Race and subtype differences in the replication of previously identified breast cancer susceptibility loci: A Bayesian approach

Over the last twenty-five years, researchers have identified several dozen genetic polymorphisms associated with breast cancer susceptibility. While many of these loci are now considered well-established risk factors for the disease, previous attempts to replicate variant-disease associations in African Americans or to identify subtype-specific risk variants have been imprecise and inconsistent. I examined the association between breast cancer subtypes and previously established candidate gene and genome-wide association study hits among white and African American women in the Carolina Breast Cancer Study. Maximum likelihood and Bayesian methods were used to estimate race and subtype-specific odds ratios (ORs) for each of 83 candidate single nucleotide polymorphisms (SNPs). Selected SNPs included several previous GWAS hits (n=22), near-GWAS hits (n=19), otherwise well-established risk loci (n=5), or SNPs in the same gene as another selected variant (n=37). Subtypes were defined using 5 immunohistochemical markers: estrogen receptors (ER), progesterone receptors (PR), human epidermal growth factor receptors 1 and 2 (HER1/2) and cytokeratin (CK) 5/6. Eighteen GWAS-identified SNPs successfully replicated in whites and ten GWAS-identified SNPs successfully replicated in African Americans. SNPs in FGFR2 and TNRC9/TOX3 were strongly associated with breast cancer in both races. Additionally, SNPs in MRPS30, MAP3K1, CDKN2A/B, ZM1Z1, LSP1, H19, and TP53 were associated with breast cancer in whites and SNPs in TLR1, ESR1, and H19 were associated with breast cancer in African Americans. Several SNPs in TNRC9/TOX3 were associated with luminal A (ER/PR+, HER2-) or basal-like disease (ER-, PR-, HER2-, HER1 or CK 5/6+), and one SNP (rs3104746) was associated with both. SNPs in FGFR2 were associated with luminal A, luminal B (ER/PR+, HER2+), and HER2+/ER-, but not basal-like disease. There were also subtype differences in the effects of SNPs in 2q35, 4p, TLR1, MAP3K1, ESR1, CDKN2A/B, ANKRD16, and ZM1Z1. These analyses provide precise, well-informed race and subtype-stratified ORs for several key breast cancer-related SNPs. These results also demonstrate the utility of Bayesian methods in genetic epidemiology and provide evidence of subtype-specific etiologies. This work may help to identify specific causal variants, locate targets for research on directed therapies, and identify high-risk individuals.Doctor of Philosoph

Hormone Therapy and Young-Onset Breast Cancer

Estrogen plus progestin hormone therapy (HT) is associated with an increased risk of postmenopausal breast cancer, but few studies have examined the impact of HT use on the risk of breast cancer in younger women. We assessed the association between estrogen plus progestin HT or unopposed estrogen HT and young-onset breast cancer using data from the Two Sister Study (2008–2010), a sister-matched study of 1,419 cases diagnosed with breast cancer before the age of 50 years and 1,665 controls. We assessed exposures up to a family-specific index age to ensure comparable opportunities for exposures and used propensity scores to control for birth cohort effects on HT use. Ever HT use was uncommon (7% and 11% in cases and controls, respectively). Use of estrogen plus progestin was not associated with an increased risk of young-onset breast cancer (odds ratio = 0.80, 95% confidence interval: 0.41, 1.59). Unopposed estrogen use was inversely associated with the risk of young-onset breast cancer (odds ratio = 0.58, 95% confidence interval: 0.34, 0.99). Duration of use, age at first use, and recency of use did not modify these associations

The role of MSC therapy in attenuating the damaging effects of the cytokine storm induced by COVID-19 on the heart and cardiovascular system

The global pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19) has led to 47m infected cases and 1.2m (2.6%) deaths. A hallmark of more severe cases of SARS-CoV-2 in patients with acute respiratory distress syndrome (ARDS) appears to be a virally-induced over-activation or unregulated response of the immune system, termed a "cytokine storm", featuring elevated levels of pro-inflammatory cytokines such as IL-2, IL-6, IL-7, IL-22, CXCL10 and TNF?. Whilst the lungs are the primary site of infection for SARS-CoV-2, in more severe cases its effects can be detected in multiple organ systems. Indeed, many COVID-19 positive patients develop cardiovascular complications, such as myocardial injury, myocarditis, cardiac arrhythmia and thromboembolism, which are associated with higher mortality. Drug and cell therapies targeting immunosuppression have been suggested to help combat the cytokine storm. In particular, mesenchymal stromal cells (MSCs), owing to their powerful immunomodulatory ability, have shown promise in early clinical studies to avoid, prevent or attenuate the cytokine storm. In this review, we will discuss the mechanistic underpinnings of the cytokine storm on the cardiovascular system, and how MSCs potentially attenuate the damage caused by the cytokine storm induced by COVID-19. We will also address how MSC transplantation could alleviate the long-term complications seen in some COVID-19 patients, such as improving tissue repair and regeneration

Amino acid-dependent cMyc expression is essential for NK cell metabolic and functional responses in mice

Natural killer (NK) cells are lymphocytes with important anti-tumour functions. Cytokine activation of NK cell glycolysis and oxidative phosphorylation (OXPHOS) are essential for robust NK cell responses. However, the mechanisms leading to this metabolic phenotype are unclear. Here we show that the transcription factor cMyc is essential for IL-2/IL-12-induced metabolic and functional responses in mice. cMyc protein levels are acutely regulated by amino acids; cMyc protein is lost rapidly when glutamine is withdrawn or when system L-amino acid transport is blocked. We identify SLC7A5 as the predominant system L-amino acid transporter in activated NK cells. Unlike other lymphocyte subsets, glutaminolysis and the tricarboxylic acid cycle do not sustain OXPHOS in activated NK cells. Glutamine withdrawal, but not the inhibition of glutaminolysis, results in the loss of cMyc protein, reduced cell growth and impaired NK cell responses. These data identify an essential role for amino acid-controlled cMyc for NK cell metabolism and function

A review of African American-white differences in risk factors for cancer: prostate cancer

African American men have higher prostate cancer incidence rates than White men, for reasons not completely understood. This review summarizes the existing literature of race-specific associations between risk factors and prostate cancer in order to examine whether associations differ

Replication of Breast Cancer Susceptibility Loci in Whites and African Americans Using a Bayesian Approach

Genome-wide association studies (GWAS) and candidate gene analyses have led to the discovery of several dozen genetic polymorphisms associated with breast cancer susceptibility, many of which are considered well-established risk factors for the disease. Despite attempts to replicate these same variant-disease associations in African Americans, the evaluable populations are often too small to produce precise or consistent results. We estimated the associations between 83 previously identified single nucleotide polymorphisms (SNPs) and breast cancer among Carolina Breast Cancer Study (1993–2001) participants using maximum likelihood, Bayesian, and hierarchical methods. The selected SNPs were previous GWAS hits (n = 22), near-hits (n = 19), otherwise well-established risk loci (n = 5), or located in the same genes as selected variants (n = 37). We successfully replicated 18 GWAS-identified SNPs in whites (n = 2,352) and 10 in African Americans (n = 1,447). SNPs in the fibroblast growth factor receptor 2 gene (FGFR2) and the TOC high mobility group box family member 3 gene (TOX3) were strongly associated with breast cancer in both races. SNPs in the mitochondrial ribosomal protein S30 gene (MRPS30), mitogen-activated protein kinase kinase kinase 1 gene (MAP3K1), zinc finger, MIZ-type containing 1 gene (ZMIZ1), and H19, imprinted maternally expressed transcript gene (H19) were associated with breast cancer in whites, and SNPs in the estrogen receptor 1 gene (ESR1) and H19 gene were associated with breast cancer in African Americans. We provide precise and well-informed race-stratified odds ratios for key breast cancer–related SNPs. Our results demonstrate the utility of Bayesian methods in genetic epidemiology and provide support for their application in small, etiologically driven investigations

Breast Cancer Subtypes and Previously Established Genetic Risk Factors: A Bayesian Approach

Gene expression analyses indicate that breast cancer is a heterogeneous disease with at least 5 immunohistologic subtypes. Despite growing evidence that these subtypes are etiologically and prognostically distinct, few studies have investigated whether they have divergent genetic risk factors. To help fill in this gap in our understanding, we examined associations between breast cancer subtypes and previously established susceptibility loci among white and African-American women in the Carolina Breast Cancer Study