Meredith Yeager

Meredith Yeager
National Cancer Institute (USA) | NCI · Human Genetics

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647
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Publications

Publications (647)
Article
Full-text available
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...
Article
Full-text available
The chr12q24.13 locus encoding OAS1–OAS3 antiviral proteins has been associated with coronavirus disease 2019 (COVID-19) susceptibility. Here, we report genetic, functional and clinical insights into this locus in relation to COVID-19 severity. In our analysis of patients of European (n = 2,249) and African (n = 835) ancestries with hospitalized ve...
Article
Full-text available
Background Oropharyngeal squamous cell carcinoma is frequently associated with high-risk HPV infection, which confers a good prognosis. Immunohistochemistry for p16 is used as a surrogate for HPV status, but discrepant results are occasionally seen. Here, we report a case with a unique pattern of partial loss of p16. Methods A 63 year old male pre...
Article
Background: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and has one of the poorest survival rates among pediatric cancers, underscoring the need to identify factors which may be leveraged to improve therapeutic options for these individuals. Methods: We carried out a genome-wide association study of overall survival (O...
Article
Following the Chernobyl nuclear power plant explosion in Ukraine in 1986, increased childhood exposure to radioactive iodine (131I), which occurred primarily through contaminated food sources, has been consistently associated with increased risk of developing papillary thyroid carcinoma (PTC). Increased frequency of cervical lymph node metastases (...
Article
Chordoma is a rare bone tumor with genetic risk factors largely unknown. We conducted a whole‐exome sequencing (WES) analysis of germline DNA from 19 familial chordoma cases in five pedigrees and 137 sporadic chordoma patients and identified 17 rare germline variants in PALB2 and BRCA2, whose products play essential roles in homologous recombinatio...
Article
Purpose A significant barrier to adoption of de-escalated treatment protocols for human papillomavirus-driven oropharyngeal cancer (HPV-OPC) is that few predictors of poor prognosis exist. We conducted the first large whole-genome sequencing (WGS) study to characterize the genetic variation of the HPV16 genome and to evaluate its association with H...
Preprint
Background Mapping of quantitative trait loci (QTL) associated with molecular phenotypes is a powerful approach for identifying the genes and molecular mechanisms underlying human traits and diseases. How the genetic architecture of molecular traits varies across human populations, however, has been less explored. To better understand the genetics...
Article
The application of whole-exome sequencing (WES) has led to the identification of high and moderate-risk variants that contribute to cutaneous melanoma susceptibility. However, confirming disease-causing variants remains challenging. We applied a gene co-expression network analysis to prioritize candidate genes identified from WES of 34 melanoma-pro...
Article
Full-text available
Oropharyngeal squamous cell carcinoma (SCC) is increasing in incidence and, in Western countries, strongly associated with transcriptionally-active high-risk human papillomavirus (HPV). Within HPV-positive tumors, there is wide morphologic diversity with numerous histologic subtypes of SCC. There are also variable degrees of keratinization, anaplas...
Preprint
Purpose: A significant barrier to adoption of de-escalated treatment protocols for human papillomavirus-driven oropharyngeal cancer (HPV-OPC) is that few predictors of poor prognosis exist. We conducted the first large whole-genome sequencing (WGS) study to characterize the genetic variation of the HPV16 genome and to evaluate its association with...
Preprint
The human papillomavirus (HPV) type 16 E7 oncogene is critical to carcinogenesis and highly conserved. Previous studies identified a preponderance of non-synonymous E7 variants amongst HPV16-positive cancer-free controls compared to those with cervical cancer. To investigate the function of E7 variants, we constructed full-length HPV16 E7 genes and...
Article
Introduction: Myelofibrosis (MF) is a rare myeloproliferative neoplasm (MPN) characterized by bone marrow fibrosis, progressive bone marrow failure, and increased risk of acute myeloid leukemia. While MF arises from somatic driver mutations in JAK2, MPL, and CALR, some MPN patients may have a heritable component. To comprehensively examine the gene...
Preprint
Full-text available
Integration of Human Papillomaviruses (HPV) is an important mechanism of carcinogenesis but is absent in a significant fraction of HPV16+ tumors. We applied long-read whole-genome sequencing (WGS) to cervical cancer cell lines and tumors. In two HPV16+ cell lines, we identified large tandem arrays of full-length and truncated viral genomes integrat...
Article
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Human papillomavirus (HPV) type 31 (HPV31) is closely related to the most carcinogenic type, HPV16, but only accounts for 4% of cervical cancer cases worldwide. Viral genetic and epigenetic variations have been associated with carcinogenesis for other high-risk HPV types, but little is known about HPV31. We sequenced 2093 HPV31 viral whole genomes...
Article
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APOBEC is a mutagenic source in human papillomavirus (HPV)-mediated malignancies, including HPV+ oropharyngeal squamous cell carcinoma (HPV + OPSCC), and in HPV genomes. It is unknown why APOBEC mutations predominate in HPV + OPSCC, or if the APOBEC-induced mutations observed in both human cancers and HPV genomes are directly linked. We performed s...
Article
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To improve risk stratification and treatment decisions for patients with acute myeloid leukemia (AML) undergoing hematopoietic cell transplantation (HCT). We used SNP-array data from the DISCOVeRY-BMT study to detect chromosomal aberrations in pre-HCT peripheral blood (collected 2–4 weeks before the administration of conditioning regimen) from 1974...
Preprint
Full-text available
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...
Article
Full-text available
Aim: Recessive genetic variation is thought to play a role in non-Hodgkin lymphoma (NHL) etiology. Runs of homozygosity (ROH), defined based on long, continuous segments of homozygous SNPs, can be used to estimate both measured and unmeasured recessive genetic variation. We sought to examine genome-wide homozygosity and NHL risk. Methods: We use...
Article
Full-text available
Background: Chordoma is a rare bone cancer with an unknown etiology. TBXT is the only chordoma susceptibility gene identified to date; germline single nucleotide variants and copy number variants in TBXT have been associated with chordoma susceptibility in familial and sporadic chordoma. However, the genetic susceptibility of chordoma remains larg...
Article
Full-text available
Background: Fanconi anemia (FA) is an inherited bone marrow failure syndrome associated with characteristic dysmorphology primarily caused by biallelic pathogenic germline variants in any of 22 different DNA repair genes. There are limited data on the specific molecular causes of FA in different ethnic groups. Methods: We performed exome sequenc...
Article
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Admixed populations are a resource to study the global genetic architecture of complex phenotypes, which is critical, considering that non-European populations are severely underrepresented in genomic studies. Here, we study the genetic architecture of BMI in children, young adults, and elderly individuals from the admixed population of Brazil. Lev...
Article
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Genomics of radiation-induced damage The potential adverse effects of exposures to radioactivity from nuclear accidents can include acute consequences such as radiation sickness, as well as long-term sequelae such as increased risk of cancer. There have been a few studies examining transgenerational risks of radiation exposure but the results have...
Article
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Genomics of radiation-induced damage The potential adverse effects of exposures to radioactivity from nuclear accidents can include acute consequences such as radiation sickness, as well as long-term sequelae such as increased risk of cancer. There have been a few studies examining transgenerational risks of radiation exposure but the results have...
Conference Paper
The 1986 Chernobyl nuclear power plant accident increased papillary thyroid cancer (PTC) incidence in surrounding regions, particularly for 131I-exposed children. To investigate the contribution of environmental radiation to PTC characteristics and improve understanding of radiation-induced carcinogenesis, we analyzed genomic, transcriptomic, and e...
Article
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We previously identified 10 lung adenocarcinoma susceptibility loci in a genome-wide association study (GWAS) conducted in the Female Lung Cancer Consortium in Asia (FLCCA), the largest genomic study of lung cancer among never-smoking women to date. Furthermore, household coal use for cooking and heating has been linked to lung cancer in Asia, espe...
Article
Background Pediatric cancers are the leading cause of death by disease in children despite improved survival rates overall. The contribution of germline genetic susceptibility to pediatric cancer survivors has not been extensively characterized. We assessed the frequency of pathogenic/likely pathogenic (P/LP) variants in 5,451 long-term pediatric c...
Article
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Age-related male Y and female X chromosome mosaicism is commonly observed in large population-based studies. To investigate the frequency of male X chromosome mosaicism, we scanned for deviations in chromosome X genotyping array intensity data in a population-based survey of 196,219 UK Biobank men. We detected 12 (0.006%) men with mosaic chromosome...
Article
Key Points Pre-HCT mosaicism is related to increased relapse risk and lower survival after unrelated HCT, independent of cytogenetics at diagnosis. Pre-HCT mosaicism could be a useful clinical tool to guide risk stratification in acute lymphoblastic leukemia patients.
Article
Human leukocyte antigen (HLA) gene variation is associated with risk of cancers, particularly those with infectious etiology or hematopoietic origin, given its role in immune presentation. Previous studies focused primarily on HLA allele/haplotype-specific associations. To answer whether associations are driven by HLA class I (essential for T-cell...
Article
Introduction: Allogeneic hematopoietic cell transplantation (HCT) is curative for myelofibrosis (MF). However, prognosis post HCT is variable. Identifying subsets of patients who can greatly benefit from HCT is important for clinical decision-making and patient counseling. The Dynamic International Prognostic Scoring System (DIPSS) score includes c...
Article
Clonal mosaicism, detectable in peripheral blood, can be an important predictor of developing a hematological malignancy. We sought to determine if mosaic events, in addition to clinical and demographic variables, contributed independent information about acute lymphoblastic leukemia (ALL) patient survival and risk of relapse after allogeneic hemat...
Article
Full-text available
Although next-generation sequencing has demonstrated great potential for novel gene discovery, confirming disease-causing genes after initial discovery remains challenging. Here, we applied a network analysis approach to prioritize candidate genes identified from whole-exome sequencing analysis of 98 cutaneous melanoma patients from 27 families. Us...
Article
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Background: Ewing sarcoma (EwS) is a rare, aggressive solid tumor of childhood, adolescence and young adulthood associated with pathognomonic EWSR1-ETS fusion oncoproteins altering transcriptional regulation. Genome-wide association studies (GWAS) have identified 6 common germline susceptibility loci but have not investigated low-frequency inherit...
Conference Paper
The immune system has several mechanisms to recognize tumor cells as foreign and eliminate them. Somatically altered genes can create peptides, or neoantigens, that class I HLA (HLA-I) molecules can present to cytotoxic T-cells. As a result, people with suppressed immune systems commonly have a higher rate of cancer. PanCancer data of 9423 tumor ex...
Conference Paper
Background: Human papillomavirus type 16 (HPV16) is one of the most common and carcinogenic HPV types associated with high risk of anal, vagina, vulva, penis and cervical neoplastic transformations. However, many genetic variants exist within this virus and not all seem to have the same carcinogenic potential. Aim: To determine HPV16 lineages and t...
Article
Full-text available
Human papillomavirus (HPV) 16 displays substantial sequence variation; four HPV16 lineages (A, B, C, and D) have been described as well as multiple sublineages. To identify molecular events associated with HPV16 carcinogenesis, we evaluated viral variation, the integration of HPV16, and somatic mutation in 96 cervical cancer samples from Guatemala....
Article
Full-text available
Intratumor heterogeneity (ITH) and tumor evolution have been well described for clear cell renal cell carcinomas (ccRCC), but they are less studied for other kidney cancer subtypes. Here we investigate ITH and clonal evolution of papillary renal cell carcinoma (pRCC) and rarer kidney cancer subtypes, integrating whole-genome sequencing and DNA meth...
Article
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Cancer risk is highly variable in carriers of the common TP53-R337H founder allele, possibly due to the influence of modifier genes. Whole-genome sequencing identified a variant in the tumor suppressor XAF1 (E134*/Glu134Ter/ rs146752602) in a subset of R337H carriers. Haplotype-defining variants were verified in 203 patients with cancer, 582 relati...
Article
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HPV35 has been found in only ~2% of invasive cervical cancers (ICC) worldwide but up to 10% in Sub‐Saharan Africa, warranting further investigation and consideration of impact on preventive strategies. We studied HPV35 and race/ethnicity, in relation to the known steps in cervical carcinogenesis, using multiple large epidemiologic studies in the U....
Article
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Importance Osteosarcoma, the most common malignant bone tumor in children and adolescents, occurs in a high number of cancer predisposition syndromes that are defined by highly penetrant germline mutations. The germline genetic susceptibility to osteosarcoma outside of familial cancer syndromes remains unclear. Objective To investigate the germlin...
Article
The Transatlantic Slave Trade transported more than 9 million Africans to the Americas between the early 16th and the mid-19th centuries. We performed a genome-wide analysis using 6,267 individuals from 25 populations to infer how different African groups contributed to North-, South-American and Caribbean populations, in the context of geographic...
Article
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Background High-resolution genome-wide SNP-arrays detect large chromosomal aberrations including copy-neutral loss of heterozygosity (CNLOH), which is not captured in conventional cytogenetics. Methods We used SNP-array genotyping data generated by the DISCOVeRY-BMT study to detect chromosomal aberrations in pre-HCT blood samples from 1,974 acute...
Article
Full-text available
Mosaic loss of Y chromosome (mLOY) is the most frequently detected somatic copy number alteration in leukocytes of men. In this study, we investigate blood cell counts as a potential mechanism linking mLOY to disease risk in 206,353 UK males. Associations between mLOY, detected by genotyping arrays, and blood cell counts were assessed by multivaria...
Article
Full-text available
HPV16 causes half of cervical cancers worldwide; for unknown reasons, most infections resolve within two years. Here, we analyze the viral genomes of 5,328 HPV16-positive case-control samples to investigate mutational signatures and the role of human APOBEC3-induced mutations in viral clearance and cervical carcinogenesis. We identify four de novo...
Preprint
Full-text available
Western South America was one of the worldwide cradles of civilization. The well known Inca Empire was the tip of the iceberg of a cultural and biological evolutionary process that started 14-11 thousand years ago. Genetic data from 18 Peruvian populations reveal that: (1) The between-population homogenization of the central-southern Andes and its...
Article
Severe aplastic anemia (SAA) is a rare disorder characterized by hypoplastic bone marrow and progressive pancytopenia. The etiology of acquired SAA is not understood but is likely related to abnormal immune responses and environmental exposures. We conducted a genome-wide association study of individuals with SAA genetically matched to healthy cont...
Preprint
Full-text available
Human papillomavirus (HPV) 16 displays substantial sequence variation; four HPV16 lineages (A, B, C, D) have been described, as well as multiple sub-lineages. To identify molecular events associated with HPV16 carcinogenesis we evaluated viral variation, the integration of HPV16, and somatic mutation in 96 cervical cancer samples from Guatemala. A...
Preprint
Full-text available
Admixed populations are a resource to study the global genetic architecture of complex phenotypes, which is critical, considering that non-European populations are severely under-represented in genomic studies. Leveraging admixture in Brazilians, whose chromosomes are mosaics of fragments of Native American, European and African origins, we used ge...
Article
Introduction: Clinical cytogenetics is the most important prognostic test for patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS); however, current tools do not provide a complete genome-wide picture of somatic chromosomal aberrations in those patients. We used a high-resolution genome-wide single-nucleotide polymorphism (S...
Article
Introduction. Acquired severe aplastic anemia (SAA) is a life-threatening disorder characterized by severe progressive pancytopenia and hypocellular bone marrow. The etiology of acquired SAA is not understood but believed to be related to abnormal immune responses to environmental exposures. We conducted a genome-wide association study (GWAS) to id...
Article
Full-text available
Background: Human papillomavirus (HPV) is a common sexually transmitted infection associated with cervical cancer that frequently occurs as a coinfection of types and subtypes. Highly similar sublineages that show over 100-fold differences in cancer risk are not distinguishable in coinfections with current typing methods. Results: We describe an...
Article
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Genetic susceptibility is likely involved in nasopharyngeal carcinoma (NPC), a cancer caused by Epstein-Barr virus (EBV) infection. Understanding of genetic factors involved in NPC and how they contribute to EBV-induced carcinogenesis is limited. We conducted whole-exome capture/sequencing among 251 individuals from 97 multiplex families from Taiwa...