Citations

Abstract Over one million biopsies are performed annually in the U.S. to evaluate suspicious breast lesions. Most biopsies lead to a diagnosis of benign breast disease (BBD) and these women have a 1.5- to fourfold increase in subsequent breast cancer (BC) risk compared with the general population. A polygenic risk score (PRS) including 313 common variants was developed to predict BC risk in the general population and has improved performance when added to existing BC prediction models. However, the value of PRS in risk prediction models among women with BBD has not been evaluated. To evaluate the role of the established PRS, BBD, and BC risk, we pooled data from 15,194 white women (6,706 BC cases and 8,488 controls) participating in five Breast Cancer Association Consortium case-control studies. BC risk associations were evaluated by self-reported BBD history and combinations of PRS expressed in tertiles using odds ratios (OR), considering the lowest category of PRS among women without BBD as the referent. Associations were also assessed in an independent case-cohort study (831 BC cases and 1,845 controls) using hazard ratios (HR). Among the case-control studies, the PRS was strongly associated with BC risk (OR=2.50 per standard deviation increase), and associations were similar in women with (OR=2.60) and without a history of BBD (OR=2.44, p-interaction=0.23). Women with BBD have a higher risk of BC than those without BBD within each level of PRS. Compared to women without BBD and in the lowest PRS category, those with BBD and PRS in the highest tertile had 5-fold increased odds of BC (OR = 5.38; 95% CI 4.73-6.13). Associations were similar in an independent case-cohort study. These findings indicate that BBD history and PRS are independent contributors to BC risk, and consideration of both simultaneously could improve breast cancer risk prediction. Future studies are needed to integrate PRS with other risk measures to refine absolute BC risk prediction among BBD patients. Associations of BC risk with combinations of PRS (tertiles) and history of BBD in five case-control studies and a case-cohort study from the Breast Cancer Association Consortium. Case-control studies Case-cohort study PRS score range History of BBD n BC cases n controls OR (95% CI)1 n BC cases n controls HR (95% CI)2 Tertile 1 (≤ -0.57) No 1009 2692 1.00 (Ref) 117 584 1.00 (Ref) Yes 508 902 1.54 (1.35-1.76) 69 163 2.05 (1.45-2.89) Tertile 2 (-0.58, -0.03) No 1469 2001 1.97 (1.78-2.17) 181 475 1.93 (1.48-2.51) Yes 760 798 2.65 (2.34-3.01) 108 170 2.99 (2.18-4.09) Tertile 3 (≥ -0.02) No 1910 1551 3.32 (3.01-3.67) 214 336 3.28 (2.52-4.26) Yes 1050 544 5.38 (4.73-6.13) 142 117 4.83 4.25-8.02) 1.Logistic regression analysis, adjusted for study site/genomic platform and age at enrollment. OR, odds ratio; CI, confidence interval.2.Cox proportional hazards regression analysis, accounting for the case-cohort study design and adjusted for age at enrollment. HR, hazard ratio; CI, confidence interval. Citation Format: Stacey J. Winham, Mark Sherman, Robert Vierkant, Bryan McCauley, Christopher Scott, Mia Gaudet, Melissa Troester, Sandhya Pruthi, Derek Radisky, Amy Degnim, Kristan Aronson, Rachel Murphy, Pascal Guenel, Therese Truong, Jenny Chang-Claude, Heiko Becher, Montserrat Garcia-Closas, Stephen Chanock, Thomas Ahearn, Xiaohong Yang, Doug Easton, Manjeet Bolla, Celine Vachon, Breast Cancer Association Consortium. Association of polygenic risk scores with breast cancer risk among women with benign breast disease. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5241.

Background and Aims: Magnetic resonance elastography (MRE) is an accurate, continuous biomarker of liver fibrosis; however, the optimal combination with clinical factors to predict the risk of incident hepatic decompensation is unknown. Therefore, we aimed to develop and validate an MRE-based prediction model for hepatic decompensation for patients with NAFLD. Approach and Results: This international multicenter cohort study included participants with NAFLD undergoing MRE from 6 hospitals. A total of 1254 participants were randomly assigned as training (n = 627) and validation (n = 627) cohorts. The primary end point was hepatic decompensation, defined as the first occurrence of variceal hemorrhage, ascites, or HE. Covariates associated with hepatic decompensation on Cox-regression were combined with MRE to construct a risk prediction model in the training cohort and then tested in the validation cohort. The median (IQR) age and MRE values were 61 (18) years and 3.5 (2.5) kPa in the training cohort and 60 (20) years and 3.4 (2.5) kPa in the validation cohort, respectively. The MRE-based multivariable model that included age, MRE, albumin, aspartate aminotransferase, and platelets had excellent discrimination for the 3- and 5-year risk of hepatic decompensation (c-statistic 0.912 and 0.891, respectively) in the training cohort. The diagnostic accuracy remained consistent in the validation cohort with a c-statistic of 0.871 and 0.876 for hepatic decompensation at 3 and 5 years, respectively, and was superior to Fibrosis-4 in both cohorts (p < 0.05). Conclusions: An MRE-based prediction model allows for accurate prediction of hepatic decompensation and assists in the risk stratification of patients with NAFLD.

Abstract Background Epidemiological studies that examined the association between Parkinson's disease (PD) and cancers led to inconsistent results, but they face a number of methodological difficulties. Objective We used results from genome‐wide association studies (GWASs) to study the genetic correlation between PD and different cancers to identify common genetic risk factors. Methods We used individual data for participants of European ancestry from the Courage‐PD (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease; PD, N = 16,519) and EPITHYR (differentiated thyroid cancer, N = 3527) consortia and summary statistics of GWASs from iPDGC (International Parkinson Disease Genomics Consortium; PD, N = 482,730), Melanoma Meta‐Analysis Consortium (MMAC), Breast Cancer Association Consortium (breast cancer), the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (prostate cancer), International Lung Cancer Consortium (lung cancer), and Ovarian Cancer Association Consortium (ovarian cancer) (N comprised between 36,017 and 228,951 for cancer GWASs). We estimated the genetic correlation between PD and cancers using linkage disequilibrium score regression. We studied the association between PD and polymorphisms associated with cancers, and vice versa, using cross‐phenotypes polygenic risk score (PRS) analyses. Results We confirmed a previously reported positive genetic correlation of PD with melanoma (G corr = 0.16 [0.04; 0.28]) and reported an additional significant positive correlation of PD with prostate cancer (G corr = 0.11 [0.03; 0.19]). There was a significant inverse association between the PRS for ovarian cancer and PD (odds ratio [OR] = 0.89 [0.84; 0.94]). Conversely, the PRS of PD was positively associated with breast cancer (OR = 1.08 [1.06; 1.10]) and inversely associated with ovarian cancer (OR = 0.95 [0.91; 0.99]). The association between PD and ovarian cancer was mostly driven by rs183211 located in an intron of the NSF gene (17q21.31). Conclusions We show evidence in favor of a contribution of pleiotropic genes to the association between PD and specific cancers. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Abstract Background Mendelian randomization (MR) studies are susceptible to metadata errors (e.g. incorrect specification of the effect allele column) and other analytical issues that can introduce substantial bias into analyses. We developed a quality control (QC) pipeline for the Fatty Acids in Cancer Mendelian Randomization Collaboration (FAMRC) that can be used to identify and correct for such errors. Methods We collated summary association statistics from fatty acid and cancer genome-wide association studies (GWAS) and subjected the collated data to a comprehensive QC pipeline. We identified metadata errors through comparison of study-specific statistics to external reference data sets (the National Human Genome Research Institute-European Bioinformatics Institute GWAS catalogue and 1000 genome super populations) and other analytical issues through comparison of reported to expected genetic effect sizes. Comparisons were based on three sets of genetic variants: (i) GWAS hits for fatty acids, (ii) GWAS hits for cancer and (iii) a 1000 genomes reference set. Results We collated summary data from 6 fatty acid and 54 cancer GWAS. Metadata errors and analytical issues with the potential to introduce substantial bias were identified in seven studies (11.6%). After resolving metadata errors and analytical issues, we created a data set of 219 842 genetic associations with 90 cancer types, generated in analyses of 566 665 cancer cases and 1 622 374 controls. Conclusions In this large MR collaboration, 11.6% of included studies were affected by a substantial metadata error or analytical issue. By increasing the integrity of collated summary data prior to their analysis, our protocol can be used to increase the reliability of downstream MR analyses. Our pipeline is available to other researchers via the CheckSumStats package (https://github.com/MRCIEU/CheckSumStats).

Wnt signaling involves multiple pathways that contribute to organ development, cell fate, inflammation, and normal stem cell renewal and maintenance. Although the homeostasis of stem cells in the gastrointestinal (GI) tract highly depends on the Wnt signaling pathway, this regulation is impaired in cancers and in aging. Overactive (uncontrolled) Wnt signaling can induce GI epithelial cancers such as colon and gastric cancer. Overactive Wnt signaling can also contribute to the initiation and progression of gastrointestinal stromal tumor, which is the most common human sarcoma occurring in the walls of the digestive organs, mainly the stomach and small intestine. Wnt expression is positively associated not only with the progression of oncogenesis but also with resistance to chemotherapy and radiotherapy. Of note, recent reports show that decreased Wnt signaling is related to intestinal stem cell aging and that overactivated Wnt signaling leads to gastric pacemaker stem cell aging in tunica muscularis. These findings indicate that Wnt signaling has different crucial aspects of cell fate determination with age in GI tunica mucosa and muscularis. In this review, we summarize the most recent advances in our understanding of Wnt signaling pathways and their role in regulating key aspects during development, carcinogenesis, inflammation, and aging, with the ultimate goal of identifying novel therapies.

PURPOSE:High-dose methotrexate (HDMTX; > 500 mg/m2) is an important component of lymphoma therapy. Serum MTX monitoring at 48 hours is the standard approach to identify those at increased risk of developing MTX toxicity. Our aim was to characterize the incidence of complications and their association with MTX levels.METHODS:A retrospective review of our institutional electronic medical record was conducted to identify patients with lymphoma who received HDMTX between January 1, 2002, and December 31, 2018. We characterized the incidence of acute kidney injury (AKI), intensive care unit (ICU) admission, length of hospital stay (LOS), and 30-day mortality across 48-hour MTX levels. To establish an association between 48-hour MTX levels and the complications listed, we performed chi-square analysis for dichotomous variables and Kruskal-Wallis for nonparametric data. Receiver operator characteristic curve analysis was performed to identify the MTX level where AKI grade ≥ 2 was more likely. Multivariate logistic regression analysis was performed to identify risk factors for this MTX level.RESULTS:We identified 642 patients with 2,804 cycles of HDMTX. The incidence of AKI was 19.1% with AKI grade ≥ 2 making up 21% of cases. Rates of AKI, ICU admission, and 30-day mortality are associated with elevated 48-hour MTX levels. There was a significant increase in median LOS with elevated MTX levels ( P < .001). Receiver operator characteristic curve analysis for AKI grade ≥ 2 demonstrated a 48-hour MTX level threshold of 1.28 μmol/L. Multivariate logistic regression analysis revealed age, male sex, elevated body surface area, higher MTX dose, monotherapy, and first cycle as independent factors.CONCLUSION:Elevated MTX levels are associated with a significant increased rate of AKI, ICU admission, prolonged LOS, and 30-day mortality. Elevated 48-hour MTX levels, particularly > 1.28 μmol/L, should alert clinicians for complications and to initiate measures to reduce MTX levels.

Abstract With aging, somatic mutations in hematopoietic stem and progenitor cells (HSPC) can give rise to clonal hematopoiesis of indeterminate potential (CHIP), a premalignant state associated with diverse age-related diseases. Here we report the largest multi-ancestry genome-wide analysis of CHIP to date (N = 1,018,305), including individuals of African (N = 85,978), Admixed American (N = 191,371), East Asian (N = 13,532), European (N = 694,015), and South Asian (N = 13,193) ancestry. Multi-ancestry meta-analyses identified 72 genome-wide significant loci, including 44 novel associations implicating genes such as AFF1 , ATF7IP , ATP8B4 , BCL2 , CEBPA , CYRIA , DNM2 , ELF1 , NKX2-3 , PIK3CB , PRDM16 , RPN1 , TERC , and TRIM4 . Notably, variants at MECOM and PHF20L1 showed opposite allelic effects between DNMT3A - and non- DNMT3A -driven CHIP, highlighting driver-specific germline influences. Implicated loci converge on pathways regulating telomere maintenance, cell-cycle control, hematopoietic transcription, DNA damage response and immune signaling. These findings support a model in which germline variation both expands the HSPC pool and biases clonal selection in a driver-dependent manner, providing a mechanistic basis for inter-individual heterogeneity in CHIP. Phenome-wide association analyses further linked CHIP to hematologic, neoplastic, and circulatory traits, with enrichment across hematopoietic and non-hematopoietic cell types. Together, this work expands the genomic and phenomic landscape of CHIP and reveals germline–somatic interactions that shape clonal evolution during aging.

AbstractBackgroundReproductive factors have been shown to be differentially associated with risk of estrogen receptor (ER)-positive and ER-negative breast cancer. However, their associations with intrinsic-like subtypes are less clear.MethodsAnalyses included up to 23 353 cases and 71 072 controls pooled from 31 population-based case-control or cohort studies in the Breast Cancer Association Consortium across 16 countries on 4 continents. Polytomous logistic regression was used to estimate the association between reproductive factors and risk of breast cancer by intrinsic-like subtypes (luminal A-like, luminal B-like, luminal B-HER2–like, HER2-enriched–like, and triple-negative breast cancer) and by invasiveness. All statistical tests were 2-sided.ResultsCompared with nulliparous women, parous women had a lower risk of luminal A-like, luminal B-like, luminal B-HER2–like, and HER2-enriched–like disease. This association was apparent only after approximately 10 years since last birth and became stronger with increasing time (odds ratio [OR] = 0.59, 95% confidence interval [CI] = 0.49 to 0.71; and OR = 0.36, 95% CI = 0.28 to 0.46 for multiparous women with luminal A-like tumors 20 to less than 25 years after last birth and 45 to less than 50 years after last birth, respectively). In contrast, parous women had a higher risk of triple-negative breast cancer right after their last birth (for multiparous women: OR = 3.12, 95% CI = 2.02 to 4.83) that was attenuated with time but persisted for decades (OR = 1.03, 95% CI = 0.79 to 1.34, for multiparous women 25 to less than 30 years after last birth). Older age at first birth (Pheterogeneity &lt; .001 for triple-negative compared with luminal A-like breast cancer) and breastfeeding (Pheterogeneity &lt; .001 for triple-negative compared with luminal A-like breast cancer) were associated with lower risk of triple-negative breast cancer but not with other disease subtypes. Younger age at menarche was associated with higher risk of all subtypes; older age at menopause was associated with higher risk of luminal A-like but not triple-negative breast cancer. Associations for in situ tumors were similar to luminal A-like.ConclusionsThis large and comprehensive study demonstrates a distinct reproductive risk factor profile for triple-negative breast cancer compared with other subtypes, with implications for the understanding of disease etiology and risk prediction.

Suicidality is increased in autism spectrum disorder (ASD), yet effective interventions are lacking. Developing biologically based approaches for preventing and treating suicidality in ASD hinges on the identification of biomarkers of suicidal ideation (SI). Here, we assessed magnetic resonance spectroscopy (MRS) markers of glutamatergic neurotransmission in ASD youth and young adults. Twenty-eight ASD participants (16–33 years) underwent 1H-MRS, and metabolites were quantified using LCModel. N-acetylaspartate (NAA), glutamate (Glu), and the NAA/Glu ratio from the left dorsolateral prefrontal cortex were compared between ASD SI+ (n = 13) and ASD SI− (n = 15) participants. We found that ASD SI+ participants had a higher NAA/Glu ratio compared ASD SI- participants. The NAA/Glu ratio also predicted SI and significantly discriminated between ASD SI+/SI− participants. All analyses including NAA and Glu alone were non-significant. Here, we provide preliminary evidence for the importance of NAA/Glu in ASD with SI, with implications for biomarker discovery. Further mechanistic research into risk and interventional approaches to address SI in ASD are needed.