Publications by authors named "Ludmila Prokunina-Olsson"

92 Publications

Intracellular Accumulation of IFN-λ4 Induces ER Stress and Results in Anti-Cirrhotic but Pro-HCV Effects.

Front Immunol 2021 23;12:692263. Epub 2021 Aug 23.

Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, United States.

polymorphisms are inversely associated with the risk of chronic hepatitis C virus (HCV) infection and cirrhosis, two major risk factors for developing hepatocellular carcinoma (HCC). To further explore these inverse associations and their molecular underpinnings, we analyzed polymorphisms represented by the genotype (presence of rs368234815-dG or rs12979860-T alleles) in HCV patients: 2969 from Japan and 2931 from Taiwan. genotype was associated with an increased risk of HCV-related HCC (OR=1.28, 95%CI=1.07-1.52, P=0.0058) in the general population of Japanese patients, but not in Taiwanese patients who achieved treatment-induced viral clearance. genotype was also associated with a decreased risk of cirrhosis (OR=0.66, 95%CI=0.46-0.93, P=0.018, in Taiwanese patients). We then engineered HepG2 cells to inducibly express IFN-λ4 in the presence or absence of interferon lambda receptor 1 (IFNLR1). Induction of IFN-λ4 resulted in its intracellular accumulation, mainly in lysosomes and late endosomes, and increased ER stress, leading to apoptosis and reduced proliferation. We identified the very-low-density lipoprotein receptor (), which facilitates HCV entry into hepatocytes, as a transcript induced by IFN-λ4 but not IFN-λ3. Our results suggest that the molecular mechanisms underlying the anti-cirrhotic but pro-HCV associations observed for polymorphisms are, at least in part, contributed by intracellular accumulation of IFN-λ4 causing ER stress in hepatic cells.
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http://dx.doi.org/10.3389/fimmu.2021.692263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419317PMC
August 2021

Genetic regulation of nonsense-mediated decay underlies association with risk of severe COVID-19.

medRxiv 2021 Jul 13. Epub 2021 Jul 13.

Genomic regions have been associated with COVID-19 susceptibility and outcomes, including the chr12q24.13 locus encoding antiviral proteins OAS1-3. Here, we report genetic, functional, and clinical insights into genetic associations within this locus. In Europeans, the risk of hospitalized vs. non-hospitalized COVID-19 was associated with a single 19Kb-haplotype comprised of 76 variants included in a 95% credible set within a large genomic fragment introgressed from Neandertals. The risk haplotype was also associated with impaired spontaneous but not treatment-induced SARS-CoV-2 clearance in a clinical trial with pegIFN-λ1. We demonstrate that two exonic variants, rs10774671 and rs1131454, affect splicing and nonsense-mediated decay of . We suggest that genetically-regulated loss of expression contributes to impaired spontaneous clearance of SARS-CoV-2 and elevated risk of hospitalization for COVID-19. Our results provide the rationale for further clinical studies using interferons to compensate for impaired spontaneous SARS-CoV-2 clearance, particularly in carriers of the risk haplotypes.
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http://dx.doi.org/10.1101/2021.07.09.21260221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8288155PMC
July 2021

IFN-λ4 is associated with increased risk and earlier occurrence of several common infections in African children.

Genes Immun 2021 05 13;22(1):44-55. Epub 2021 Apr 13.

Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA.

Genetic polymorphisms within the IFNL3/IFNL4 genomic region, which encodes type III interferons, have been strongly associated with clearance of hepatitis C virus. We hypothesized that type III interferons might be important for the immune response to other pathogens as well. In a cohort of 914 Malian children, we genotyped functional variants IFNL4-rs368234815, IFNL4-rs117648444, and IFNL3-rs4803217 and analyzed episodes of malaria, gastrointestinal, and respiratory infections recorded at 30,626 clinic visits from birth up to 5 years of age. Compared to children with the rs368234815-TT/TT genotype (IFN-λ4-Null), rs368234815-dG allele was most strongly associated with an earlier time-to-first episode of gastrointestinal infections (p = 0.003). The risk of experiencing an infection episode during the follow-up was also significantly increased with rs368234815-dG allele, with OR = 1.53, 95%CI (1.13-2.07), p = 0.005 for gastrointestinal infections and OR = 1.30, 95%CI (1.02-1.65), p = 0.033 for malaria. All the associations for the moderately linked rs4803217 (r = 0.78 in this set) were weaker and lost significance after adjusting for rs368234815. We also analyzed all outcomes in relation to IFN-λ4-P70S groups. Our results implicate IFN-λ4 and not IFN-λ3 as the primary functional cause of genetic associations with increased overall risk and younger age at first clinical episodes but not with recurrence or intensity of several common pediatric infections.
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http://dx.doi.org/10.1038/s41435-021-00127-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042471PMC
May 2021

Targeted Deep Sequencing of Bladder Tumors Reveals Novel Associations between Cancer Gene Mutations and Mutational Signatures with Major Risk Factors.

Clin Cancer Res 2021 Jul 13;27(13):3725-3733. Epub 2021 Apr 13.

Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland.

Purpose: Exome- and whole-genome sequencing of muscle-invasive bladder cancer has revealed important insights into the molecular landscape; however, there are few studies of non-muscle-invasive bladder cancer with detailed risk factor information.

Experimental Design: We examined the relationship between smoking and other bladder cancer risk factors and somatic mutations and mutational signatures in bladder tumors. Targeted sequencing of frequently mutated genes in bladder cancer was conducted in 322 formalin-fixed paraffin-embedded bladder tumors from a population-based case-control study. Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI), evaluating mutations and risk factors. We used SignatureEstimation to extract four known single base substitution mutational signatures and Poisson regression to calculate risk ratios (RR) and 95% CIs, evaluating signatures and risk factors.

Results: Non-silent mutations were more common in females than males (OR = 1.83; 95% CI, 1.05-3.19). There was striking heterogeneity in the relationship between smoking status and established single base substitution signatures: current smoking status was associated with greater Signature mutations compared with former ( = 0.024) and never smoking (RR = 1.40; 95% CI, 1.09-1.80; = 0.008), former smoking was associated with greater APOBEC-Signature13 mutations ( = 0.05), and never smoking was associated with greater APOBEC-Signature2 mutations (RR = 1.54; 95% CI, 1.17-2.01; = 0.002). There was evidence that smoking duration (the component most strongly associated with bladder cancer risk) was associated with Signature mutations and APOBEC-Signature13 mutations among current ( = 0.005) and former smokers ( = 0.0004), respectively.

Conclusions: These data quantify the contribution of bladder cancer risk factors to mutational burden and suggest different signature enrichments among never, former, and current smokers.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8254772PMC
July 2021

Targeting natural splicing plasticity of APOBEC3B restricts its expression and mutagenic activity.

Commun Biol 2021 03 22;4(1):386. Epub 2021 Mar 22.

Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

APOBEC3A (A3A) and APOBEC3B (A3B) enzymes drive APOBEC-mediated mutagenesis. Identification of factors affecting the activity of these enzymes could help modulate mutagenesis and associated clinical outcomes. Here, we show that canonical and alternatively spliced A3A and A3B isoforms produce corresponding mutagenic and non-mutagenic enzymes. Increased expression of the mutagenic A3B isoform predicted shorter progression-free survival in bladder cancer. We demonstrate that the production of mutagenic vs. non-mutagenic A3B protein isoforms was considerably affected by inclusion/skipping of exon 5 in A3B. Furthermore, exon 5 skipping, resulting in lower levels of mutagenic A3B enzyme, could be increased in vitro. Specifically, we showed the effects of treatment with an SF3B1 inhibitor affecting spliceosome interaction with a branch point site in intron 4, or with splice-switching oligonucleotides targeting exon 5 of A3B. Our results underscore the clinical role of A3B and implicate alternative splicing of A3B as a mechanism that could be targeted to restrict APOBEC-mediated mutagenesis.
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http://dx.doi.org/10.1038/s42003-021-01844-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985488PMC
March 2021

Interferons and viruses induce a novel truncated ACE2 isoform and not the full-length SARS-CoV-2 receptor.

Nat Genet 2020 12 19;52(12):1283-1293. Epub 2020 Oct 19.

Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes COVID-19, utilizes angiotensin-converting enzyme 2 (ACE2) for entry into target cells. ACE2 has been proposed as an interferon-stimulated gene (ISG). Thus, interferon-induced variability in ACE2 expression levels could be important for susceptibility to COVID-19 or its outcomes. Here, we report the discovery of a novel, transcriptionally independent truncated isoform of ACE2, which we designate as deltaACE2 (dACE2). We demonstrate that dACE2, but not ACE2, is an ISG. In The Cancer Genome Atlas, the expression of dACE2 was enriched in squamous tumors of the respiratory, gastrointestinal and urogenital tracts. In vitro, dACE2, which lacks 356 amino-terminal amino acids, was non-functional in binding the SARS-CoV-2 spike protein and as a carboxypeptidase. Our results suggest that the ISG-type induction of dACE2 in IFN-high conditions created by treatments, an inflammatory tumor microenvironment or viral co-infections is unlikely to increase the cellular entry of SARS-CoV-2 and promote infection.
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http://dx.doi.org/10.1038/s41588-020-00731-9DOI Listing
December 2020

Association of donor IFNL4 genotype and non-relapse mortality after unrelated donor myeloablative haematopoietic stem-cell transplantation for acute leukaemia: a retrospective cohort study.

Lancet Haematol 2020 Oct;7(10):e715-e723

Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA.

Background: The interferon lambda 4 gene (IFNL4) regulates immune responses by controlling the production of IFNλ4, a type III interferon. We hypothesised that IFNλ4 could play a role in infection clearance or alloreactivity in patients with acute leukaemia who received a myeloablative 10/10 HLA-matched haematopoietic stem-cell transplantation (HSCT). Therefore, we aimed to assess the association between recipient and donor IFNL4 genotype with post-HSCT survival outcomes in patients with acute leukaemia.

Methods: We did a two-stage retrospective cohort study using the Center for International Blood and Marrow Transplant Research (CIBMTR) repository and database, in which nearly all patients underwent the procedure in the USA. We included patients with acute myeloid leukaemia or acute lymphocytic leukaemia, who received a HSCT at any age from an unrelated 10/10 HLA-matched donor, with a myeloablative conditioning regimen, between Jan 1, 2000, and Dec 31, 2008, and had a pre-HSCT recipient or donor blood sample available. The discovery dataset included patients from an existing National Cancer Institute (NCI) cohort of the CIBMTR database, in which donor and recipient IFNL4 polymorphisms (rs368234815, rs12979860, and rs117648444) were genotyped with TaqMan assays. According to their genotype, donors and recipients were categorised into IFNL4-positive, if they had at least one copy of the allele that supports the production of IFNλ4, or IFNL4-null for the analyses. The findings were independently validated with patients from the DISCOVeRY-BMT cohort (validation dataset) with existing Illumina array genotype data. We also did a combined analysis using data from patients included in both the NCI and DISCOVeRY-BMT cohorts.

Findings: We assessed 404 patients (who had a HSCT from Jan 9, 2004, to Dec 26, 2008) in the discovery dataset and 1245 patients in the validation dataset (HSCT Jan 7, 2000, to Dec 26, 2008). The combined analysis included 1593 overlapping participants in both cohorts. Donor, but not recipient IFNL4-positive genotype was associated with increased risk of non-relapse mortality (HR 1·60, 95% CI 1·23-2·10; p=0·0005 in the discovery dataset; 1·22, 1·05-1·40; p=0·0072 in the validation dataset; and 1·27, 1·12-1·45; p=0·0001 in the combined dataset). Associations with post-HSCT overall survival were as follows: HR 1·24, 95% CI 1·02-1·51; p=0·034 in the discovery dataset; 1·10, 0·98-1·20; p=0·10 in the validation dataset; and 1·11, 1·02-1·22; p=0·018 in the combined dataset.

Interpretation: Prioritising HSCT donors with the IFNL4-null genotype might decrease non-relapse mortality and improve overall survival without substantially limiting the donor pool. If these findings are validated, IFNL4 genotype could be added to the donor selection algorithm.

Funding: The National Cancer Institute Intramural Research Program. For full funding list see Acknowledgments.
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http://dx.doi.org/10.1016/S2352-3026(20)30294-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735535PMC
October 2020

Interferons and viruses induce a novel primate-specific isoform dACE2 and not the SARS-CoV-2 receptor ACE2.

bioRxiv 2020 Jul 20. Epub 2020 Jul 20.

Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which causes COVID-19, utilizes angiotensin-converting enzyme 2 (ACE2) for entry into target cells. has been proposed as an interferon-stimulated gene (ISG). Thus, interferon-induced variability in expression levels could be important for susceptibility to COVID-19 or its outcomes. Here, we report the discovery of a novel, primate-specific isoform of , which we designate as . We demonstrate that , but not , is an ISG. , dACE2, which lacks 356 N-terminal amino acids, was non-functional in binding the SARS-CoV-2 spike protein and as a carboxypeptidase. Our results reconcile current knowledge on expression and suggest that the ISG-type induction of in IFN-high conditions created by treatments, inflammatory tumor microenvironment, or viral co-infections is unlikely to affect the cellular entry of SARS-CoV-2 and promote infection.
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http://dx.doi.org/10.1101/2020.07.19.210955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7386494PMC
July 2020

When the Smoke Clears mA from a Y Chromosome-Linked lncRNA, Men Get an Increased Risk of Cancer.

Cancer Res 2020 07;80(13):2718-2719

Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, NCI, NIH, Bethesda, Maryland.

Long noncoding RNAs (lncRNA) have been implicated in many diseases, including cancer. Although these disease-associated effects have been mostly attributed to the ability of lncRNAs to function as regulatory noncoding transcripts, there is growing evidence that lncRNAs may also encode functional micropeptides. In the current issue of , Wu and colleagues report a micropeptide encoded by a Y chromosome-linked lncRNA that may explain the higher incidence of esophageal cancer in male smokers. Furthermore, this report provides broader insights related to the molecular epidemiology of male-dominant and smoking-driven cancers and may also help explain some cancer-related associations with mosaic Y chromosome loss..
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http://dx.doi.org/10.1158/0008-5472.CAN-20-0961DOI Listing
July 2020

COVID-19 and emerging viral infections: The case for interferon lambda.

J Exp Med 2020 05;217(5)

Division of Immunology, Division of Gastroenterology, Harvard Medical School, Boston Children's Hospital, Boston, MA.

With the first reports on coronavirus disease 2019 (COVID-19), which is caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the scientific community working in the field of type III IFNs (IFN-λ) realized that this class of IFNs could play an important role in this and other emerging viral infections. In this Viewpoint, we present our opinion on the benefits and potential limitations of using IFN-λ to prevent, limit, and treat these dangerous viral infections.
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http://dx.doi.org/10.1084/jem.20200653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7155807PMC
May 2020

Variation in the Human Leukocyte Antigen system and risk for endemic Burkitt lymphoma in northern Uganda.

Br J Haematol 2020 05 18;189(3):489-499. Epub 2020 Feb 18.

Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Endemic Burkitt lymphoma (eBL) is an aggressive childhood B-cell lymphoma associated with Plasmodium falciparum (Pf) malaria and Epstein-Barr virus (EBV) infections. Variation in the Human Leukocyte Antigen (HLA) system is suspected to play a role, but assessments using less accurate serology-based HLA typing techniques in small studies yielded conflicting results. We studied 200 eBL cases and 400 controls aged 0-15 years enrolled in northern Uganda and typed by accurate high-resolution HLA sequencing methods. HLA results were analyzed at one- or two-field resolution. Odds ratios and 95% confidence intervals (aOR, 95% CI) for eBL risk associated with common HLA alleles versus alleles that were rare (<1%) or differed by <2% between the cases and controls as the reference category, were estimated using multiple logistic regression adjusting for age, sex, microgeography, region, malaria positivity and treatment history, and genetic variants associated with eBL. Compared to the controls, eBL cases had a lower frequency of HLA-A*02 (aOR = 0·59, 95% CI 0·38-0·91), HLA-B*41 (aOR = 0·36, 95% CI 0·13-1·00), and HLA-B*58 alleles (aOR = 0·59, 95% CI 0·36-0·97). eBL cases had a lower frequency of HLA-DPB1 homozygosity (aOR = 0·57, 95% CI 0·40-0·82) but a higher frequency of HLA-DQA1 homozygosity (aOR = 2·19, 95% CI 1·42-3·37). Our results suggest that variation in HLA may be associated with eBL risk.
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http://dx.doi.org/10.1111/bjh.16398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7192769PMC
May 2020

APOBEC3B expression in breast cancer cell lines and tumors depends on the estrogen receptor status.

Carcinogenesis 2020 08;41(8):1030-1037

Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Increased exposure to estrogen is associated with an elevated risk of breast cancer. Considering estrogen as a possible mutagen, we hypothesized that exposure to estrogen alone or in combination with the DNA-damaging chemotherapy drug, cisplatin, could induce expression of genes encoding enzymes involved in APOBEC-mediated mutagenesis. To test this hypothesis, we measured the expression of APOBEC3A (A3A) and APOBEC3B (A3B) genes in two breast cancer cell lines treated with estradiol, cisplatin or their combination. These cell lines, T-47D (ER+) and MDA-MB-231 (ER-), differed by the status of the estrogen receptor (ER). Expression of A3A was not detectable in any conditions tested, while A3B expression was induced by treatment with cisplatin and estradiol in ER+ cells but was not affected by estradiol in ER- cells. In The Cancer Genome Atlas, expression of A3B was significantly associated with genotypes of a regulatory germline variant rs17000526 upstream of the APOBEC3 cluster in 116 ER- breast tumors (P = 0.006) but not in 387 ER+ tumors (P = 0.48). In conclusion, we show that in breast cancer cell lines, A3B expression was induced by estradiol in ER+ cells and by cisplatin regardless of ER status. In ER+ breast tumors, the effect of estrogen may be masking the association of rs17000526 with A3B expression, which was apparent in ER- tumors. Our results provide new insights into the differential etiology of ER+ and ER- breast cancer and the possible role of A3B in this process through a mitogenic rather than the mutagenic activity of estrogen.
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http://dx.doi.org/10.1093/carcin/bgaa002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7422621PMC
August 2020

Immune gene expression profiling reveals heterogeneity in luminal breast tumors.

Breast Cancer Res 2019 12 19;21(1):147. Epub 2019 Dec 19.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA.

Background: Heterogeneity of immune gene expression patterns of luminal breast cancer (BC), which is clinically heterogeneous and overall considered as low immunogenic, has not been well studied especially in non-European populations. Here, we aimed at characterizing the immune gene expression profile of luminal BC in an Asian population and associating it with patient characteristics and tumor genomic features.

Methods: We performed immune gene expression profiling of tumor and adjacent normal tissue in 92 luminal BC patients from Hong Kong using RNA-sequencing data and used unsupervised consensus clustering to stratify tumors. We then used luminal patients from The Cancer Genome Atlas (TCGA, N = 564) and a Korean breast cancer study (KBC, N = 112) as replication datasets.

Results: Based on the expression of 130 immune-related genes, luminal tumors were stratified into three distinct immune subtypes. Tumors in one subtype showed higher level of tumor-infiltrating lymphocytes (TILs), characterized by T cell gene activation, higher expression of immune checkpoint genes, higher nonsynonymous mutation burden, and higher APOBEC-signature mutations, compared with other luminal tumors. The high-TIL subtype was also associated with lower ESR1/ESR2 expression ratio and increasing body mass index. The comparison of the immune profile in tumor and matched normal tissue suggested a tumor-derived activation of specific immune responses, which was only seen in high-TIL patients. Tumors in a second subtype were characterized by increased expression of interferon-stimulated genes and enrichment for TP53 somatic mutations. The presence of three immune subtypes within luminal BC was replicated in TCGA and KBC, although the pattern was more similar in Asian populations. The germline APOBEC3B deletion polymorphism, which is prevalent in East Asian populations and was previously linked to immune activation, was not associated with immune subtypes in our study. This result does not support the hypothesis that the germline APOBEC3B deletion polymorphism is the driving force for immune activation in breast tumors in Asian populations.

Conclusion: Our findings suggest that immune gene expression and associated genomic features could be useful to further stratify luminal BC beyond the current luminal A/B classification and a subset of luminal BC patients may benefit from checkpoint immunotherapy, at least in Asian populations.
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http://dx.doi.org/10.1186/s13058-019-1218-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6924001PMC
December 2019

It Takes Two (Genomes) to Cancer: Paired Viral and Host Transcriptome Analysis Provides New Insights about EBV Carcinogenicity.

Cancer Res 2019 12;79(23):5917-5919

Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, NCI, NIH, Bethesda, Maryland.

The discovery of Epstein-Barr virus (EBV) in 1964 gave birth to the field of viral oncology. Despite significant scientific and clinical developments in research on several other viruses discovered and linked to cancer risk much later, our understanding of EBV as a carcinogen and a possible target for therapeutic interventions remains limited. In this issue of , Chakravorty and colleagues present results of massive reanalysis of public RNA-sequencing data for 291 control and 1,051 tumor samples representing 15 cancer types. Their paired analysis of the viral and host transcriptome sheds light on mechanisms of EBV carcinogenicity and provides new leads for translational applications..
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http://dx.doi.org/10.1158/0008-5472.CAN-19-2996DOI Listing
December 2019

Genetics Helps to Find Synergy for Immune Checkpoint and Targeted Combination Therapies.

Cancer Res 2019 11;79(21):5476-5478

Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, NCI, NIH, Bethesda, Maryland.

Checkpoint inhibitors, including anti-PD-L1 therapy, emerged as a treatment option for many cancer types, albeit with limited response rates. Combinations of immune-based and -targeted therapies are needed to achieve synergistic antitumor effects and provide much needed treatment personalization and improved response. Genetic alterations can be used as molecular drug targets and as biomarkers to select patients for specific therapies and their combinations. Fukumoto and colleagues present a promising example of this approach for the treatment of ovarian cancer with inactivating ARID1A mutations using a combination of the checkpoint and histone deacetylase inhibitors..
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http://dx.doi.org/10.1158/0008-5472.CAN-19-2528DOI Listing
November 2019

The Association between the Comprehensive Epstein-Barr Virus Serologic Profile and Endemic Burkitt Lymphoma.

Cancer Epidemiol Biomarkers Prev 2020 01 16;29(1):57-62. Epub 2019 Oct 16.

Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, NCI, Bethesda, Maryland.

Background: The discovery of Epstein-Barr virus (EBV) in Burkitt lymphoma tumors represented the first link between a virus and cancer in humans, but the underlying role of this virus in endemic Burkitt lymphoma remains unclear. Nearly all children in Burkitt lymphoma-endemic areas are seropositive for EBV, but only a small percentage develop disease. Variation in EBV-directed immunity could be an explanatory cofactor.

Methods: We examined serum from 150 Burkitt lymphoma cases and 150 controls using a protein microarray that measured IgG and IgA antibodies against 202 sequences across the entire EBV proteome. Variation in the EBV-directed antibody repertoire between Burkitt lymphoma cases and controls was assessed using unpaired tests. ORs quantifying the association between anti-EBV IgG response tertiles and Burkitt lymphoma status were adjusted for age, sex, and study year.

Results: Thirty-three anti-EBV IgG responses were elevated in Burkitt lymphoma cases compared with controls ( ≤ 0.0003). Burkitt lymphoma-associated IgG elevations were strongest for EBV proteins involved in viral replication and antiapoptotic signaling. Specifically, we observed ORs ≥4 for BMRF1 (early antigen), BBLF1 (tegument protein), BHRF1 (Bcl-2 homolog), BZLF1 (Zebra), BILF2 (glycoprotein), BLRF2 [viral capsid antigen (VCA)p23], BDLF4, and BFRF3 (VCAp18). Adjustment for malaria exposure and inheritance of the sickle cell variant did not alter associations.

Conclusions: Our data suggest that the anti-EBV serologic profile in patients with Burkitt lymphoma is altered, with strong elevations in 33 of the measured anti-EBV IgG antibodies relative to disease-free children.

Impact: The Burkitt lymphoma-specific signature included EBV-based markers relevant for viral replication and antiapoptotic activity, providing clues for future Burkitt lymphoma pathogenesis research.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-0551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954331PMC
January 2020

Metabolic Changes in Chronic Hepatitis C Patients Who Carry IFNL4-ΔG and Achieve Sustained Virologic Response With Direct-Acting Antiviral Therapy.

J Infect Dis 2020 01;221(1):102-109

Division of Clinical Care and Research, Institute of Human Virology, Baltimore, Maryland.

Background: Clearance of hepatitis C virus (HCV) results in rapid changes in metabolic parameters early in direct-acting antiviral (DAA) therapy. Long-term changes after sustained virologic response (SVR) remain unknown.

Methods: We investigated longitudinal changes in metabolic and inflammatory outcomes in chronic hepatitis C (CHC) patients: low-density lipoprotein (LDL), high-density lipoprotein, triglycerides, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) using a general linear model for repeated measurements at 5 clinical time points and by human immunodeficiency virus (HIV) coinfection and IFNL4 genotype.

Results: The mean LDL increased markedly during DAA therapy (pre-DAA, 86.6 to DAA, 107.4 mg/dL; P < .0001), but then it decreased to 97.7 mg/dL by post-SVR year 1 (P < .001 compared with DAA; P = .0013 compared with SVR). In patients who carry the IFNL4-ΔG allele, mean LDL increased during treatment, then decreased at post-SVR year 1; however, in patients with TT/TT, genotype did not change during and after DAA treatment. The mean ALT and AST normalized rapidly between pre-DAA and DAA, whereas only mean ALT continued to decrease until post-SVR. Metabolic and inflammatory outcomes were similar by HIV-coinfection status.

Conclusions: Changes in LDL among CHC patients who achieved SVR differed by IFNL4 genotype, which implicates the interferon-λ4 protein in metabolic changes observed in HCV-infected patients.
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http://dx.doi.org/10.1093/infdis/jiz435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325530PMC
January 2020

What makes the hepatitis C virus evolve?

Elife 2019 09 3;8. Epub 2019 Sep 3.

Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, United States.

Polymorphisms in the gene that affect both the presence and the form of the coded protein are associated with changes in the hepatitis C virus.
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http://dx.doi.org/10.7554/eLife.50148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721787PMC
September 2019

The IFN-λ4 Conundrum: When a Good Interferon Goes Bad.

J Interferon Cytokine Res 2019 10 26;39(10):636-641. Epub 2019 Jun 26.

Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

Since its discovery in 2013, interferon lambda 4 (IFN-λ4) has received a reputation as a paradoxical type III IFN. Difficulties in detecting IFN-λ4, especially in secreted form even led to questions about its existence. However, the genetic ability to generate IFN-λ4, determined by the presence of the rs368234815-ΔG allele, is the strongest predictor of impaired clearance of hepatitis C virus (HCV) infection in humans. Significant modulation of IFN-λ4 activity by a genetic variant (P70S) supports IFN-λ4, and not other type III IFNs encoded in the same genomic locus, as the primary functional cause of the association with HCV clearance. Although the ability to produce IFN-λ4 is associated with decreased HCV clearance, the recombinant IFN-λ4 is active against HCV and other viruses. These observations present an apparent conundrum-when and how does a presumably good IFN, with anti-HCV activity, interfere with the ability to clear HCV? In this review, we discuss findings that suggest potential mechanisms for explaining this conundrum.
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http://dx.doi.org/10.1089/jir.2019.0044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6767864PMC
October 2019

Genetics of the Human Interferon Lambda Region.

J Interferon Cytokine Res 2019 10 8;39(10):599-608. Epub 2019 May 8.

Division of Cancer Epidemiology and Genetics, Laboratory of Translational Genomics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

Humans are polymorphic in their ability to produce type-III interferons. Most individuals of African ancestry are genetically capable of generating all 4 type-III interferons (IFN-λ1, 2, 3, and 4), whereas the majority of individuals of European and Asian ancestry lack IFN-λ4 and thus can generate only IFN-λ1, 2, and 3. All 4 type-III IFNs are encoded by genes located within a ∼55 kb genomic region on human chromosome 19. Although IFN-λ4 appears to be important in animals, genetic alterations acquired in the Hominidae lineage, and particularly in humans, resulted in the elimination of IFN-λ4 or restriction of its activity, suggesting that IFN-λ4 function might be detrimental to human health. Genetic variants within the region, including those controlling production and activity of IFN-λ4, have been strongly associated with clearance of hepatitis C virus (HCV) infection. There is growing evidence for association of the same genetic variants with a multitude of other disease conditions. This article reviews the genetic landscape of the human genetic locus, with an emphasis on the genetic control of IFN-λ4 production and activity, and its association with viral clearance.
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http://dx.doi.org/10.1089/jir.2019.0043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6767866PMC
October 2019

Meeting Overview: Interferon Lambda-Disease Impact and Therapeutic Potential.

J Interferon Cytokine Res 2019 10 17;39(10):586-591. Epub 2019 Apr 17.

Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

A meeting entitled, "Interferon Lambda: Disease Impact and Translational Potential," was held on the campus of the National Institutes of Health in Bethesda, Maryland, on October 25-26, 2018. To our knowledge, this was the first meeting that focused exclusively on interferon lambda (IFN-λ). The meeting's purpose was to enhance interdisciplinary communication and promote new collaborations. The gathering brought together an international group of scientists from a wide range of disciplines. Sessions included: IFN-λ Biology, Therapy and Genetic Variation; IFN-λ and Hepatitis C Virus Infection; IFN-λ in Other Infections; and IFN-λ-Hepatic Fibrosis and Cancer. The next meeting on IFN-λ is planned for 2020.
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http://dx.doi.org/10.1089/jir.2019.0018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6767859PMC
October 2019

APOBEC-mediated Mutagenesis as a Likely Cause of FGFR3 S249C Mutation Over-representation in Bladder Cancer.

Eur Urol 2019 07 8;76(1):9-13. Epub 2019 Apr 8.

Institut Curie, CNRS, UMR144, Molecular Oncology team, PSL Research University, Paris, France. Electronic address:

FGFR3 is one of the most frequently mutated genes in bladder cancer and a driver of an oncogenic dependency. Here we report that only the most common recurrent FGFR3 mutation, S249C (TCC→TGC), represents an APOBEC-type motif and is probably caused by the APOBEC-mediated mutagenic process, accounting for its over-representation. We observed significant enrichment of the APOBEC mutational signature and overexpression of AID/APOBEC gene family members in bladder tumors with S249C compared to tumors with other recurrent FGFR3 mutations. Analysis of replication fork directionality suggests that the coding strand of FGFR3 is predominantly replicated as a lagging strand template that could favor the formation of hairpin structures, facilitating mutagenic activity of APOBEC enzymes. In vitro APOBEC deamination assays confirmed S249 as an APOBEC target. We also found that the FGFR3 S249C mutation was common in three other cancer types with an APOBEC mutational signature, but rare in urothelial tumors without APOBEC mutagenesis and in two diseases probably related to aging. PATIENT SUMMARY: We propose that APOBEC-mediated mutagenesis can generate clinically relevant driver mutations even within suboptimal motifs, such as in the case of FGFR3 S249C, one of the most common mutations in bladder cancer. Knowledge about the etiology of this mutation will improve our understanding of the molecular mechanisms of bladder cancer.
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http://dx.doi.org/10.1016/j.eururo.2019.03.032DOI Listing
July 2019

Genetic signatures of gene flow and malaria-driven natural selection in sub-Saharan populations of the "endemic Burkitt Lymphoma belt".

PLoS Genet 2019 03 8;15(3):e1008027. Epub 2019 Mar 8.

Stanford Cancer Institute, Stanford University, Stanford, California, United States of America.

Populations in sub-Saharan Africa have historically been exposed to intense selection from chronic infection with falciparum malaria. Interestingly, populations with the highest malaria intensity can be identified by the increased occurrence of endemic Burkitt Lymphoma (eBL), a pediatric cancer that affects populations with intense malaria exposure, in the so called "eBL belt" in sub-Saharan Africa. However, the effects of intense malaria exposure and sub-Saharan populations' genetic histories remain poorly explored. To determine if historical migrations and intense malaria exposure have shaped the genetic composition of the eBL belt populations, we genotyped ~4.3 million SNPs in 1,708 individuals from Ghana and Northern Uganda, located on opposite sides of eBL belt and with ≥ 7 months/year of intense malaria exposure and published evidence of high incidence of BL. Among 35 Ghanaian tribes, we showed a predominantly West-Central African ancestry and genomic footprints of gene flow from Gambian and East African populations. In Uganda, the North West population showed a predominantly Nilotic ancestry, and the North Central population was a mixture of Nilotic and Southern Bantu ancestry, while the Southwest Ugandan population showed a predominant Southern Bantu ancestry. Our results support the hypothesis of diverse ancestral origins of the Ugandan, Kenyan and Tanzanian Great Lakes African populations, reflecting a confluence of Nilotic, Cushitic and Bantu migrations in the last 3000 years. Natural selection analyses suggest, for the first time, a strong positive selection signal in the ATP2B4 gene (rs10900588) in Northern Ugandan populations. These findings provide important baseline genomic data to facilitate disease association studies, including of eBL, in eBL belt populations.
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http://dx.doi.org/10.1371/journal.pgen.1008027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6426263PMC
March 2019

APOBEC Mutagenesis and Copy-Number Alterations Are Drivers of Proteogenomic Tumor Evolution and Heterogeneity in Metastatic Thoracic Tumors.

Cell Rep 2019 03;26(10):2651-2666.e6

Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20814, USA. Electronic address:

Intratumor mutational heterogeneity has been documented in primary non-small-cell lung cancer. Here, we elucidate mechanisms of tumor evolution and heterogeneity in metastatic thoracic tumors (lung adenocarcinoma and thymic carcinoma) using whole-exome and transcriptome sequencing, SNP array for copy-number alterations (CNAs), and mass-spectrometry-based quantitative proteomics of metastases obtained by rapid autopsy. APOBEC mutagenesis, promoted by increased expression of APOBEC3 region transcripts and associated with a high-risk APOBEC3 germline variant, correlated with mutational tumor heterogeneity. TP53 mutation status was associated with APOBEC hypermutator status. Interferon pathways were enriched in tumors with high APOBEC mutagenesis and IFN-γ-induced expression of APOBEC3B in lung adenocarcinoma cells, suggesting that the immune microenvironment may promote mutational heterogeneity. CNAs occurring late in tumor evolution correlated with downstream transcriptomic and proteomic heterogeneity, although global proteomic heterogeneity was significantly greater than transcriptomic and CNA heterogeneity. These results illustrate key mechanisms underlying multi-dimensional heterogeneity in metastatic thoracic tumors.
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http://dx.doi.org/10.1016/j.celrep.2019.02.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6461561PMC
March 2019

Associations between IgG reactivity to Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) antigens and Burkitt lymphoma in Ghana and Uganda case-control studies.

EBioMedicine 2019 Jan 20;39:358-368. Epub 2018 Dec 20.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address:

Background: Endemic Burkitt lymphoma (eBL) is an aggressive childhood B-cell lymphoma linked to Plasmodium falciparum (Pf) malaria in sub-Saharan Africa. We investigated antibody reactivity to several human receptor-binding domains of the Pf erythrocyte membrane protein 1 (PfEMP1) that play a key role in malaria pathogenesis and are targets of acquired immunity to malaria.

Methods: Serum/plasma IgG antibody reactivity was measured to 22 Pf antigens, including 18 to PfEMP1 CIDR domains between cases and controls from two populations (149 eBL cases and 150 controls from Ghana and 194 eBL cases and 600 controls from Uganda). Adjusted odds ratios (aORs) for case-control associations were estimated by logistic regression.

Findings: There was stronger reactivity to the severe malaria associated CIDRα1 domains than other CIDR domains both in cases and controls. eBL cases reacted to fewer antigens than controls (Ghana: p = 0·001; Uganda: p = 0·03), with statistically significant lower ORs associated with reactivity to 13+ antigens in Ghana (aOR 0·39, 95% CI 0·24-0·63; p = 0·00011) and Uganda (aOR 0·60, 95% CI 0.41-0·88; p = 0·008). eBL was inversely associated with reactivity, coded as quartiles, to group A variant CIDRδ1 (p = 0·035) in Ghana and group B CD36-binding variants CIDRα2·2 (p = 0·006) and CIDRα2·4 (p = 0·033) in Uganda, and positively associated with reactivity to SERA5 in Ghana (p = 0·017) and Uganda (p = 0·007) and group A CIDRα1·5 variant in Uganda only (p = 0·034).

Interpretation: eBL cases reacted to fewer antigens than controls using samples from two populations, Ghana and Uganda. Attenuated humoral immunity to Pf EMP1 may contribute to susceptibility to low-grade malaria and eBL risk.

Funding: Intramural Research Program, National Cancer Institute and National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services.
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http://dx.doi.org/10.1016/j.ebiom.2018.12.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355394PMC
January 2019

-ΔG is associated with prostate cancer among men at increased risk of sexually transmitted infections.

Commun Biol 2018 14;1:191. Epub 2018 Nov 14.

Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA.

Sexually transmitted infections can reach the prostate gland where their harmful effects are mediated by innate immunity, including interferons. Humans are polymorphic for the germline dinucleotide variant, rs368234815-TT/ΔG, in the gene encoding interferon λ4. Since the ΔG allele has been linked to impaired viral clearance, we hypothesized that potential exposure to sexually transmitted pathogens, as assessed by the number of lifetime sexual partners, may increase prostate cancer risk in an ΔG-dependent manner. Accordingly, we find that men with 10 or more sexual partners and at least one copy of ΔG have a significantly increased risk of prostate cancer while those with the same number of partners but lacking ΔG do not. Moreover, a test for effect modification shows a positive interaction between the number of lifetime partners and ΔG in the development of aggressive prostate cancer. Based on these findings, we conclude that a gene-environment interaction between ΔG and sexual activity may increase the risk of prostate cancer.
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http://dx.doi.org/10.1038/s42003-018-0193-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235841PMC
November 2018
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