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To investigate large structural clonal mosaicism of chromosome X, we analysed the SNP microarray intensity data of 38,303 women from cancer genome-wide association studies (20,878 cases and 17,425 controls) and detected 124 mosaic X events >2 Mb in 97 (0.2

Background: Mosaic loss of chromosome Y (mLOY) in leukocytes of men reflects genomic instability from aging, smoking, and environmental exposures. A similar mosaic loss of chromosome X (mLOX) occurs among women. However, the associations between mLOY, mLOX, and risk of incident heart diseases are unclear., Methods and Results: We estimated associations between mLOY, mLOX, and risk of incident heart diseases requiring hospitalization, including atrial fibrillation, myocardial infarction, ischemic heart disease, cardiomyopathy, and heart failure. We analyzed 190 613 men and 224 853 women with genotyping data from the UK Biobank. Among these participants, there were 37 037 men with mLOY and 13 978 women with mLOX detected using the Mosaic Chromosomal Alterations caller. Multivariable Cox regression was used to estimate hazard ratios (HRs) and 95% CIs of each incident heart disease in relation to mLOY in men and mLOX in women. Additionally, Mendelian randomization was conducted to estimate causal associations. Among men, detectable mLOY was associated with elevated risk of atrial fibrillation (HR, 1.06 [95% CI, 1.03-1.11]). The associations were apparent in both never smokers (HR, 1.07 [95% CI, 1.01-1.14]) and ever smokers (HR, 1.05 [95% CI, 1.01-1.11]) as well as men aged >60 and ≤60 years. Mendelian randomization analyses supported causal associations between mLOY and atrial fibrillation (HR MR-PRESSO , 1.15 [95% CI, 1.13-1.18]). Among postmenopausal women, we found a suggestive inverse association between detectable mLOX and atrial fibrillation risk (HR, 0.90 [95% CI, 0.83-0.98]). However, associations with mLOY and mLOX were not found for other heart diseases., Conclusions: Our findings suggest that mLOY and mLOX reflect sex-specific biological processes or exposure profiles related to incident atrial fibrillation requiring hospitalization.

We performed a series of integrative analyses including transcriptome-wide association studies (TWASs) and proteome-wide association studies (PWASs) of renal cell carcinoma (RCC) to nominate and prioritize molecular targets for laboratory investigation. On the basis of a genome-wide association study (GWAS) of 29,020 affected individuals and 835,670 control individuals and prediction models trained in transcriptomic reference models, our TWAS across four kidney transcriptomes (GTEx kidney cortex, kidney tubules, TCGA-KIRC [The Cancer Genome Atlas kidney renal clear-cell carcinoma], and TCGA-KIRP [TCGA kidney renal papillary cell carcinoma]) identified 38 gene associations (false-discovery rate <5%) in at least two of four transcriptomic panels and identified 12 genes that were independent of GWAS susceptibility regions. Analyses combining TWAS associations across 48 tissues from GTEx identified associations that were replicable in tumor transcriptomes for 23 additional genes. Analyses by the two major histologic types (clear-cell RCC and papillary RCC) revealed subtype-specific associations, although at least three gene associations were common to both subtypes. PWAS identified 13 associated proteins, all mapping to GWAS-significant loci. TWAS-identified genes were enriched for active enhancer or promoter regions in RCC tumors and hypoxia-inducible factor binding sites in relevant cell lines. Using gene expression correlation, common cancers (breast and prostate) and RCC risk factors (e.g., hypertension and BMI) display genetic contributions shared with RCC. Our work identifies potential molecular targets for RCC susceptibility for downstream functional investigation., Competing Interests: Declaration of interests K.S. receives research support from Gilead, GSK, Novo Nordisk, Bayer, Regeneron, Calico, and Novartis. K.S. is on the advisory board of Jnana Therapeutics and has received consulting fees from Pfizer and Jnana. Declaration of interests for the Renal Cancer Genetics Consortium, which contributed toward acquisition of the individual-level data, can be referred to as a part of Purdue et al.(10) The other named authors in the manuscript have no competing interests to declare. It is to be noted that the individual-level data contributed by The Renal Cancer Genetics Consortium is now publicly available, and the current analyses were conducted with summary-level data only., (Published by Elsevier Inc.)

Deciphering the genetic basis of prostate-specific antigen (PSA) levels may improve their utility for prostate cancer (PCa) screening. Using genome-wide association study (GWAS) summary statistics from 95,768 PCa-free men, we conducted a transcriptome-wide association study (TWAS) to examine impacts of genetically predicted gene expression on PSA. Analyses identified 41 statistically significant (p < 0.05/12,192 = 4.10 × 10 -6 ) associations in whole blood and 39 statistically significant (p < 0.05/13,844 = 3.61 × 10 -6 ) associations in prostate tissue, with 18 genes associated in both tissues. Cross-tissue analyses identified 155 statistically significantly (p < 0.05/22,249 = 2.25 × 10 -6 ) genes. Out of 173 unique PSA-associated genes across analyses, we replicated 151 (87.3%) in a TWAS of 209,318 PCa-free individuals from the Million Veteran Program. Based on conditional analyses, we found 20 genes (11 single tissue, nine cross-tissue) that were associated with PSA levels in the discovery TWAS that were not attributable to a lead variant from a GWAS. Ten of these 20 genes replicated, and two of the replicated genes had colocalization probability of >0.5: CCNA2 and HIST1H2BN. Six of the 20 identified genes are not known to impact PCa risk. Fine-mapping based on whole blood and prostate tissue revealed five protein-coding genes with evidence of causal relationships with PSA levels. Of these five genes, four exhibited evidence of colocalization and one was conditionally independent of previous GWAS findings. These results yield hypotheses that should be further explored to improve understanding of genetic factors underlying PSA levels., Competing Interests: Declaration of interests J.S.W. is a non-employee and cofounder of Avail Bio. H.L. is named on a patent for assays to measure intact PSA and a patent for a statistical method to detect prostate cancer commercialized by OPKO Health (4KScore). H.L. receives royalties from sales of the assay and has stock in OPKO Health. H.L. serves on the Scientific Advisory Board for Fujirebio Diagnostics Inc and owns stock in Diaprost AB and Acousort AB. R.E.G. consults for Hunton Andrews Kurth LLC on subject matter unrelated to this study., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Mosaic loss of the X chromosome (mLOX) is the most common clonal somatic alteration in leukocytes of female individuals 1,2 , but little is known about its genetic determinants or phenotypic consequences. Here, to address this, we used data from 883,574 female participants across 8 biobanks; 12% of participants exhibited detectable mLOX in approximately 2% of leukocytes. Female participants with mLOX had an increased risk of myeloid and lymphoid leukaemias. Genetic analyses identified 56 common variants associated with mLOX, implicating genes with roles in chromosomal missegregation, cancer predisposition and autoimmune diseases. Exome-sequence analyses identified rare missense variants in FBXO10 that confer a twofold increased risk of mLOX. Only a small fraction of associations was shared with mosaic Y chromosome loss, suggesting that distinct biological processes drive formation and clonal expansion of sex chromosome missegregation. Allelic shift analyses identified X chromosome alleles that are preferentially retained in mLOX, demonstrating variation at many loci under cellular selection. A polygenic score including 44 allelic shift loci correctly inferred the retained X chromosomes in 80.7% of mLOX cases in the top decile. Our results support a model in which germline variants predispose female individuals to acquiring mLOX, with the allelic content of the X chromosome possibly shaping the magnitude of clonal expansion., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Childhood radioactive iodine exposure from the Chornobyl accident increased papillary thyroid carcinoma (PTC) risk. While cervical lymph node metastases (cLNM) are well-recognized in pediatric PTC, the PTC metastatic process and potential radiation association are poorly understood. Here, we analyze cLNM occurrence among 428 PTC with genomic landscape analyses and known drivers ( 131 I-exposed = 349, unexposed = 79; mean age = 27.9 years). We show that cLNM are more frequent in PTC with fusion (55%) versus mutation (30%) drivers, although the proportion varies by specific driver gene (RET-fusion = 71%, BRAF-mutation = 38%, RAS-mutation = 5%). cLNM frequency is not associated with other characteristics, including radiation dose. cLNM molecular profiling (N = 47) demonstrates 100% driver concordance with matched primary PTCs and highly concordant mutational spectra. Transcriptome analysis reveals 17 differentially expressed genes, particularly in the HOXC cluster and BRINP3; the strongest differentially expressed microRNA also is near HOXC10. Our findings underscore the critical role of driver alterations and provide promising candidates for elucidating the biological underpinnings of PTC cLNM., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Motivation: The acquisition of somatic mutations in hematopoietic stem and progenitor stem cells with resultant clonal expansion, termed clonal hematopoiesis (CH), is associated with increased risk of hematologic malignancies and other adverse outcomes. CH is generally present at low allelic fractions, but clonal expansion and acquisition of additional mutations leads to hematologic cancers in a small proportion of individuals. With high depth and high sensitivity sequencing, CH can be detected in most adults and its clonal trajectory mapped over time. However, accurate CH variant calling is challenging due to the difficulty in distinguishing low frequency CH mutations from sequencing artifacts. The lack of well-validated bioinformatic pipelines for CH calling may contribute to lack of reproducibility in studies of CH., Results: Here, we developed ArCH, an Artifact filtering Clonal Hematopoiesis variant calling pipeline for detecting single nucleotide variants and short insertions/deletions by combining the output of four variant calling tools and filtering based on variant characteristics and sequencing error rate estimation. ArCH is an end-to-end cloud-based pipeline optimized to accept a variety of inputs with customizable parameters adaptable to multiple sequencing technologies, research questions, and datasets. Using deep targeted sequencing data generated from six acute myeloid leukemia patient tumor: normal dilutions, 31 blood samples with orthogonal validation, and 26 blood samples with technical replicates, we show that ArCH improves the sensitivity and positive predictive value of CH variant detection at low allele frequencies compared to standard application of commonly used variant calling approaches., Availability and Implementation: The code for this workflow is available at: https://github.com/kbolton-lab/ArCH., (© The Author(s) 2024. Published by Oxford University Press.)

Knowledge of Ewing sarcoma (EWS) risk factors is exceedingly limited; however, multiple small, independent studies have suggested a possible connection between hernia and EWS. By leveraging hernia summary statistics from the UK Biobank and a recently published genome-wide association study of EWS (733 EWS cases and 1,346 controls), we conducted a genetic investigation of the relationship of 5 hernia types (diaphragmatic, inguinal, umbilical, femoral, and ventral) and EWS. We discovered a positive causal relationship between inguinal hernia and EWS (OR 1.27, 95% confidence interval [CI] 1.01-1.59, and p = 0.041) through Mendelian randomization analysis. Further analyses suggested shared pathways through three genes: HMGA2, LOX, and FBXW7. Diaphragmatic hernia showed a stronger causal relationship with EWS among all of the hernia types (OR 2.26, 95% CI 1.30-3.95, p = 0.004), but no statistically significant local correlation pattern was observed. No evidence of a causal or genetic relationship was observed between EWS and the other three hernia types, including umbilical hernia, despite a previous report indicating an OR as high as 3.3. The finding of our genetic analysis provided additional support to the hypothesis that EWS and hernias may share a common origin., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023. Published by Elsevier Inc.)

The majority of disease-associated variants identified through genome-wide association studies are located outside of protein-coding regions. Prioritizing candidate regulatory variants and gene targets to identify potential biological mechanisms for further functional experiments can be challenging. To address this challenge, we developed FORGEdb ( https://forgedb.cancer.gov/ ; https://forge2.altiusinstitute.org/files/forgedb.html ; and https://doi.org/10.5281/zenodo.10067458 ), a standalone and web-based tool that integrates multiple datasets, delivering information on associated regulatory elements, transcription factor binding sites, and target genes for over 37 million variants. FORGEdb scores provide researchers with a quantitative assessment of the relative importance of each variant for targeted functional experiments., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

JAK2 V617F is the most common driver mutation in primary or secondary myelofibrosis for which allogeneic hematopoietic cell transplantation (HCT) is the only curative treatment. Knowledge of the prognostic utility of JAK2 alterations in the HCT setting is limited. We identified all patients with MF who received HCT between 2000 and 2016 and had a pre-HCT blood sample (N = 973) available at the Center of International Blood and Marrow Transplant Research biorepository. PacBio sequencing and single nucleotide polymorphism-array genotyping were used to identify JAK2V617F mutation and associated mosaic chromosomal alterations (mCAs), respectively. Cox proportional hazard models were used for HCT outcome analyses. Genomic testing was complete for 924 patients with MF (634 primary MF [PMF], 135 postpolycythemia vera [PPV-MF], and 155 postessential thrombocytopenia [PET-MF]). JAK2V617F affected 562 patients (57.6% of PMF, 97% of PPV-MF, and 42.6% of PET-MF). Almost all patients with mCAs involving the JAK2 region (97.9%) were JAK2V617-positive. In PMF, JAK2V617F mutation status, allele burden, or identified mCAs were not associated with disease progression/relapse, nonrelapse mortality (NRM), or overall survival. Almost all PPV-MF were JAK2V617F-positive (97%), with no association between HCT outcomes and mutation allele burden or mCAs. In PET-MF, JAK2V617F high mutation allele burden (≥60%) was associated with excess risk of NRM, restricted to transplants received in the era of JAK inhibitors (2013-2016; hazard ratio = 7.65; 95% confidence interval = 2.10-27.82; P = .002). However, allele burden was not associated with post-HCT disease progression/relapse or survival. Our findings support the concept that HCT can mitigate the known negative effect of JAK2V617F in patients with MF, particularly for PMF and PPV-MF., (Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution.)

In high-income countries, mosaic chromosomal alterations in peripheral blood leukocytes are associated with an elevated risk of adverse health outcomes, including hematologic malignancies. We investigate mosaic chromosomal alterations in sub-Saharan Africa among 931 children with Burkitt lymphoma, an aggressive lymphoma commonly characterized by immunoglobulin-MYC chromosomal rearrangements, 3822 Burkitt lymphoma-free children, and 674 cancer-free men from Ghana. We find autosomal and X chromosome mosaic chromosomal alterations in 3.4% and 1.7% of Burkitt lymphoma-free children, and 8.4% and 3.7% of children with Burkitt lymphoma (P-values = 5.7×10 -11 and 3.74×10 -2 , respectively). Autosomal mosaic chromosomal alterations are detected in 14.0% of Ghanaian men and increase with age. Mosaic chromosomal alterations in Burkitt lymphoma cases include gains on chromosomes 1q and 8, the latter spanning MYC, while mosaic chromosomal alterations in Burkitt lymphoma-free children include copy-neutral loss of heterozygosity on chromosomes 10, 14, and 16. Our results highlight mosaic chromosomal alterations in sub-Saharan African populations as a promising area of research., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Glyphosate is the most commonly used herbicide worldwide and has been implicated in the development of certain hematologic cancers. Although mechanistic studies in human cells and animals support the genotoxic effects of glyphosate, evidence in human populations is scarce., Objectives: We evaluated the association between lifetime occupational glyphosate use and mosaic loss of chromosome Y (mLOY) as a marker of genotoxicity among male farmers., Methods: We analyzed blood-derived DNA from 1,606 farmers ≥ 50 years of age in the Biomarkers of Exposure and Effect in Agriculture study, a subcohort of the Agricultural Health Study. mLOY was detected using genotyping array intensity data in the pseudoautosomal region of the sex chromosomes. Cumulative lifetime glyphosate use was assessed using self-reported pesticide exposure histories. Using multivariable logistic regression, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between glyphosate use and any detectable mLOY (overall mLOY) or mLOY affecting ≥ 10 % of cells (expanded mLOY)., Results: Overall, mLOY was detected in 21.4% of farmers, and 9.8% of all farmers had expanded mLOY. Increasing total lifetime days of glyphosate use was associated with expanded mLOY [highest vs. lowest quartile; OR = 1.75 (95% CI: 1.00, 3.07), p trend = 0.03 ] but not with overall mLOY; the associations with expanded mLOY were most apparent among older ( ≥ 70 years of age) men [ OR = 2.30 (95% CI: 1.13, 4.67), p trend = 0.01 ], never smokers [ OR = 2.32 (95% CI: 1.04, 5.21), p trend = 0.04 ], and nonobese men [ OR = 2.04 (95% CI: 0.99, 4.19), p trend = 0.03 ]. Similar patterns of associations were observed for intensity-weighted lifetime days of glyphosate use., Discussion: High lifetime glyphosate use could be associated with mLOY affecting a larger fraction of cells, suggesting glyphosate could confer genotoxic or selective effects relevant for clonal expansion. As the first study to investigate this association, our findings contribute novel evidence regarding the carcinogenic potential of glyphosate and require replication in future studies. https://doi.org/10.1289/EHP12834.

Age-related clonal expansion of cells harbouring mosaic chromosomal alterations (mCAs) is one manifestation of clonal haematopoiesis. Identifying factors that influence the generation and promotion of clonal expansion of mCAs are key to investigate the role of mCAs in health and disease. Herein, we report on widely measured serum biomarkers and their possible association with mCAs, which could provide new insights into molecular alterations that promote acquisition and clonal expansion. We performed a cross-sectional investigation of the association of 32 widely measured serum biomarkers with autosomal mCAs, mosaic loss of the Y chromosome, and mosaic loss of the X chromosome in 436 784 cancer-free participants from the UK Biobank. mCAs were associated with a range of commonly measured serum biomarkers such as lipid levels, circulating sex hormones, blood sugar homeostasis, inflammation and immune function, vitamins and minerals, kidney function, and liver function. Biomarker levels in participants with mCAs were estimated to differ by up to 5% relative to mCA-free participants, and individuals with higher cell fraction mCAs had greater deviation in mean biomarker values. Polygenic scores associated with sex hormone binding globulin, vitamin D, and total cholesterol were also associated with mCAs. Overall, we observed commonly used clinical serum biomarkers related to disease risk are associated with mCAs, suggesting mechanisms involved in these diseases could be related to mCA proliferation and clonal expansion., (Published by Oxford University Press 2023.)

Clonal hematopoiesis (CH)-age-related expansion of mutated hematopoietic clones-can differ in frequency and cellular fitness by CH type (e.g., mutations in driver genes (CHIP), gains/losses and copy-neutral loss of chromosomal segments (mCAs), and loss of sex chromosomes). Co-occurring CH raises questions as to their origin, selection, and impact. We integrate sequence and genotype array data in up to 482,378 UK Biobank participants to demonstrate shared genetic architecture across CH types. Our analysis suggests a cellular evolutionary trade-off between different types of CH, with LOY occurring at lower rates in individuals carrying mutations in established CHIP genes. We observed co-occurrence of CHIP and mCAs with overlap at TET2, DNMT3A, and JAK2, in which CHIP precedes mCA acquisition. Furthermore, individuals carrying overlapping CH had high risk of future lymphoid and myeloid malignancies. Finally, we leverage shared genetic architecture of CH traits to identify 15 novel loci associated with leukemia risk., (© 2023. Springer Nature Limited.)

Objectives: People with HIV (PWH) have an elevated risk of non-Hodgkin lymphoma (NHL) and other diseases. Studying clonal hematopoiesis (CH), the clonal expansion of mutated hematopoietic stem cells, could provide insights regarding elevated NHL risk., Design: Cohort analysis of participants in the Multicenter AIDS Cohort Study ( N  = 5979)., Methods: Mosaic chromosomal alterations (mCAs), a type of CH, were detected from genotyping array data using MoChA. We compared CH prevalence in men with HIV (MWH) to HIV-uninfected men using logistic regression, and among MWH, assessed the associations of CH with NHL incidence and overall mortality using Poisson regression., Results: Comparing MWH to HIV-uninfected men, we observed no difference in the frequency of autosomal mCAs (3.9% vs. 3.6%, P -value = 0.09) or mosaic loss of the Y chromosome (mLOY) (1.4% vs. 2.9%, P -value = 0.13). Autosomal mCAs involving copy-neutral loss of heterozygosity (CN-LOH) of chromosome 14q were more common in MWH. Among MWH, mCAs were not associated with subsequent NHL incidence (autosomal mCA P -value = 0.65, mLOY P -value = 0.48). However, two MWH with diffuse large B-cell lymphoma had overlapping CN-LOH mCAs on chromosome 19 spanning U2AF2 (involved in RNA splicing), and one MWH with Burkitt lymphoma had high-frequency mCAs involving chromosome 1 gain and chromosome 17 CN-LOH (cell fractions 22.1% and 25.0%, respectively). mCAs were not associated with mortality among MWH (autosomal mCA P -value = 0.52, mLOY P -value = 0.93)., Conclusions: We found limited evidence for a relationship between HIV infection and mCAs. Although mCAs were not significantly associated with NHL, mCAs detected in several NHL cases indicate a need for further investigation., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The rule of thumb that there is little gain in statistical power by obtaining more than 4 controls per case, is based on type-1 error α = 0.05. However, association studies that evaluate thousands or millions of associations use smaller α and may have access to plentiful controls. We investigate power gains, and reductions in p-values, when increasing well beyond 4 controls per case, for small α., Methods: We calculate the power, the median expected p-value, and the minimum detectable odds-ratio (OR), as a function of the number of controls/case, as α decreases., Results: As α decreases, at each ratio of controls per case, the increase in power is larger than for α = 0.05. For α between 10 -6 and 10 -9 (typical for thousands or millions of associations), increasing from 4 controls per case to 10-50 controls per case increases power. For example, a study with power = 0.2 (α = 5 × 10 -8 ) with 1 control/case has power = 0.65 with 4 controls/case, but with 10 controls/case has power = 0.78, and with 50 controls/case has power = 0.84. For situations where obtaining more than 4 controls per case provides small increases in power beyond 0.9 (at small α), the expected p-value can decrease by orders-of-magnitude below α. Increasing from 1 to 4 controls/case reduces the minimum detectable OR toward the null by 20.9%, and from 4 to 50 controls/case reduces by an additional 9.7%, a result which applies regardless of α and hence also applies to "regular" α = 0.05 epidemiology., Conclusions: At small α, versus 4 controls/case, recruiting 10 or more controls/cases can increase power, reduce the expected p-value by 1-2 orders of magnitude, and meaningfully reduce the minimum detectable OR. These benefits of increasing the controls/case ratio increase as the number of cases increases, although the amount of benefit depends on exposure frequencies and true OR. Provided that controls are comparable to cases, our findings suggest greater sharing of comparable controls in large-scale association studies., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Prostate-specific antigen (PSA) screening for prostate cancer remains controversial because it increases overdiagnosis and overtreatment of clinically insignificant tumors. Accounting for genetic determinants of constitutive, non-cancer-related PSA variation has potential to improve screening utility. In this study, we discovered 128 genome-wide significant associations (P < 5 × 10 -8 ) in a multi-ancestry meta-analysis of 95,768 men and developed a PSA polygenic score (PGS PSA ) that explains 9.61% of constitutive PSA variation. We found that, in men of European ancestry, using PGS-adjusted PSA would avoid up to 31% of negative prostate biopsies but also result in 12% fewer biopsies in patients with prostate cancer, mostly with Gleason score <7 tumors. Genetically adjusted PSA was more predictive of aggressive prostate cancer (odds ratio (OR) = 3.44, P = 6.2 × 10 -14 , area under the curve (AUC) = 0.755) than unadjusted PSA (OR = 3.31, P = 1.1 × 10 -12 , AUC = 0.738) in 106 cases and 23,667 controls. Compared to a prostate cancer PGS alone (AUC = 0.712), including genetically adjusted PSA improved detection of aggressive disease (AUC = 0.786, P = 7.2 × 10 -4 ). Our findings highlight the potential utility of incorporating PGS for personalized biomarkers in prostate cancer screening., (© 2023. The Author(s).)

Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (P interaction  = 0.0058). These findings provide new insights into the etiology of lung adenocarcinoma in individuals from East Asian populations, which could be important in developing translational applications., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Multiple myeloma (MM) arises following malignant proliferation of plasma cells in the bone marrow, that secrete high amounts of specific monoclonal immunoglobulins or light chains, resulting in the massive production of unfolded or misfolded proteins. Autophagy can have a dual role in tumorigenesis, by eliminating these abnormal proteins to avoid cancer development, but also ensuring MM cell survival and promoting resistance to treatments. To date no studies have determined the impact of genetic variation in autophagy-related genes on MM risk. We performed meta-analysis of germline genetic data on 234 autophagy-related genes from three independent study populations including 13,387 subjects of European ancestry (6863 MM patients and 6524 controls) and examined correlations of statistically significant single nucleotide polymorphisms (SNPs; p < 1 × 10 -9 ) with immune responses in whole blood, peripheral blood mononuclear cells (PBMCs), and monocyte-derived macrophages (MDM) from a large population of healthy donors from the Human Functional Genomic Project (HFGP). We identified SNPs in six loci, CD46 , IKBKE , PARK2 , ULK4 , ATG5 , and CDKN2A associated with MM risk ( p = 4.47 × 10 -4 -5.79 × 10 -14 ). Mechanistically, we found that the ULK4 rs6599175 SNP correlated with circulating concentrations of vitamin D3 ( p = 4.0 × 10 -4 ), whereas the IKBKE rs17433804 SNP correlated with the number of transitional CD24 + CD38 + B cells ( p = 4.8 × 10 -4 ) and circulating serum concentrations of Monocyte Chemoattractant Protein (MCP)-2 ( p = 3.6 × 10 -4 ). We also found that the CD46 rs1142469 SNP correlated with numbers of CD19 + B cells, CD19 + CD3 - B cells, CD5 + IgD - cells, IgM - cells, IgD - IgM - cells, and CD4 - CD8 - PBMCs ( p = 4.9 × 10 -4 -8.6 × 10 -4 ) and circulating concentrations of interleukin (IL)-20 ( p = 0.00082). Finally, we observed that the CDKN2A rs2811710 SNP correlated with levels of CD4 + EMCD45RO + CD27 - cells ( p = 9.3 × 10 -4 ). These results suggest that genetic variants within these six loci influence MM risk through the modulation of specific subsets of immune cells, as well as vitamin D3 - , MCP-2 - , and IL20-dependent pathways.

Ewing sarcoma (EwS) is a rare bone and soft tissue malignancy driven by chromosomal translocations encoding chimeric transcription factors, such as EWSR1-FLI1, that bind GGAA motifs forming novel enhancers that alter nearby expression. We propose that germline microsatellite variation at the 6p25.1 EwS susceptibility locus could impact downstream gene expression and EwS biology. We performed targeted long-read sequencing of EwS blood DNA to characterize variation and genomic features important for EWSR1-FLI1 binding. We identified 50 microsatellite alleles at 6p25.1 and observed that EwS-affected individuals had longer alleles (>135 bp) with more GGAA repeats. The 6p25.1 GGAA microsatellite showed chromatin features of an EWSR1-FLI1 enhancer and regulated expression of RREB1, a transcription factor associated with RAS/MAPK signaling. RREB1 knockdown reduced proliferation and clonogenic potential and reduced expression of cell cycle and DNA replication genes. Our integrative analysis at 6p25.1 details increased binding of longer GGAA microsatellite alleles with acquired EWSR-FLI1 to promote Ewing sarcomagenesis by RREB1-mediated proliferation., Competing Interests: Declaration of interests The authors declare no competing interests., (Published by Elsevier Inc.)

The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial is a prospective cohort study of nearly 155,000 U.S. volunteers aged 55-74 at enrollment in 1993-2001. We developed the PLCO Atlas Project, a large resource for multi-trait genome-wide association studies (GWAS), by genotyping participants with available DNA and genomic consent. Genotyping on high-density arrays and imputation was performed, and GWAS were conducted using a custom semi-automated pipeline. Association summary statistics were generated from a total of 110,562 participants of European, African and Asian ancestry. Application programming interfaces (APIs) and open-source software development kits (SKDs) enable exploring, visualizing and open data access through the PLCO Atlas GWAS Explorer website, promoting Findable, Accessible, Interoperable, and Re-usable (FAIR) principles. Currently the GWAS Explorer hosts association data for 90 traits and >78,000,000 genomic markers, focusing on cancer and cancer-related phenotypes. New traits will be posted as association data becomes available. The PLCO Atlas is a FAIR resource of high-quality genetic and phenotypic data with many potential reuse opportunities for cancer research and genetic epidemiology., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

The most recent genome-wide association study (GWAS) of cutaneous melanoma identified 54 risk-associated loci, but functional variants and their target genes for most have not been established. Here, we performed massively parallel reporter assays (MPRAs) by using malignant melanoma and normal melanocyte cells and further integrated multi-layer annotation to systematically prioritize functional variants and susceptibility genes from these GWAS loci. Of 1,992 risk-associated variants tested in MPRAs, we identified 285 from 42 loci (78% of the known loci) displaying significant allelic transcriptional activities in either cell type (FDR < 1%). We further characterized MPRA-significant variants by motif prediction, epigenomic annotation, and statistical/functional fine-mapping to create integrative variant scores, which prioritized one to six plausible candidate variants per locus for the 42 loci and nominated a single variant for 43% of these loci. Overlaying the MPRA-significant variants with genome-wide significant expression or methylation quantitative trait loci (eQTLs or meQTLs, respectively) from melanocytes or melanomas identified candidate susceptibility genes for 60% of variants (172 of 285 variants). CRISPRi of top-scoring variants validated their cis-regulatory effect on the eQTL target genes, MAFF (22q13.1) and GPRC5A (12p13.1). Finally, we identified 36 melanoma-specific and 45 melanocyte-specific MPRA-significant variants, a subset of which are linked to cell-type-specific target genes. Analyses of transcription factor availability in MPRA datasets and variant-transcription-factor interaction in eQTL datasets highlighted the roles of transcription factors in cell-type-specific variant functionality. In conclusion, MPRAs along with variant scoring effectively prioritized plausible candidates for most melanoma GWAS loci and highlighted cellular contexts where the susceptibility variants are functional., Competing Interests: Declaration of interests The authors declare no competing interests., (Published by Elsevier Inc.)

Motivation: The Division of Cancer Epidemiology and Genetics (DCEG) and the Division of Cancer Prevention (DCP) at the National Cancer Institute (NCI) have recently generated genome-wide association study (GWAS) data for multiple traits in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Genomic Atlas project. The GWAS included 110 000 participants. The dissemination of the genetic association data through a data portal called GWAS Explorer, in a manner that addresses the modern expectations of FAIR reusability by data scientists and engineers, is the main motivation for the development of the open-source JavaScript software development kit (SDK) reported here., Results: The PLCO GWAS Explorer resource relies on a public stateless HTTP application programming interface (API) deployed as the sole backend service for both the landing page's web application and third-party analytical workflows. The core PLCOjs SDK is mapped to each of the API methods, and also to each of the reference graphic visualizations in the GWAS Explorer. A few additional visualization methods extend it. As is the norm with web SDKs, no download or installation is needed and modularization supports targeted code injection for web applications, reactive notebooks (Observable) and node-based web services., Availability and Implementation: code at https://github.com/episphere/plco; project page at https://episphere.github.io/plco., (Published by Oxford University Press 2022.)

Myelofibrosis is a rare myeloproliferative neoplasm (MPN) with high risk for progression to acute myeloid leukemia. Our integrated genomic analysis of up to 933 myelofibrosis cases identifies 6 germline susceptibility loci, 4 of which overlap with previously identified MPN loci. Virtual karyotyping identifies high frequencies of mosaic chromosomal alterations (mCAs), with enrichment at myelofibrosis GWAS susceptibility loci and recurrently somatically mutated MPN genes (e.g., JAK2). We replicate prior MPN associations showing germline variation at the 9p24.1 risk haplotype confers elevated risk of acquiring JAK2 V617F mutations, demonstrating with long-read sequencing that this relationship occurs in cis. We also describe recurrent 9p24.1 large mCAs that selectively retained JAK2 V617F mutations. Germline variation associated with longer telomeres is associated with increased myelofibrosis risk. Myelofibrosis cases with high-frequency JAK2 mCAs have marked reductions in measured telomere length - suggesting a relationship between telomere biology and myelofibrosis clonal expansion. Our results advance understanding of the germline-somatic interaction at JAK2 and implicate mCAs involving JAK2 as strong promoters of clonal expansion of those mutated clones., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Genome-wide association studies (GWAS) of multiple myeloma in populations of European ancestry (EA) identified and confirmed 24 susceptibility loci. For other cancers (e.g., colorectum and melanoma), risk loci have also been associated with patient survival., Methods: We explored the possible association of all the known risk variants and their polygenic risk score (PRS) with multiple myeloma overall survival (OS) in multiple populations of EA [the International Multiple Myeloma rESEarch (IMMEnSE) consortium, the International Lymphoma Epidemiology consortium, CoMMpass, and the German GWAS] for a total of 3,748 multiple myeloma cases. Cox proportional hazards regression was used to assess the association between each risk SNP with OS under the allelic and codominant models of inheritance. All analyses were adjusted for age, sex, country of origin (for IMMEnSE) or principal components (for the others) and disease stage (ISS). SNP associations were meta-analyzed., Results: SNP associations were meta-analyzed. From the meta-analysis, two multiple myeloma risk SNPs were associated with OS (P &lt; 0.05), specifically POT1-AS1-rs2170352 [HR = 1.37; 95% confidence interval (CI) = 1.09-1.73; P = 0.007] and TNFRSF13B-rs4273077 (HR = 1.19; 95% CI = 1.01-1.41; P = 0.04). The association between the combined 24 SNP MM-PRS and OS, however, was not significant., Conclusions: Overall, our results did not support an association between the majority of multiple myeloma risk SNPs and OS., Impact: This is the first study to investigate the association between multiple myeloma PRS and OS in multiple myeloma., (©2022 American Association for Cancer Research.)

Large-scale human genetic data 1-3 have shown that cancer mutations display strong tissue-selectivity, but how this selectivity arises remains unclear. Here, using experimental models, functional genomics and analyses of patient samples, we demonstrate that the lineage transcription factor paired box 8 (PAX8) is required for oncogenic signalling by two common genetic alterations that cause clear cell renal cell carcinoma (ccRCC) in humans: the germline variant rs7948643 at 11q13.3 and somatic inactivation of the von Hippel-Lindau tumour suppressor (VHL) 4-6 . VHL loss, which is observed in about 90% of ccRCCs, can lead to hypoxia-inducible factor 2α (HIF2A) stabilization 6,7 . We show that HIF2A is preferentially recruited to PAX8-bound transcriptional enhancers, including a pro-tumorigenic cyclin D1 (CCND1) enhancer that is controlled by PAX8 and HIF2A. The ccRCC-protective allele C at rs7948643 inhibits PAX8 binding at this enhancer and downstream activation of CCND1 expression. Co-option of a PAX8-dependent physiological programme that supports the proliferation of normal renal epithelial cells is also required for MYC expression from the ccRCC metastasis-associated amplicons at 8q21.3-q24.3 (ref. 8 ). These results demonstrate that transcriptional lineage factors are essential for oncogenic signalling and that they mediate tissue-specific cancer risk associated with somatic and inherited genetic variants., (© 2022. The Author(s).)

Background: Uveal melanoma (UM), a rare malignant tumor of the eye, is predominantly observed in populations of European ancestry. UMs carrying a monosomy 3 (M3) frequently relapse mainly in the liver, whereas UMs with disomy 3 (D3) are associated with more favorable outcome. Here, we explored the UM genetic predisposition factors in a large genome-wide association study (GWAS) of 1142 European UM patients and 882 healthy controls ., Methods: We combined 2 independent datasets (Global Screening Array) with the dataset described in a previously published GWAS in UM (Omni5 array), which were imputed separately and subsequently merged. Patients were stratified according to their chromosome 3 status, and identified UM risk loci were tested for differential association with M3 or D3 subgroups. All statistical tests were 2-sided., Results: We recapitulated the previously identified risk locus on chromosome 5 on CLPTM1L (rs421284: odds ratio [OR] =1.58, 95% confidence interval [CI] = 1.35 to 1.86; P = 1.98 × 10-8) and identified 2 additional risk loci involved in eye pigmentation: IRF4 locus on chromosome 6 (rs12203592: OR = 1.76, 95% CI = 1.44 to 2.16; P = 3.55 × 10-8) and HERC2 locus on chromosome 15 (rs12913832: OR= 0.57, 95% CI = 0.48 to 0.67; P = 1.88 × 10-11). The IRF4 rs12203592 single-nucleotide polymorphism was found to be exclusively associated with risk for the D3 UM subtype (ORD3 = 2.73, 95% CI = 1.87 to 3.97; P = 1.78 × 10-7), and the HERC2 rs12913832 single-nucleotide polymorphism was exclusively associated with risk for the M3 UM subtype (ORM3 = 2.43, 95% CI = 1.79 to 3.29; P = 1.13 × 10-8). However, the CLPTM1L risk locus was equally statistically significant in both subgroups., Conclusions: This work identified 2 additional UM risk loci known for their role in pigmentation. Importantly, we demonstrate that UM tumor biology and metastatic potential are influenced by patients' genetic backgrounds., (© The Author(s) 2021. Published by Oxford University Press.)

Genome-wide association studies have identified thousands of genetic susceptibility loci associated with cancer as well as other traits and diseases. Mapping germline variation in identified genetic susceptibility regions to alterations in nearby gene expression nominates candidate genes potentially related to disease risk for further functional investigation. We developed LDexpress as an online resource that integrates population-specific linkage disequilibrium data from the 1000 Genomes (1000G) project and tissue-specific expression data from the Genotype-Tissue Expression project to better study regional germline variation impacting gene expression. LDexpress is a publicly available web tool designed to be easy to use, flexible to conduct a wide range of variant queries, and quick to efficiently investigate dozens of query variants across multiple tissue types. We demonstrate the utility of LDexpress using example genomic queries and anticipate this tool will accelerate understanding of disease etiology by uncovering associations of regional germline variation to nearby gene expression., (© 2021. The Author(s).)

Acquired somatic mutations in hematopoietic stem and progenitor cells (clonal hematopoiesis or CH) are associated with advanced age, increased risk of cardiovascular and malignant diseases, and decreased overall survival. These adverse sequelae may be mediated by altered inflammatory profiles observed in patients with CH. A pro-inflammatory immunologic profile is also associated with worse outcomes of certain infections, including SARS-CoV-2 and its associated disease Covid-19. Whether CH predisposes to severe Covid-19 or other infections is unknown. Among 525 individuals with Covid-19 from Memorial Sloan Kettering (MSK) and the Korean Clonal Hematopoiesis (KoCH) consortia, we show that CH is associated with severe Covid-19 outcomes (OR = 1.85, 95%=1.15-2.99, p = 0.01), in particular CH characterized by non-cancer driver mutations (OR = 2.01, 95% CI = 1.15-3.50, p = 0.01). We further explore the relationship between CH and risk of other infections in 14,211 solid tumor patients at MSK. CH is significantly associated with risk of Clostridium Difficile (HR = 2.01, 95% CI: 1.22-3.30, p = 6×10 -3 ) and Streptococcus/Enterococcus infections (HR = 1.56, 95% CI = 1.15-2.13, p = 5×10 -3 ). These findings suggest a relationship between CH and risk of severe infections that warrants further investigation., (© 2021. The Author(s).)