The CHK1 inhibitor prexasertib in BRCA wild-type platinum-resistant recurrent high-grade serous ovarian carcinoma: a phase 2 trial.

The multi-cohort phase 2 trial NCT02203513 was designed to evaluate the clinical activity of the CHK1 inhibitor (CHK1i) prexasertib in patients with breast or ovarian cancer. Here we report the activity of CHK1i in platinum-resistant high-grade serous ovarian carcinoma (HGSOC) with measurable and biopsiable disease (cohort 5), or without biopsiable disease (cohort 6). The primary endpoint was objective response rate (ORR). Secondary outcomes were safety and progression-free survival (PFS). 49 heavily pretreated patients were enrolled (24 in cohort 5, 25 in cohort 6). Among the 39 RECISTv1.1-evaluable patients, ORR was 33.3% in cohort 5 and 28.6% in cohort 6. Primary endpoint was not evaluable due to early stop of the trial. The median PFS was 4 months in cohort 5 and 6 months in cohort 6. Toxicity was manageable. Translational research was an exploratory endpoint. Potential biomarkers were investigated using pre-treatment fresh biopsies and serial blood samples. Transcriptomic analysis revealed high levels of DNA replication-related genes (POLA1, POLE, GINS3) associated with lack of clinical benefit [defined post-hoc as PFS < 6 months]. Subsequent preclinical experiments demonstrated significant cytotoxicity of POLA1 silencing in combination with CHK1i in platinum-resistant HGSOC cell line models. Therefore, POLA1 expression may be predictive for CHK1i resistance, and the concurrent POLA1 inhibition may improve the efficacy of CHK1i monotherapy in this hard-to-treat population, deserving further investigation.

Genetic drivers of heterogeneity in type 2 diabetes pathophysiology.

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.

Sequencing-based functional assays for classification of BRCA2 variants in mouse ESCs.

Sequencing of genes, such as BRCA1 and BRCA2, is recommended for individuals with a personal or family history of early onset and/or bilateral breast and/or ovarian cancer or a history of male breast cancer. Such sequencing efforts have resulted in the identification of more than 17,000 BRCA2 variants. The functional significance of most variants remains unknown; consequently, they are called variants of uncertain clinical significance (VUSs). We have previously developed mouse embryonic stem cell (mESC)-based assays for functional classification of BRCA2 variants. We now developed a next-generation sequencing (NGS)-based approach for functional evaluation of BRCA2 variants using pools of mESCs expressing 10-25 BRCA2 variants from a given exon. We use this approach for functional evaluation of 223 variants listed in ClinVar. Our functional classification of BRCA2 variants is concordant with the classification reported in ClinVar or those reported by other orthogonal assays.

Saturation genome editing of 11 codons and exon 13 of BRCA2 coupled with chemotherapeutic drug response accurately determines pathogenicity of variants.

The unknown pathogenicity of a significant number of variants found in cancer-related genes is attributed to limited epidemiological data, resulting in their classification as variant of uncertain significance (VUS). To date, Breast Cancer gene-2 (BRCA2) has the highest number of VUSs, which has necessitated the development of several robust functional assays to determine their functional significance. Here we report the use of a humanized-mouse embryonic stem cell (mESC) line expressing a single copy of the human BRCA2 for a CRISPR-Cas9-based high-throughput functional assay. As a proof-of-principle, we have saturated 11 codons encoded by BRCA2 exons 3, 18, 19 and all possible single-nucleotide variants in exon 13 and multiplexed these variants for their functional categorization. Specifically, we used a pool of 180-mer single-stranded donor DNA to generate all possible combination of variants. Using a high throughput sequencing-based approach, we show a significant drop in the frequency of non-functional variants, whereas functional variants are enriched in the pool of the cells. We further demonstrate the response of these variants to the DNA-damaging agents, cisplatin and olaparib, allowing us to use cellular survival and drug response as parameters for variant classification. Using this approach, we have categorized 599 BRCA2 variants including 93-single nucleotide variants (SNVs) across the 11 codons, of which 28 are reported in ClinVar. We also functionally categorized 252 SNVs from exon 13 into 188 functional and 60 non-functional variants, demonstrating that saturation genome editing (SGE) coupled with drug sensitivity assays can enhance functional annotation of BRCA2 VUS.

Early Immune Changes Support Signet Ring Cell Dormancy in CDH1-Driven Hereditary Diffuse Gastric Carcinogenesis.

Stage IA gastric adenocarcinoma, characterized by foci of intramucosal signet ring cells (SRC), is found in nearly all asymptomatic patients with germline pathogenic CDH1 variants and hereditary diffuse gastric cancer syndrome (HDGC). The molecular steps involved in initiating malignant transformation and promoting SRC dormancy in HDGC are unknown. Here, whole-exome bulk RNA sequencing (RNA-seq) of SRCs and adjacent non-SRC epithelium (NEP) was performed on laser-capture microdissected (LCM) regions of interest found in risk-reducing total gastrectomy specimens from patients with HDGC (Clinicaltrials.gov ID: NCT03030404). In total, 20 patients (6 male, 14 female) with confirmed HDGC were identified. Analysis of differentially expressed genes (DEG) demonstrated upregulation of certain individual EMT and proliferation genes. However, no oncogenic pathways were found to be upregulated in SRCs. Rather, SRC regions had significant enrichment in pathways involved in T-cell signaling. CIBERSORTx predicted significant increases in the presence of regulatory T cells (Treg) specific to SRC regions. IHC confirmed an increase in FOXP3+ cells in SRC foci, as well as elevations in CD4+ T cells and HLA-DR staining. In summary, the tumor immune microenvironment is microscopically inseparable from stage IA gastric SRCs using a granular isolation technique. An elevation in CD4+ T cells within SRC regions correlates with clinically observed SRC dormancy, while Treg upregulation represents a potential immune escape mechanism. IMPLICATIONS: Characterization of the tumor-immune microenvironment in HDGC underscores the potential for the immune system to shape the transcriptional profile of the earliest tumors, which suggests immune-directed therapy as a potential cancer interception strategy in diffuse-type gastric cancer.

Immunologic Assessment of Tumors from a Race-matched Military Cohort Identifies Mast Cell Depletion as a Marker of Prostate Cancer Progression.

Elucidating the cellular immune components underlying aggressive prostate cancer, especially among African American (AA) men who are disproportionately affected by this disease compared with Caucasian American (CA) men, will support more inclusive precision medicine treatment strategies. We aimed to evaluate which immune-related genes and cell types are differentially expressed in AA tumors and how immunobiology impacts prostate cancer progression. We purified nucleic acid from tumor biopsies, obtained following radical prostatectomy, from 51 patients (AA = 26, CA = 25). Gene expression was measured using the NanoString platform from which we estimated immune cell abundances and assessed differences between groups based on clinicopathologic data. Product-limit estimates determined associations with biochemical recurrence (BCR)-free and metastasis-free survival. DVL2 and KLRC2 were significantly upregulated in CA tumors and were also associated with worse disease progression. No significant differences in immune cell abundances by race were observed. Highly significant reductions in abundances of mast cells versus tumor-infiltrating lymphocytes (TIL) were found in men with high-grade pathologies and in men who later developed metastases. Low ratios of mast cells versus TILs were associated with worse BCR-free survival and metastasis-free survival. Although estimated immune cell abundances were not different by race, we identified genes involved in metabolism and natural killer cell functions that were differentially expressed between AA and CA tumors. Among the entire cohort, depletion of mast cells within prostatectomy tumors was characteristic of advanced disease and susceptibility to disease progression. Significance: Our findings demonstrate that there are immune-related genes and pathways that differ by race. Impaired intratumoral cellular immune composition, especially for TIL-normalized mast cells, may be vital in predicting and contributing to prostate cancer disease progression.

BLM overexpression as a predictive biomarker for CHK1 inhibitor response in PARP inhibitor-resistant BRCA-mutant ovarian cancer.

Poly(ADP-ribose) polymerase inhibitors (PARPis) have changed the treatment paradigm in breast cancer gene (BRCA)-mutant high-grade serous ovarian carcinoma (HGSC). However, most patients eventually develop resistance to PARPis, highlighting an unmet need for improved therapeutic strategies. Using high-throughput drug screens, we identified ataxia telangiectasia and rad3-related protein/checkpoint kinase 1 (CHK1) pathway inhibitors as cytotoxic and further validated the activity of the CHK1 inhibitor (CHK1i) prexasertib in PARPi-sensitive and -resistant BRCA-mutant HGSC cells and xenograft mouse models. CHK1i monotherapy induced DNA damage, apoptosis, and tumor size reduction. We then conducted a phase 2 study (NCT02203513) of prexasertib in patients with BRCA-mutant HGSC. The treatment was well tolerated but yielded an objective response rate of 6% (1 of 17; one partial response) in patients with previous PARPi treatment. Exploratory biomarker analyses revealed that replication stress and fork stabilization were associated with clinical benefit to CHK1i. In particular, overexpression of Bloom syndrome RecQ helicase (BLM) and cyclin E1 (CCNE1) overexpression or copy number gain/amplification were seen in patients who derived durable benefit from CHK1i. BRCA reversion mutation in previously PARPi-treated BRCA-mutant patients was not associated with resistance to CHK1i. Our findings suggest that replication fork-related genes should be further evaluated as biomarkers for CHK1i sensitivity in patients with BRCA-mutant HGSC.

Association of TP53 Single Nucleotide Polymorphisms with Prostate Cancer in a Racially Diverse Cohort of Men.

Growing evidence indicates the involvement of a genetic component in prostate cancer (CaP) susceptibility and clinical severity. Studies have reported the role of germline mutations and single nucleotide polymorphisms (SNPs) of TP53 as possible risk factors for cancer development. In this single institutional retrospective study, we identified common SNPs in the TP53 gene in AA and CA men and performed association analyses for functional TP53 SNPs with the clinico-pathological features of CaP. The SNP genotyping analysis of the final cohort of 308 men (212 AA; 95 CA) identified 74 SNPs in the TP53 region, with a minor allele frequency (MAF) of at least 1%. Two SNPs were non-synonymous in the exonic region of TP53: rs1800371 (Pro47Ser) and rs1042522 (Arg72Pro). The Pro47Ser variant had an MAF of 0.01 in AA but was not detected in CA. Arg72Pro was the most common SNP, with an MAF of 0.50 (0.41 in AA; 0.68 in CA). Arg72Pro was associated with a shorter time to biochemical recurrence (BCR) (p = 0.046; HR = 1.52). The study demonstrated ancestral differences in the allele frequencies of the TP53 Arg72Pro and Pro47Ser SNPs, providing a valuable framework for evaluating CaP disparities among AA and CA men.

Multi-ancestry genome-wide study in >2.5 million individuals reveals heterogeneity in mechanistic pathways of type 2 diabetes and complications.

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes. To characterise the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study (GWAS) data from 2,535,601 individuals (39.7% non-European ancestry), including 428,452 T2D cases. We identify 1,289 independent association signals at genome-wide significance (P<5×10-8) that map to 611 loci, of which 145 loci are previously unreported. We define eight non-overlapping clusters of T2D signals characterised by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial, and enteroendocrine cells. We build cluster-specific partitioned genetic risk scores (GRS) in an additional 137,559 individuals of diverse ancestry, including 10,159 T2D cases, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned GRS are more strongly associated with coronary artery disease and end-stage diabetic nephropathy than an overall T2D GRS across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings demonstrate the value of integrating multi-ancestry GWAS with single-cell epigenomics to disentangle the aetiological heterogeneity driving the development and progression of T2D, which may offer a route to optimise global access to genetically-informed diabetes care.

Five-year survival of patients with late-stage prostate cancer: comparison of the Military Health System and the U.S. general population.

BACKGROUND: While the 5-year survival rate for local and regional prostate cancer is nearly 100%, it decreases dramatically for advanced tumours. Accessibility to health care is an important factor for cancer prognosis. The U.S. Military Health System (MHS) provides universal health care to its beneficiaries, reducing financial barriers to medical care. However, whether the universal care translates into improved survival among patients with advanced prostate cancer in the MHS is unknown. In this study, we compared the MHS and the U.S. general population in survival of patients with advanced prostate cancer (stages III and IV). METHODS: The MHS patients (N = 5379) were identified from the Department of Defense's (DoD) Automated Central Tumor Registry (ACTUR). Patients in the U.S. general population (N = 21,516) were identified from the Surveillance, Epidemiology, and End Results (SEER) programme. The two populations were matched on age, race, and diagnosis year. RESULTS: The ACTUR patients exhibited longer 5-year survival than the matched SEER patients (HR = 0.74, 95% CI = 0.67-0.83), after adjustment for the potential confounders. The improved survival was observed for ages 50 years or older, both White patients and Black patients, all tumour stages and grades. This was also demonstrated despite the receipt of surgery or radiation treatment. CONCLUSIONS: MHS beneficiaries with advanced prostate cancer had longer survival than their counterparts in the U.S. general population.

Phase I Study and Cell-Free DNA Analysis of T-DM1 and Metronomic Temozolomide for Secondary Prevention of HER2-Positive Breast Cancer Brain Metastases.

PURPOSE: Preclinical data showed that prophylactic, low-dose temozolomide (TMZ) significantly prevented breast cancer brain metastasis. We present results of a phase I trial combining T-DM1 with TMZ for the prevention of additional brain metastases after previous occurrence and local treatment in patients with HER2+ breast cancer. PATIENTS AND METHODS: Eligible patients had HER2+ breast cancer with brain metastases and were within 12 weeks of whole brain radiation therapy (WBRT), stereotactic radiosurgery, and/or surgery. Standard doses of T-DM1 were administered intravenously every 21 days (3.6 mg/kg) and TMZ was given orally daily in a 3+3 phase I dose escalation design at 30, 40, or 50 mg/m2, continuously. DLT period was one 21-day cycle. Primary endpoint was safety and recommended phase II dose. Symptom questionnaires, brain MRI, and systemic CT scans were performed every 6 weeks. Cell-free DNA sequencing was performed on patients' plasma and CSF. RESULTS: Twelve women enrolled, nine (75%) with prior SRS therapy and three (25%) with prior WBRT. Grade 3 or 4 AEs included thrombocytopenia (1/12), neutropenia (1/12), lymphopenia (6/12), and decreased CD4 (6/12), requiring pentamidine for Pneumocystis jirovecii pneumonia prophylaxis. No DLT was observed. Four patients on the highest TMZ dose underwent dose reductions. At trial entry, 6 of 12 patients had tumor mutations in CSF, indicating ongoing metastatic colonization despite a clear MRI. Median follow-up on study was 9.6 m (2.8-33.9); only 2 patients developed new parenchymal brain metastases. Tumor mutations varied with patient outcome. CONCLUSIONS: Metronomic TMZ in combination with standard dose T-DM1 shows low-grade toxicity and potential activity in secondary prevention of HER2+ brain metastases.

Race-specific prostate cancer outcomes in a cohort of low and favorable-intermediate risk patients who underwent external beam radiation therapy from 1990 to 2017.

BACKGROUND: Previous research exploring the role of race on prostate cancer (PCa) outcomes has demonstrated greater rates of disease progression and poorer overall survival for African American (AA) compared to Caucasian American (CA) men. The current study examines self-reported race as a predictor of long-term PCa outcomes in patients with low and favorable-intermediate risk disease treated with external beam radiation therapy (EBRT). METHODS: This retrospective cohort study examined patients who were consented to enrollment in the Center for Prostate Disease Research Multicenter National Database between January 01, 1990 and December 31, 2017. Men self-reporting as AA or CA who underwent EBRT for newly diagnosed National Comprehensive Cancer Network-defined low or favorable-intermediate risk PCa were included. Dependent study outcomes included: biochemical recurrence-free survival, (ii) distant metastasis-free survival, and (iii) overall survival. Each outcome was modeled as a time-to-event endpoint using race-stratified Kaplan-Meier estimation curves and multivariable Cox proportional hazards analysis. RESULTS: Of 840 men included in this study, 268 (32%) were AA and 572 (68%) were CA. The frequency of biochemical recurrence, distant metastasis, and deaths from any cause was 151 (18.7%), 29 (3.5%), and 333 (39.6%), respectively. AA men had a significantly younger median age at time of EBRT and slightly higher biopsy Gleason scores. Multivariable Cox proportional hazards analyses demonstrated no racial differences in any of the study endpoints. CONCLUSIONS: These findings reveal no racial disparity in PCa outcomes for AA compared to CA men, in a long-standing, longitudinal cohort of patients with comparable access to cancer care.

Race-specific prostate cancer outcomes in a cohort of military health care beneficiaries undergoing surgery: 1990-2017.

BACKGROUND: There is substantial variability in prostate cancer (PCa) mortality rates across Caucasian American (CA), African American (AA), Asian, and Hispanic men; however, these estimates are unable to disentangle race or ethnicity from confounding factors. The current study explores survival differences in long-term PCa outcomes between self-reported AA and CA men, and examines clinicopathologic features across self-reported CA, AA, Asian, and Hispanic men. METHODS: This retrospective cohort study utilized the Center for Prostate Disease Research (CPDR) Multi-center National Database from 1990 to 2017. Subjects were consented at military treatment facilities nationwide. AA, CA, Asian, or Hispanic men who underwent radical prostatectomy (RP) for localized PCa within the first year of diagnosis were included in the analyses. Time from RP to biochemical recurrence (BCR), BCR to metastasis, and metastasis to overall death were evaluated using Kaplan-Meier unadjusted estimation curves and adjusted Cox proportional hazards regression. RESULTS: This study included 7067 men, of whom 5155 (73%) were CA, 1468 (21%) were AA, 237 (3%) were Asian, and 207 (3%) were Hispanic. AA men had a significantly decreased time from RP to BCR compared to CA men (HR = 1.25, 95% CI = 1.06-1.48, p = 0.01); however, no difference was observed between AA and CA men for a time from BCR to metastasis (HR = 0.73, 95% CI = 0.39-1.33, p = 0.302) and time from metastasis to overall death (HR = 0.67, 95% CI = 0.36-1.26, p = 0.213). CONCLUSIONS: In an equal access health care setting, AA men had a shorter survival time from RP to BCR, but comparable survival time from BCR to metastasis and metastasis to overall death.

Germline mutation landscape of DNA damage repair genes in African Americans with prostate cancer highlights potentially targetable RAD genes.

In prostate cancer, emerging data highlight the role of DNA damage repair genes (DDRGs) in aggressive forms of the disease. However, DDRG mutations in African American men are not yet fully defined. Here, we profile germline mutations in all known DDRGs (N = 276) using whole genome sequences from blood DNA of a matched cohort of patients with primary prostate cancer comprising of 300 African American and 300 European Ancestry prostate cancer patients, to determine whether the mutation status can enhance patient stratification for specific targeted therapies. Here, we show that only 13 of the 46 DDRGs identified with pathogenic/likely pathogenic mutations are present in both African American and European ancestry patients. Importantly, RAD family genes (RAD51, RAD54L, RAD54B), which are potentially targetable, as well as PMS2 and BRCA1, are among the most frequently mutated DDRGs in African American, but not in European Ancestry patients.

Identification of a dysfunctional exon-skipping splice variant in GLUT9/SLC2A9 causal for renal hypouricemia type 2.

Renal hypouricemia (RHUC) is a pathological condition characterized by extremely low serum urate and overexcretion of urate in the kidney; this inheritable disorder is classified into type 1 and type 2 based on causative genes encoding physiologically-important urate transporters, URAT1 and GLUT9, respectively; however, research on RHUC type 2 is still behind type 1. We herein describe a typical familial case of RHUC type 2 found in a Slovak family with severe hypouricemia and hyperuricosuria. Via clinico-genetic analyses including whole exome sequencing and in vitro functional assays, we identified an intronic GLUT9 variant, c.1419+1G>A, as the causal mutation that could lead the expression of p.Gly431GlufsTer28, a functionally-null variant resulting from exon 11 skipping. The causal relationship was also confirmed in another unrelated Macedonian family with mild hypouricemia. Accordingly, non-coding regions should be also kept in mind during genetic diagnosis for hypouricemia. Our findings provide a better pathogenic understanding of RHUC and pathophysiological importance of GLUT9.

Impact of Age and Race on Health-Related Quality of Life Outcomes in Patients Undergoing Radical Prostatectomy for Localized Prostate Cancer.

OBJECTIVES: To investigate impact of age and race on health-related quality of life (HRQoL) in men undergoing radical prostatectomy (RP) using a prospectively maintained, racially diverse cohort. METHODS: The Center for Prostate Disease Research Multicenter National Database was used to identify patients receiving RP from 2007-2017. The Expanded PCa Index Composite and 36 Item Short-Form Health Survey were completed at baseline and regular intervals. Groups were stratified based on age: <60, 60-70, >70. Longitudinal patterns in HRQoL were assessed using linear regression models, adjusting for baseline HRQoL, demographics, and clinical characteristics. RESULTS: In 626 patients undergoing RP, 278 (44.4%) were <60, 291 (46.5%) were 60-70, 57 (9.1%) were >70. Older men had worse baseline urinary bother (P<.01) and sexual HRQoL (P<.01). Baseline urinary function was similar for older and younger men. Post-RP urinary and sexual HRQoL was significantly lower in men >70. However, when adjusting for baseline HRQoL, race, NCCN risk, and comorbidities, no difference was found between age groups in urinary function or bother, or sexual function. Sexual bother was worse in older men until 48 months post-operatively but subsequently improved to levels similar to younger patients. Race independently affected HRQoL outcomes with older African American men reporting worse urinary function and sexual bother. CONCLUSIONS: When accounting for baseline HRQoL, age does not independently predict worse HRQoL outcomes. Older and younger men experience similar declines in urinary and sexual domain scores after RP. Our findings may be used to better inform patients regarding their expected post RP HRQoL and guide treatment decision-making.

Meta-Analyses of Splicing and Expression Quantitative Trait Loci Identified Susceptibility Genes of Glioma.

BACKGROUND: The functions of most glioma risk alleles are unknown. Very few studies had evaluated expression quantitative trait loci (eQTL), and insights of susceptibility genes were limited due to scarcity of available brain tissues. Moreover, no prior study had examined the effect of glioma risk alleles on alternative RNA splicing. OBJECTIVE: This study explored splicing quantitative trait loci (sQTL) as molecular QTL and improved the power of QTL mapping through meta-analyses of both cis eQTL and sQTL. METHODS: We first evaluated eQTLs and sQTLs of the CommonMind Consortium (CMC) and Genotype-Tissue Expression Project (GTEx) using genotyping, or whole-genome sequencing and RNA-seq data. Alternative splicing events were characterized using an annotation-free method that detected intron excision events. Then, we conducted meta-analyses by pooling the eQTL and sQTL results of CMC and GTEx using the inverse variance-weighted model. Afterward, we integrated QTL meta-analysis results (Q < 0.05) with the Glioma International Case Control Study (GICC) GWAS meta-analysis (case:12,496, control:18,190), using a summary statistics-based mendelian randomization (SMR) method. RESULTS: Between CMC and GTEx, we combined the QTL data of 354 unique individuals of European ancestry. SMR analyses revealed 15 eQTLs in 11 loci and 32 sQTLs in 9 loci relevant to glioma risk. Two loci only harbored sQTLs (1q44 and 16p13.3). In seven loci, both eQTL and sQTL coexisted (2q33.3, 7p11.2, 11q23.3 15q24.2, 16p12.1, 20q13.33, and 22q13.1), but the target genes were different for five of these seven loci. Three eQTL loci (9p21.3, 20q13.33, and 22q13.1) and 4 sQTL loci (11q23.3, 16p13.3, 16q12.1, and 20q13.33) harbored multiple target genes. Eight target genes of sQTLs (C2orf80, SEC61G, TMEM25, PHLDB1, RP11-161M6.2, HEATR3, RTEL1-TNFRSF6B, and LIME1) had multiple alternatively spliced transcripts. CONCLUSION: Our study revealed that the regulation of transcriptome by glioma risk alleles is complex, with the potential for eQTL and sQTL jointly affecting gliomagenesis in risk loci. QTLs of many loci involved multiple target genes, some of which were specific to alternative splicing. Therefore, quantitative trait loci that evaluate only total gene expression will miss many important target genes.

Retinal Nerve Fiber Layer Thickness in Healthy Eyes of Black, Chinese, and Latino Americans: A Population-Based Multiethnic Study.

PURPOSE: To compare peripapillary retinal nerve fiber layer (RNFL) thickness among healthy adults by race and ethnicity and to identify determinants of RNFL thickness. DESIGN: Population-based cross-sectional study. PARTICIPANTS: Data from 6133 individuals (11 585 eyes) from 3 population-based studies in Los Angeles County, California, 50 years of age or older and of self-described African, Chinese, or Latin American ancestry. METHODS: We measured RNFL thickness and optic nerve head parameters using the Cirrus HD-OCT 4000. Multivariate linear mixed regression was used to evaluate factors associated with RNFL thickness among participants without ocular diseases. MAIN OUTCOME MEASURES: Determinants and modifiers of RNFL thickness. RESULTS: The mean age of the participants was 60.1 years (standard deviation, 7.4 years). Black Americans showed the lowest RNFL thickness and smallest cup-to-disc ratio (CDR), and Chinese Americans showed the largest CDR and disc area after adjusting for age and gender (all P < 0.05). Per each 10-year older age group, the average RNFL thickness was 2.5 µm (95% confidence interval [CI], 1.8-3.1 µm), 2.8 µm (95% CI, 2.3-3.3 µm), and 3.5 µm (95% CI, 2.9-4.1 µm) thinner for Black, Chinese, and Latino Americans, respectively (age trend P < 0.05 and interaction P = 0.041). Black Americans compared with Chinese Americans, older age, male gender, hypertension, diabetes, greater axial length (AL), bigger disc area, and lower scan signal strength were associated with thinner average RNFL. Race, age, AL, disc area, and scan signal strength consistently were associated with RNFL thickness in all quadrants, whereas gender, hypertension, and diabetes were associated with RNFL thickness in select quadrants. Age and race explained the greatest proportion of variance of RNFL thickness. CONCLUSIONS: Clinically important differences in RNFL thickness are present in healthy adults 50 years of age or older from different racial and ethnic groups of the same age, with the thinnest measures observed in Black Americans. This difference remains after accounting for disc size and AL. Furthermore, age-related RNFL thinning differs by race and ethnicity. Longitudinal studies are needed to verify our findings and to assess the influence of race and ethnicity in the clinical application of RNFL thickness.

A Mitochondrial Genome-Wide Association Study of Cataract in a Latino Population.

Purpose: Over 9.5 million Latinos could be affected by cataracts by 2050. However, no known cataract genetic risk alleles have been identified in Latinos. Moreover, no mitochondrial genome-wide association studies (MiWAS) have been conducted on cataracts in a Latino cohort despite the association between mitochondrial dysfunction and cataracts. Our purpose was to identify a mitochondrial DNA variant that associated with cataracts in a large-scale Latino population. Methods: We conducted an MiWAS to identify mitochondrial single-nucleotide polymorphisms that modify cataract risk in nearly 3500 individuals enrolled in the Los Angles Latino Eye Study cohort, the largest Latino-specific cohort with comprehensive cataract data. Our analytic strategy for MiWAS included logistic regression on cataract occurrence while controlling for mitochondrial genetic ancestry, age, and biological sex. Results: We found that MitoG228A (rs41323649) alternative allele carriers experienced a five times greater risk for cataracts compared with reference allele carriers. Alternative allele carriers also developed cataracts earlier in life compared with reference allele carriers. Intracohort cross-validation with 10-fold resampling and five repeats showed that the effect of MitoG228A remained significant. Conclusions: MitoG228A increased risk for cataracts five-fold in approximately 3500 Latinos. To the best of our knowledge, this is the first cataract MiWAS on a large-scale Latino population. This association needs to be validated in an independent cohort. Translational Relevance: Our discovery hypothesis-generating study suggest MitoG228A has potential to be used as a risk factor in the clinic and as a target for therapeutics. With validation via an independent cohort, MitoG228A could be used to estimate cataract risk for a Latino to reduce complications later in life.