Nat Genet
June 2023
Tau deposition is one of two hallmark features of biologically defined Alzheimer's disease (AD) and is more closely related to cognitive decline than amyloidosis. Further, not all amyloid-positive individuals develop tauopathy, resulting in wide heterogeneity in clinical outcomes across the population with AD. We hypothesized that a polygenic risk score (PRS) based on tau PET (tau PRS) would capture the aggregate inherited susceptibility/resistance architecture influencing tau accumulation, beyond solely the measurement of amyloid-β burden.
View Article and Find Full Text PDFBackground: Appropriately designed preclinical patient-derived xenograft (PDX) experiments are important to accurately inform human clinical trials. There is little experimental design guidance regarding choosing the number of PDX lines to study, and the number of mice within each PDX line.
Methods: Retrospective data from IDH-wildtype glioblastoma preclinical experiments evaluating a uniform regimen of fractionated radiation (RT), temozolomide (TMZ) chemotherapy, and concurrent RT/TMZ across 27 PDX lines were used to evaluate experimental designs and empirically estimate statistical power for ANOVA and Cox regression.
Tau deposition is a key biological feature of Alzheimer's disease that is closely related to cognitive impairment. However, it remains poorly understood why certain individuals may be more susceptible to tau deposition while others are more resistant. The recent availability of assessment of tau burden through positron emission tomography provides an opportunity to test the hypothesis that common genetic variants may influence tau deposition.
View Article and Find Full Text PDFBackground: The four most commonly-mutated genes in clear cell renal cell carcinoma (ccRCC) tumors are BAP1, PBRM1, SETD2 and VHL. And, there are currently 14 known RCC germline variants that have been reproducibly shown to be associated with RCC risk. However, the association of germline genetics with tumor genetics and clinical aggressiveness are unknown.
View Article and Find Full Text PDFBecause polygenic risk scores (PRSs) for coronary heart disease (CHD) are derived from mainly European ancestry (EA) cohorts, their validity in African ancestry (AA) and Hispanic ethnicity (HE) individuals is unclear. We investigated associations of "restricted" and genome-wide PRSs with CHD in three major racial and ethnic groups in the U.S.
View Article and Find Full Text PDFImportance: Spontaneous coronary artery dissection (SCAD), an idiopathic disorder that predominantly affects young to middle-aged women, has emerged as an important cause of acute coronary syndrome, myocardial infarction, and sudden cardiac death.
Objective: To identify common single-nucleotide variants (SNVs) associated with SCAD susceptibility.
Design, Setting, And Participants: This single-center genome-wide association study examined approximately 5 million genotyped and imputed SNVs and subsequent SNV-targeted replication analysis results in individuals enrolled in the Mayo Clinic SCAD registry from August 30, 2011, to August 2, 2018.
Lipid levels are important markers for the development of cardio-metabolic diseases. Although hundreds of associated loci have been identified through genetic association studies, the contribution of genetic factors to variation in lipids is not fully understood, particularly in U.S.
View Article and Find Full Text PDFImportance: Per the World Health Organization 2016 integrative classification, newly diagnosed glioblastomas are separated into isocitrate dehydrogenase gene 1 or 2 (IDH)-wild-type and IDH-mutant subtypes, with median patient survival of 1.2 and 3.6 years, respectively.
View Article and Find Full Text PDFBackground: Glioblastoma (GBM) represents an aggressive cancer type with a median survival of only 14 months. With fewer than 5% of patients surviving 5 years, comprehensive profiling of these rare patients could elucidate prognostic biomarkers that may confer better patient outcomes. We utilized multiple molecular approaches to characterize the largest patient cohort of isocitrate dehydrogenase (IDH)-wildtype GBM long-term survivors (LTS) to date.
View Article and Find Full Text PDFBackground: Single-gene mutation syndromes account for some familial glioma (FG); however, they make up only a small fraction of glioma families. Gliomas can be classified into 3 major molecular subtypes based on isocitrate dehydrogenase (IDH) mutation and 1p/19q codeletion. We hypothesized that the prevalence of molecular subtypes might differ in familial versus sporadic gliomas and that tumors in the same family should have the same molecular subtype.
View Article and Find Full Text PDFGenome-wide association studies (GWAS) have transformed our understanding of glioma susceptibility, but individual studies have had limited power to identify risk loci. We performed a meta-analysis of existing GWAS and two new GWAS, which totaled 12,496 cases and 18,190 controls. We identified five new loci for glioblastoma (GBM) at 1p31.
View Article and Find Full Text PDFBackground: In tamoxifen-treated patients, breast cancer recurrence differs according to CYP2D6 genotype and endoxifen steady-state concentrations (Endx Css). The ¹³C-dextromethorphan breath test (DM-BT), labeled with ¹³C at the O-CH3 moiety, measures CYP2D6 enzyme activity. We sought to examine the ability of the DM-BT to identify known CYP2D6 genotypic poor metabolizers and examine the correlation between DM-BT and Endx Css.
View Article and Find Full Text PDFGlioma, the most common central nervous system cancer in adults, has poor prognosis. Here we identify a new SNP associated with glioma risk, rs1920116 (near TERC), that reached genome-wide significance (Pcombined = 8.3 × 10(-9)) in a meta-analysis of genome-wide association studies (GWAS) of high-grade glioma and replication data (1,644 cases and 7,736 controls).
View Article and Find Full Text PDFBackground: Genome-wide association studies have implicated single nucleotide polymorphisms (SNPs) in 7 genes as glioma risk factors, including 2 (TERT, RTEL1) involved in telomerase structure/function. We examined associations of these 7 established glioma risk loci with age at diagnosis among patients with glioma.
Methods: SNP genotype data were available for 2286 Caucasian glioma patients from the University of California, San Francisco (n = 1434) and the Mayo Clinic (n = 852).
Purpose: Mammographic breast density (MBD) is decreased by tamoxifen, but the effect of aromatase inhibitors is less clear.
Experimental Design: We enrolled early-stage postmenopausal patients with breast cancer initiating adjuvant aromatase inhibitor therapy and ascertained mammograms before and at an average 10 months of aromatase inhibitor therapy. We matched cases to healthy postmenopausal women (controls) from a large mammography screening cohort on age, baseline body mass index, baseline MBD, and interval between mammograms.
Introduction: Recent discoveries of inherited glioma risk loci and acquired IDH mutations are providing new insights into glioma etiology. IDH mutations are common in lower grade gliomas and secondary glioblastomas and uncommon in primary glioblastomas. Because the inherited variant in 11q23 has been associated with risk of lower grade glioma and not with glioblastomas, we hypothesized that this variant increases susceptibility to IDH-mutated gliomas, but not to IDH-wild-type gliomas.
View Article and Find Full Text PDFVariants at 8q24.21 have been shown to be associated with glioma development. By means of tag SNP genotyping and imputation, pooled next-generation sequencing using long-range PCR and subsequent validation SNP genotyping, we identified seven low-frequency SNPs at 8q24.
View Article and Find Full Text PDFBackground: Increasing evidence shows chemotherapy in combination with vascular endothelial growth factor (VEGF) inhibition is a clinically active therapy for patients with metastatic melanoma (MM).
Methods: A phase 2 trial was conducted in chemotherapy-naive patients with unresectable stage IV MM who were randomized to temozolomide (200 mg/m(2) on days 1 through 5) and bevacizumab (10 mg/kg intravenously on days 1 and 15) every 28 days (Regimen TB) or nab-paclitaxel (100 mg/m(2) , or 80 mg/m(2) post-addendum 5 secondary to toxicity, on days 1, 8, and 15), bevacizumab (10 mg/kg on days 1 and 15), and carboplatin (area under the curve [AUC] 6 on day 1, or AUC 5 post-addendum 5) every 28 days (Regimen ABC). Accrual goal was 41 patients per regimen.
Purpose: Glioblastoma is a devastating, incurable disease with few known prognostic factors. Here, we present the first genome-wide survival and validation study for glioblastoma.
Experimental Design: Cox regressions for survival with 314,635 inherited autosomal single-nucleotide polymorphisms (SNP) among 315 San Francisco Adult Glioma Study patients for discovery and three independent validation data sets [87 Mayo Clinic, 232 glioma patients recruited from several medical centers in Southeastern United States (GliomaSE), and 115 The Cancer Genome Atlas patients] were used to identify SNPs associated with overall survival for Caucasian glioblastoma patients treated with the current standard of care, resection, radiation, and temozolomide (total n = 749).
The 19p13.1 breast cancer susceptibility locus is a modifier of breast cancer risk in BRCA1 mutation carriers and is also associated with the risk of ovarian cancer. Here, we investigated 19p13.
View Article and Find Full Text PDFTo identify new risk variants for cutaneous basal cell carcinoma, we performed a genome-wide association study of 16 million SNPs identified through whole-genome sequencing of 457 Icelanders. We imputed genotypes for 41,675 Illumina SNP chip-typed Icelanders and their relatives. In the discovery phase, the strongest signal came from rs78378222[C] (odds ratio (OR) = 2.
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