Novel breast cancer susceptibility loci under linkage peaks identified in African ancestry consortia.

BACKGROUND: Expansion of genome-wide association studies across population groups is needed to improve our understanding of shared and unique genetic contributions to breast cancer. We performed association and replication studies guided by a priori linkage findings from African ancestry (AA) relative pairs. METHODS: We performed fixed-effect inverse-variance weighted meta-analysis under three significant AA breast cancer linkage peaks (3q26-27, 12q22-23, and 16q21-22) in 9241 AA cases and 10 193 AA controls. We examined associations with overall breast cancer as well as estrogen receptor (ER)-positive and negative subtypes (193,132 SNPs). We replicated associations in the African-ancestry Breast Cancer Genetic Consortium (AABCG). RESULTS: In AA women, we identified two associations on chr12q for overall breast cancer (rs1420647, OR = 1.15, p = 2.50×10-6; rs12322371, OR = 1.14, p = 3.15×10-6), and one for ER-negative breast cancer (rs77006600, OR = 1.67, p = 3.51×10-6). On chr3, we identified two associations with ER-negative disease (rs184090918, OR = 3.70, p = 1.23×10-5; rs76959804, OR = 3.57, p = 1.77×10-5) and on chr16q we identified an association with ER-negative disease (rs34147411, OR = 1.62, p = 8.82×10-6). In the replication study, the chr3 associations were significant and effect sizes were larger (rs184090918, OR: 6.66, 95% CI: 1.43, 31.01; rs76959804, OR: 5.24, 95% CI: 1.70, 16.16). CONCLUSION: The two chr3 SNPs are upstream to open chromatin ENSR00000710716, a regulatory feature that is actively regulated in mammary tissues, providing evidence that variants in this chr3 region may have a regulatory role in our target organ. Our study provides support for breast cancer variant discovery using prioritization based on linkage evidence.

The interrelationship between obesity and race in breast cancer prognosis: a prospective cohort study.

BACKGROUND: Obesity is associated with an increased breast cancer risk in postmenopausal women and may contribute to worse outcomes. Black women experience higher obesity and breast cancer mortality rates than non-Black women. We examined associations between race, obesity, and clinical tumor stage with breast cancer prognosis. METHODS: We conducted a prospective cohort study in 1,110 breast cancer patients, using univariable and multivariable Cox regression analyses to evaluate the effects of obesity, race/ethnicity, and clinical tumor stage on progression-free and overall survival (PFS and OS). RESULTS: 22% of participants were Black, 64% were Hispanic White, and 14% were non-Hispanic White or another race. 39% of participants were obese (body mass index [BMI] ≥ 30 kg/m2). In univariable analyses, tumor stage III-IV was associated with worse PFS and OS compared to tumor stage 0-II (hazard ratio [HR] = 4.68, 95% confidence interval [CI] = 3.52-6.22 for PFS and HR = 5.92, 95% CI = 4.00-8.77 for OS). Multivariable analysis revealed an association between Black race and worse PFS in obese (HR = 2.19, 95% CI = 1.06-4.51) and non-obese (HR = 2.11, 95% CI = 1.05-4.21) women with tumors staged 0-II. Obesity alone was not associated with worse PFS or OS. CONCLUSIONS: Results suggest a complex interrelationship between obesity and race in breast cancer prognosis. The association between the Black race and worse PFS in tumor stages 0-II underscores the importance of early intervention in this group. Future studies are warranted to evaluate whether alternative measures of body composition and biomarkers are better prognostic indicators than BMI among Black breast cancer survivors.

Development and initial validation of the parental response to adolescents' emotions scale: A mixed methods approach.

An exploratory mixed methods design was used to explore age-appropriate characteristics of parental response to emotion (PRE) during adolescence in Chinese families and develop the parental response to adolescents' emotions scale (C-PRAES). Qualitative interviews with 21 parent-adolescent dyads were employed to explore characteristics of PRE in adolescence and generate item pools. Structural validity, criterion validity, measurement invariance across informants (adolescents vs. parents, mothers vs. fathers) and consistency reliability were examined in the quantitative phase (Nadolescent = 702, Nparent = 476). New age-appropriate strategies were generated from qualitative phase: Guidance in reappraisal, Allowing independent regulation, and Avoiding escalation of conflict. The formal version of the C-PRAES comprised items in two dimensions (supportive/non-supportive) and exhibited good validity, reliability, and measurement invariance.

Parent-adolescent Congruence and Discrepancy in Perceived Parental Emotion Socialization to Anger and Sadness: Using Response Surface Analysis to Examine the Links with Adolescent Depressive Symptoms.

Parents and adolescents often hold discrepant perceptions of parental emotion socialization, which reflect misunderstandings in parent-adolescent communication on emotions and have potential detrimental effects on mental health of adolescents. The present study investigated the associations between parent-adolescent congruence and discrepancy in parental emotion socialization perception to two specific negative emotions (anger and sadness) and depressive symptoms in Chinese adolescents. A total of 372 adolescents (48.4% female, Mage = 13.43, SDage = 0.49) and their parents (79.6% mother, Mage = 41.15, SDage = 5.46) participated in this study. Both parents and adolescents reported perceived parental emotion socialization to anger and sadness, and adolescents reported depressive symptoms. Data were analyzed using polynomial regression and response surface analyses. Both congruence and discrepancy in parent and adolescent's reports were associated with adolescent depressive symptoms. A higher level of adolescent depressive symptoms was associated with higher parent-adolescent congruence in supportive responses to anger, sadness, and nonsupportive responses to anger. A higher level of depressive symptoms was associated with inconsistent reporting of supportive responses to sadness and nonsupportive responses to anger (only when parents had a more positive view than adolescents). This study highlights the significance of evaluating parent-child communication process by assessing perceived emotion socialization from both parents and adolescents and analyzing the reporting congruence and discrepancy. It also suggests that enhancing effective communication regarding parental emotion socialization could be a promising target for adolescent mental health promotion programs.

Parent- and Adolescent-Driven Effects in Emotion-Related Communication and Longitudinal Relationships with Depressive Symptoms in Adolescents.

Communication on emotions is an important aspect of parent-adolescent communication, yet its process and effects remain less examined in families of adolescents. This study examined the bidirectional association between parental responses to adolescents' emotions and adolescents' emotional communication behaviors, and further examined their longitudinal predictive effects on adolescent depressive symptoms. The potential moderating role of adolescent gender was also examined. A total of 503 adolescents (Mage = 13.45, SD = 0.50; 44.73% females) participated in this study, with 438 adolescents completing the three-wave longitudinal survey. Adolescents' emotional communication behaviors, parental responses to emotions, and depressive symptoms were reported. The bidirectional relationship was examined using cross-lagged panel models, while the parent- and adolescent-driven effects of emotional communication on adolescent depressive symptoms and the moderation effect of adolescent gender were examined using multi-group structural equation modeling. The findings revealed gender-specific patterns in parent-adolescent communication on emotions. Significant parent- and adolescent-driven effects of positive communication behaviors on adolescent depressive symptoms were found. However, only negative communication behaviors initiated by parents predicted adolescent depressive symptoms, with this effect mediated by adolescents' negative communication behaviors. This study deepened the understanding of characteristics and effects of parent-child emotional communication during adolescence, which has implications for interventions aiming at improving parent-adolescent relationship and adolescents' mental health.

Acute manganese toxicosis related to joint health supplement ingestion in two dogs.

Two unrelated dogs residing in the same house including an 11-year-old, female spayed, mixed breed dog and a 7-year-old, female spayed, mixed breed dog ingested approximately 75 capsules of a human joint health supplement (Ligaplex I; Standard Process, WI, USA). A total of 2,062 mg of manganese was ingested between both dogs. Dog 1 developed acute fulminant liver failure and a severe coagulopathy that led to hepatic fractures and exsanguination from hemoabdomen. The estimated maximum time from ingestion of the joint health supplement to death was 36 to 48 h. Histologic examination revealed severe periportal hepatic necrosis with mild evidence of preexisiting liver disease and renal tubular epithelial necrosis. Manganese concentrations in liver and kidney tissue were severely increased. Dog 2 developed a severe acute liver injury and was hospitalized for 6 days. Therapies provided during hospitalization included intravenous fluids, maropitant, pantoprazole, N-acetylcysteine, vitamin C, S-adenosylmethionine, and silybin. The dog was treated long-term with S-adenosylmethionine, silybin, ursodiol, and vitamin C. Clinical and biochemical resolution occurred on the recheck examination that took place on day 44. The veterinary literature is comprised of only 2 reports containing 3 dogs that describe acute manganese intoxication. Here, we provide a detailed description of 2 dogs that developed manganese-induced toxicosis after ingestion of a human joint health supplement.

Metabolomics in Radiotherapy-Induced Early Adverse Skin Reactions of Breast Cancer Patients.

Background: Early adverse skin reactions (EASRs) are common side effects of radiotherapy (RT) that impact the quality of life of breast cancer patients. This study used global metabolomics profiles of breast cancer populations to identify metabolic pathways and biomarkers significantly associated with RT-induced EASRs to identify potential targets for precision interventions. Methods: We used a frequency-matched study design to identify pre-RT urine samples from 60 female breast cancer patients (30 with high and 30 with low EASRs) for metabolomic analysis by Metabolon Inc. using UPLC-MS/MS and GC-MS. Using MetaboAnalyst, we performed metabolomic data analysis and visualization on 84 candidate metabolites from 478 total compounds. We used the Oncology Nursing Society (ONS) Skin Toxicity Criteria (0-6) for EASRs assessment. Results: Seven metabolic pathways were significantly associated with RT-induced EASRs, including alanine, aspartate, and glutamate metabolism (p = 0.0028), caffeine metabolism (p = 0.0360), pentose and glucuronate interconversions (p = 0.0028), glycine, serine, and threonine metabolism (p = 0.0360), beta-alanine metabolism (p = 0.0210), pantothenate and CoA biosynthesis (p = 0.0028), and glutathione metabolism (p = 0.0490). The alanine, aspartate, and glutamate metabolic pathway had the lowest false discovery rate (FDR)-adjusted p-value and the highest impact value of 0.60. Thirteen metabolite biomarkers were significantly associated with RT-induced EASRs. Conclusion: Our data show that the alanine, aspartate, and glutamate metabolism pathways had the highest impact value on RT-induced EASRs. Future larger studies are warranted to validate our findings and facilitate targeted interventions for preventing or mitigating RT-induced EASRs, offering a promising direction for further research and clinical applications.

The association of breast surgery ASPIRE: breast pain pathway rapid evaluation project - study protocol.

Background: Breast pain accounts for 20-40% of new referrals to breast units in the UK and these patients have a very low risk of breast cancer. Patients have previously been assessed in resource-intensive, cancer-exclusion, one stop clinics, which are now failing to meet government targets due to excessive demand. UK Breast units are increasingly piloting Breast Pain-only Pathways (BPP) to assess these patients, and there is no consensus for the optimal pathway. The aim of this prospective multicentre study is to assess the safety and patient satisfaction of different BPPs to inform future BPP design and implementation. Methods: All UK breast units will be invited to join the ASPIRE study between January 2023 and December 2023. Units with a BPP are invited to submit their pathway for evaluation; and those without a BPP who see patients with breast pain-only in a one stop clinics setting are also invited to join the study to evaluate the traditional pathway model concurrently. Patient satisfaction assessments will be collected after their initial consultation and patient outcomes, including subsequent cancer diagnosis, will be followed up at 12 months to determine if they have cancer diagnosis after discharge to assess pathway safety.

Antibody production relies on the tRNA inosine wobble modification to meet biased codon demand.

Antibodies are produced at high rates to provide immunoprotection, which puts pressure on the B cell translational machinery. Here, we identified a pattern of codon usage conserved across antibody genes. One feature thereof is the hyperutilization of codons that lack genome-encoded Watson-Crick transfer RNAs (tRNAs), instead relying on the posttranscriptional tRNA modification inosine (I34), which expands the decoding capacity of specific tRNAs through wobbling. Antibody-secreting cells had increased I34 levels and were more reliant on I34 for protein production than naïve B cells. Furthermore, antibody I34-dependent codon usage may influence B cell passage through regulatory checkpoints. Our work elucidates the interface between the tRNA pool and protein production in the immune system and has implications for the design and selection of antibodies for vaccines and therapeutics.

Immunogenicity Risk Assessment of Process-Related Impurities in An Engineered T Cell Receptor Cellular Product.

Cell therapies such as genetically modified T cells have emerged as a promising and viable treatment for hematologic cancers and are being aggressively pursued for a wide range of diseases and conditions that were previously difficult to treat or had no cure. The process development requires genetic modifications to T cells to express a receptor (engineered T cell receptor (eTCR)) of specific binding qualities to the desired target. Protein reagents utilized during the cell therapy manufacturing process, to facilitate these genetic modifications, are often present as process-related impurities at residual levels in the final drug product and can represent a potential immunogenicity risk upon infusion. This manuscript presents a framework for the qualification of an assay for assessing the immunogenicity risk of AA6 and Cas9 residuals. The same framework applies for other residuals; however, AAV6 and Cas9 were selected as they were residuals from the manufacturing of an engineered T cell receptor cellular product in development. The manuscript: 1) elucidates theoretical risks, 2) summarizes analytical data collected during process development, 3) describes the qualification of an in vitro human PBMC cytokine release assay to assess immunogenicity risk from cellular product associated process residuals; 4) identifies a multiplexed inflammatory innate and adaptive cytokine panel with pre-defined criteria using relevant positive controls; and 5) discusses qualification challenges and potential solutions for establishing meaningful thresholds. The assessment is not only relevant to establishing safe exposure levels of these residuals but also in guiding risk assessment and CMC strategy during the conduct of clinical trials.

Mitochondrial respiration in microglia is essential for response to demyelinating injury but not proliferation.

Microglia are necessary for central nervous system (CNS) function during development and play roles in ageing, Alzheimer's disease and the response to demyelinating injury1-5. The mitochondrial respiratory chain (RC) is necessary for conventional T cell proliferation6 and macrophage-dependent immune responses7-10. However, whether mitochondrial RC is essential for microglia proliferation or function is not known. We conditionally deleted the mitochondrial complex III subunit Uqcrfs1 (Rieske iron-sulfur polypeptide 1) in the microglia of adult mice to assess the requirement of microglial RC for survival, proliferation and adult CNS function in vivo. Notably, mitochondrial RC function was not required for survival or proliferation of microglia in vivo. RNA sequencing analysis showed that loss of RC function in microglia caused changes in gene expression distinct from aged or disease-associated microglia. Microglia-specific loss of mitochondrial RC function is not sufficient to induce cognitive decline. Amyloid-ß plaque coverage decreased and microglial interaction with amyloid-ß plaques increased in the hippocampus of 5xFAD mice with mitochondrial RC-deficient microglia. Microglia-specific loss of mitochondrial RC function did impair remyelination following an acute, reversible demyelinating event. Thus, mitochondrial respiration in microglia is dispensable for proliferation but is essential to maintain a proper response to CNS demyelinating injury.

Using genome and transcriptome data from African-ancestry female participants to identify putative breast cancer susceptibility genes.

African-ancestry (AA) participants are underrepresented in genetics research. Here, we conducted a transcriptome-wide association study (TWAS) in AA female participants to identify putative breast cancer susceptibility genes. We built genetic models to predict levels of gene expression, exon junction, and 3' UTR alternative polyadenylation using genomic and transcriptomic data generated in normal breast tissues from 150 AA participants and then used these models to perform association analyses using genomic data from 18,034 cases and 22,104 controls. At Bonferroni-corrected P < 0.05, we identified six genes associated with breast cancer risk, including four genes not previously reported (CTD-3080P12.3, EN1, LINC01956 and NUP210L). Most of these genes showed a stronger association with risk of estrogen-receptor (ER) negative or triple-negative than ER-positive breast cancer. We also replicated the associations with 29 genes reported in previous TWAS at P < 0.05 (one-sided), providing further support for an association of these genes with breast cancer risk. Our study sheds new light on the genetic basis of breast cancer and highlights the value of conducting research in AA populations.

Case-Case Genome-Wide Analyses Identify Subtype-Informative Variants That Confer Risk for Breast Cancer.

Breast cancer includes several subtypes with distinct characteristic biological, pathologic, and clinical features. Elucidating subtype-specific genetic etiology could provide insights into the heterogeneity of breast cancer to facilitate the development of improved prevention and treatment approaches. In this study, we conducted pairwise case-case comparisons among five breast cancer subtypes by applying a case-case genome-wide association study (CC-GWAS) approach to summary statistics data of the Breast Cancer Association Consortium. The approach identified 13 statistically significant loci and eight suggestive loci, the majority of which were identified from comparisons between triple-negative breast cancer (TNBC) and luminal A breast cancer. Associations of lead variants in 12 loci remained statistically significant after accounting for previously reported breast cancer susceptibility variants, among which, two were genome-wide significant. Fine mapping implicated putative functional/causal variants and risk genes at several loci, e.g., 3q26.31/TNFSF10, 8q22.3/NACAP1/GRHL2, and 8q23.3/LINC00536/TRPS1, for TNBC as compared with luminal cancer. Functional investigation further identified rs16867605 at 8q22.3 as a SNP that modulates the enhancer activity of GRHL2. Subtype-informative polygenic risk scores (PRS) were derived, and patients with a high subtype-informative PRS had an up to two-fold increased risk of being diagnosed with TNBC instead of luminal cancers. The CC-GWAS PRS remained statistically significant after adjusting for TNBC PRS derived from traditional case-control GWAS in The Cancer Genome Atlas and the African Ancestry Breast Cancer Genetic Consortium. The CC-GWAS PRS was also associated with overall survival and disease-specific survival among patients with breast cancer. Overall, these findings have advanced our understanding of the genetic etiology of breast cancer subtypes, particularly for TNBC. Significance: The discovery of subtype-informative genetic risk variants for breast cancer advances our understanding of the etiologic heterogeneity of breast cancer, which could accelerate the identification of targets and personalized strategies for prevention and treatment.

Genome-wide association analyses of breast cancer in women of African ancestry identify new susceptibility loci and improve risk prediction.

We performed genome-wide association studies of breast cancer including 18,034 cases and 22,104 controls of African ancestry. Genetic variants at 12 loci were associated with breast cancer risk (P < 5 × 10-8), including associations of a low-frequency missense variant rs61751053 in ARHGEF38 with overall breast cancer (odds ratio (OR) = 1.48) and a common variant rs76664032 at chromosome 2q14.2 with triple-negative breast cancer (TNBC) (OR = 1.30). Approximately 15.4% of cases with TNBC carried six risk alleles in three genome-wide association study-identified TNBC risk variants, with an OR of 4.21 (95% confidence interval = 2.66-7.03) compared with those carrying fewer than two risk alleles. A polygenic risk score (PRS) showed an area under the receiver operating characteristic curve of 0.60 for the prediction of breast cancer risk, which outperformed PRS derived using data from females of European ancestry. Our study markedly increases the population diversity in genetic studies for breast cancer and demonstrates the utility of PRS for risk prediction in females of African ancestry.