75, 0.94; OR(hom) = 0.81, 95% CI 0.51, 1.30; P(trend) = 0.002) but not for those who had their menarche age ≤11 years (OR(het) = 1.06, 95% CI 0.95, 1.19, OR(hom) = 1.07, 95% CI 0.67, 1.72; P(trend) = 0.29).ConclusionsTo our knowledge rs10235235 is the first single nucleotide polymorphism to be associated with both breast cancer risk and age at menarche consistent with the well-documented association between later age at menarche and a reduction in breast cancer risk. These associations are likely mediated via an effect on circulating hormone levels.

ObjectiveThe newly proposed National Institute on Aging-Alzheimer's Association (NIA-AA) criteria for mild cognitive impairment (MCI) due to Alzheimer disease (AD) suggest a combination of clinical features and biomarker measures, but their performance in the community is not known.MethodsThe Mayo Clinic Study of Aging (MCSA) is a population-based longitudinal study of nondemented subjects in Olmsted County, Minnesota. A sample of 154 MCI subjects from the MCSA was compared to a sample of 58 amnestic MCI subjects from the Alzheimer's Disease Neuroimaging Initiative 1 (ADNI-1) to assess the applicability of the criteria in both settings and to assess their outcomes.ResultsFourteen percent of MCSA and 16% of ADNI-1 of subjects were biomarker negative. In addition, 14% of MCSA and 12% of ADNI-1 subjects had evidence for amyloid deposition only, whereas 43% of MCSA and 55% of ADNI-1 subjects had evidence for amyloid deposition plus neurodegeneration (magnetic resonance imaging atrophy, fluorodeoxyglucose positron emission tomography hypometabolism, or both). However, a considerable number of subjects had biomarkers inconsistent with the proposed AD model; for example, 29% of MCSA subjects and 17% of ADNI-1 subjects had evidence for neurodegeneration without amyloid deposition. These subjects may not be on an AD pathway. Neurodegeneration appears to be a key factor in predicting progression relative to amyloid deposition alone.InterpretationThe NIA-AA criteria apply to most MCI subjects in both the community and clinical trials settings; however, a sizeable proportion of subjects had conflicting biomarkers, which may be very important and need to be explored.

In 2010, we put forward a hypothetical model of the major biomarkers of Alzheimer's disease (AD). The model was received with interest because we described the temporal evolution of AD biomarkers in relation to each other and to the onset and progression of clinical symptoms. Since then, evidence has accumulated that supports the major assumptions of this model. Evidence has also appeared that challenges some of our assumptions, which has allowed us to modify our original model. Refinements to our model include indexing of individuals by time rather than clinical symptom severity; incorporation of interindividual variability in cognitive impairment associated with progression of AD pathophysiology; modifications of the specific temporal ordering of some biomarkers; and recognition that the two major proteinopathies underlying AD biomarker changes, amyloid β (Aβ) and tau, might be initiated independently in sporadic AD, in which we hypothesise that an incident Aβ pathophysiology can accelerate antecedent limbic and brainstem tauopathy.