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Papers by Nikol Mladkova

BMC Cancer

Background Immune checkpoint inhibitors (ICI) treatment in recurrent/metastatic (R/M) head and ne... more Background Immune checkpoint inhibitors (ICI) treatment in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) offers new therapeutic venues. We have previously developed a predictive survival model in this patient population based on clinical parameters, and the purpose of this study was to expand the study cohort and internally validate the model. Methods A single institutional retrospective analysis of R/M HNSCC patients treated with ICI. Clinical parameters collected included p-16 status, hemoglobin (Hb), albumin (Alb), lactate dehydrogenase (LDH), neutrophil, lymphocyte and platelet counts. Cox proportional hazard regression was used to assess the impact of patient characteristics and clinical variables on survival. A nomogram was created using the rms package to generate individualized survival prediction. Results 201 patients were included, 47 females (23%), 154 males (77%). Median age was 61 years (IQR: 55-68). P-16 negative (66%). Median OS was 12 month...

Journal of Clinical Oncology, 2021

6038 Background: Immune checkpoint inhibitors (ICI) are currently approved in the treatment of pa... more 6038 Background: Immune checkpoint inhibitors (ICI) are currently approved in the treatment of patients (pts) with recurrent-metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). The majority of pts will progress on ICI. Little is known regarding the best treatment approach for this patient population. We previously showed that the combination of weekly carboplatin, paclitaxel and cetuximab was associated with reduced risk of grade 3/4 toxicities, which makes it an ideal regimen in this setting. Here; we report the outcomes of pts with R/M HNSCC who were treated with chemotherapy alone vs weekly chemotherapy plus cetuximab after progression on ICI. Methods: Between January 15th 2016 and April 9th 2020, 154 pts who progressed on ICI were analyzed. Among these pts, 64 had received subsequent systemic therapy and met the inclusion criteria. Progression Free Survival (PFS) was defined as the time elapsed between initiation of subsequent chemotherapy and tumor progression or de...

Journal of Clinical Oncology, 2021

6030 Background: Immune checkpoint inhibitors (ICI) therapy is approved for patients (pts) with r... more 6030 Background: Immune checkpoint inhibitors (ICI) therapy is approved for patients (pts) with recurrent-metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). The majority of pts will die within two years of diagnosis. We have shown that pretreatment clinical characteristics may predict overall survival (OS). Here, we expand our analysis to a total of 201 pts. Methods: Between January 15,2016 and April 9, 2020, 201 pts with R/M HNSCC were treated with ICI as first, second line and beyond. Data on p16 status, hemoglobin (Hb), albumin, lactate dehydrogenase (LDH), neutrophil, platelet and lymphocyte count was recorded initially. OS was defined from the start of ICI to death. Progression Free Survival (PFS) was defined from the start of ICI to disease progression (PD) or death. A nomogram was created using the rms package to generate individualized survival prediction. Results: 201 pts were analyzed, sex: 154 male (77%), 47 female (23%), median age 61 (IQR: 55-68). ICI drug:...

ABSTRACTIgA nephropathy (IgAN) is a progressive form of kidney disease defined by glomerular depo... more ABSTRACTIgA nephropathy (IgAN) is a progressive form of kidney disease defined by glomerular deposition of IgA. We performed a genome-wide association study involving 10,146 kidney biopsy-diagnosed IgAN cases and 28,751 matched controls across 17 international cohorts. We defined 30 independent genome-wide significant risk loci jointly explaining 11% of disease risk. A total of 16 loci were novel, including TNFSF4, REL, CD28, CXCL8/PF4V1, LY86, LYN, ANXA3, TNFSF8/15, REEP3, ZMIZ1, RELA, ETS1, IGH, IRF8, TNFRSF13B and FCAR. The SNP-based heritability of IgAN was estimated at 23%. We observed a positive genetic correlation between IgAN and total serum IgA levels, allergy, tonsillectomy, and several infections, and a negative correlation with inflammatory bowel disease. All significant non-HLA loci shared with serum IgA levels had a concordant effect on the risk of IgAN. Moreover, IgAN loci were globally enriched in gene orthologs causing abnormal IgA levels when genetically manipulate...

International Journal of Radiation Oncology*Biology*Physics, 2021

PURPOSE/OBJECTIVE(S) Olfactory neuroblastoma (ONB) and sinonasal undifferentiated carcinoma (SNUC... more PURPOSE/OBJECTIVE(S) Olfactory neuroblastoma (ONB) and sinonasal undifferentiated carcinoma (SNUC) are rare sinonasal cancers with distinct clinical courses. Methylomic differences between these entities have not been previously explored. The aims of this study were to compare genome-wide methylomes of ONB and SNUC, and to explore candidate tissue of origin of SNUC using a comparative methylomics approach. MATERIALS/METHODS We included a total of 87 sinonasal malignancy samples. Genome-wide methylome data were obtained with an SNP-based human microarray for 71 ONB-like samples (44 "definitive" ONB samples, 27 ONB-resembling samples) and 10 IDH2-mutatnt SNUC samples. RNA sequencing data for a further 3 ONB and 3 SNUC samples were included. Methylomes were compared between ONB and SNUC samples and to publicly available methylation data for 195 tissue samples representing an array of tumors and normal tissues using R. Strict quality control was performed. RESULTS A total of 41 ONB and 9 SNUC samples passed QC and were included in the final analysis. A total of 89,016 differentially methylated probes had adjusted P-value < 0.01, the majority (90.4%) of which were hypermethylated in SNUC and located predominantly in regulatory regions, likely reflecting IDH2 mutation. The remaining 9.6% were hypomethylated in SNUC samples and were commonly located in intergenic regions. Top differentially methylated regions were GATA3, IGF2, LSP1, NKX6-2 and UNCX. NKX6-2 and UNCX were not expressed in SNUC RNAseq data. Gene set enrichment analysis (GSEA) of differentially hypermethylated CpG-island associated probes with at least 2.5-fold-decrease in SNUC RNA-seq data showed enrichment of EZH2 targets, H3K27 bound genes consistent with previous GSEA in IDH2-mutat sarcomas, in addition to WNT pathway, olfactory transduction, lipid & carbohydrate metabolism and genes pertaining to the nervous system (P < 0.0001). On Pearson's correlation-based analysis, ONB clustered with neuronal samples while SNUC clustered with medulloblastoma (MB) and malignant peripheral nerve sheath tumor (MPNST). On separate correlation, SNUC clustered with T-cell lymphoma, MPNST and MB. On examination of the top 300 differentially methylated probes, SNUC again clustered with MPNST and MB and with a neural crest cluster. On deconvolution analysis, both ONB and SNUC samples showed a predominant T-cell presence, which was significantly higher in SNUC (P < 0.001). CONCLUSION ONB and SNUC possess distinct methylomes. PRC2 complex dysregulation may represent a key driver of a genome-wide repressive phenotype in IDH2-mutant SNUC samples leading to a dedifferentiated phenotype and may be a potential avenue for targeted therapies in the future. The presence of T-cell infiltration in both tumors represents a potential avenue for exploration of therapeutic checkpoint inhibition. Genome-wide methylomics suggests SNUC may be derived from neuronal tissue and we are currently involved in further transomic approaches to independently validate this hypothesis.

International Journal of Radiation Oncology*Biology*Physics, 2021

Laryngoscope Investigative Otolaryngology, 2021

Background: Olfactory neuroblastoma (ONB) or esthesioneuroblastoma (ENB) is a rare malignancy of ... more Background: Olfactory neuroblastoma (ONB) or esthesioneuroblastoma (ENB) is a rare malignancy of the nasal cavity believed to arise from the olfactory epithelium. The goal of this study was to systematically review the genomics, epigenetics, and cytogenetics of ONB and to understand the potential clinical implications of these studies. Methods: A systematic literature review was performed for articles published before May 2020 using Cochrane, Embase, Pubmed, and Scopus databases. Inclusion criteria included genomics, cytogenetics, and epigenetics studies on ONB. Exclusion criteria included studies not in English or systematic reviews. Articles and abstracts were reviewed by two independent reviewers to reduce bias during article selection and synthesis of results. Of the 36 studies included in this review, 24 were research articles and 12 were abstracts. Results: Although recurrent mutations among ONB tumors are uncommon, alterations in TP53,

Asian Pacific Journal of Cancer Care, 2020

The COVID-19 global pandemic represents a unique challenge affecting all aspects of current life ... more The COVID-19 global pandemic represents a unique challenge affecting all aspects of current life including the delivery of healthcare around the globe. Radiation treatment is an integral part in the management of many pediatric malignancies, and the aim is to provide our institutional experience and trainee perspective on the delivery of radiation treatment during this era to facilitate further discussion regarding the practical impact of the pandemic on the treatment of childhood cancers and trainee education. Overall, the effect of the virus on the population of children with malignancies and its possible impact on their overall outcome is uncertain. The impact on trainee education is inevitable but can be mitigated in the context of adequate personal safety measures and online education. The authors strongly advocate for data sharing among facilities to determine the optimal safety measures that decrease the likelihood of COVID-19 transmission yet do not compromise the delivery o...

Nature Communications, 2020

Membranous Nephropathy (MN) is a rare autoimmune cause of kidney failure. Here we report a genome... more Membranous Nephropathy (MN) is a rare autoimmune cause of kidney failure. Here we report a genome-wide association study (GWAS) for primary MN in 3,782 cases and 9,038 controls of East Asian and European ancestries. We discover two previously unreported loci, NFKB1 ( rs230540, OR = 1.25, P = 3.4 × 10−12) and IRF4 ( rs9405192, OR = 1.29, P = 1.4 × 10−14), fine-map the PLA2R1 locus ( rs17831251, OR = 2.25, P = 4.7 × 10−103) and report ancestry-specific effects of three classical HLA alleles: DRB1*1501 in East Asians (OR = 3.81, P = 2.0 × 10−49), DQA1*0501 in Europeans (OR = 2.88, P = 5.7 × 10−93), and DRB1*0301 in both ethnicities (OR = 3.50, P = 9.2 × 10−23 and OR = 3.39, P = 5.2 × 10−82, respectively). GWAS loci explain 32% of disease risk in East Asians and 25% in Europeans, and correctly re-classify 20–37% of the cases in validation cohorts that are antibody-negative by the serum anti-PLA2R ELISA diagnostic test. Our findings highlight an unusual genetic architecture of MN, with ...

International Journal of Molecular Sciences, 2019

Background: Cutaneous squamous cell carcinoma (cSCC) incidence continues to rise with increasing ... more Background: Cutaneous squamous cell carcinoma (cSCC) incidence continues to rise with increasing morbidity and mortality, with limited treatment options for advanced disease. Future improvements in targeted therapy will rely on advances in genomic/transcriptomic understanding and the use of model systems for basic research. We describe here the panel of 16 primary and metastatic cSCC cell lines developed and characterised over the past three decades in our laboratory in order to provide such a resource for future preclinical research and drug screening. Methods: Primary keratinocytes were isolated from cSCC tumours and metastases, and cell lines were established. These were characterised using short tandem repeat (STR) profiling and genotyped by whole exome sequencing. Multiple in vitro assays were performed to document their morphology, growth characteristics, migration and invasion characteristics, and in vivo xenograft growth. Results: STR profiles of the cSCC lines allow the con...

Journal of Clinical Oncology, 2019

e17546 Background: Head and neck cancers represent a diverse group of tumors linked with HPV infe... more e17546 Background: Head and neck cancers represent a diverse group of tumors linked with HPV infection, alcohol and smoking that contribute to cancer morbidity and mortality globally. Sox2 and Nanog are transcription factors that maintain pluripotency in embryonic stem cells, and their individual expression has been associated with prognosis in head and neck tumors previously. Methods: TCGA dataset containing 522 tumor samples with RNAseq data, clinical information (anatomically classified as 133 oral tongue, 117 laryngeal, 73 oral cavity, 63 floor of mouth, 45 tonsillar, 27 base of tongue and 70 other samples) and 44 normal samples with RNAseq data available was used to detect differentially expressed genes in head and neck tumors. The levels of each gene were then transformed to z-score per patient and classified as over- or under-expressed if those were 2 SD away from the mean. The expression levels were then correlated with survival in individual patients for all tumor combined....

Oncogene, 2018

Glioblastomas (GBMs) are the most aggressive primary brain tumors, with an average survival of le... more Glioblastomas (GBMs) are the most aggressive primary brain tumors, with an average survival of less than 15 months. Therefore, there is a critical need to develop novel therapeutic strategies for GBM. This study aimed to assess the prognostic value of miR-4516 and investigate its oncogenic functions and the underlying cellular and molecular mechanisms in GBM. To determine the correlation between miR-4516 expression and overall survival of patients with GBM, total RNAs were isolated from 268 FFPE tumor samples, miR expression was assayed (simultaneously) using the nCounter human miRNA v3a assay followed by univariable and multivariable survival analyses. Further, in vitro and in vivo studies were conducted to define the role of miR-4516 in GBM tumorigenesis and the underlying molecular mechanisms. Upon multivariable analysis, miR-4516 was correlated with poor prognosis in GBM patients (HR=1.49, 95%CI: 1.12-1.99, p=0.01). Interestingly, the significance of miR-4516 was retained including MGMT methylation status. Overexpression of miR-4516 significantly enhanced cell proliferation and invasion of GBM cells both in vitro and in vivo. While conducting downstream targeting studies, we found that the

Aberrant O-glycosylation of serum immunoglobulin A1 (IgA1) represents a heritable pathogenic defe... more Aberrant O-glycosylation of serum immunoglobulin A1 (IgA1) represents a heritable pathogenic defect in IgA nephropathy, the most common form of glomerulonephritis worldwide, but specific genetic factors involved in its determination are not known. We performed a quantitative GWAS for serum levels of galactose-deficient IgA1 (Gd-IgA1) in 2,633 subjects of European and East Asian ancestry and discovered two genome-wide significant loci, in C1GALT1 (rs13226913, P = 3.2 x 10-11) and C1GALT1C1 (rs5910940, P = 2.7 x 10-8). These genes encode molecular partners essential for enzymatic O-glycosylation of IgA1. We demonstrated that these two loci explain approximately 7% of variability in circulating Gd-IgA1 in Europeans, but only 2% in East Asians. Notably, the Gd-IgA1-increasing allele of rs13226913 is common in Europeans, but rare in East Asians. Moreover, rs13226913 represents a strong cis-eQTL for C1GALT1, which encodes the key enzyme responsible for the transfer of galactose to O-linke...

Journal of the American Society of Nephrology : JASN, Jan 3, 2016

An intronic variant at the complement factor H (CFH) gene on chromosome 1q32 (rs6677604) associat... more An intronic variant at the complement factor H (CFH) gene on chromosome 1q32 (rs6677604) associates with risk of IgA nephropathy (IgAN), but the association signal has not been uniformly replicated in Han Chinese populations. We investigated whether the causal sequence variant resides in the CFH gene or the neighboring complement factor H-related 1 (CFHR1) gene and CFHR3, which harbor an 84-kb combined deletion (CFHR3,1Δ) in linkage disequilibrium with rs6677604. Imputation of 1000 Genomes Project data did not suggest new causal single-nucleotide variants within the CFH cluster. We next performed copy number analysis across the CFH locus in two independent Han Chinese case-control cohorts (combined n=3581). The CFHR3,1Δ and rs6677604-A alleles were rare (4.4% in patients and 7.1% in controls) and in strong linkage disequilibrium with each other (r(2)=0.95); of these alleles, CFHR3,1Δ associated more significantly with decreased risk of IgAN (odds ratio [OR], 0.56; 95% confidence int...

Hepatology (Baltimore, Md.), Jun 9, 2016

Using publicly available data from inbred mouse strains, we conducted a genome-wide association s... more Using publicly available data from inbred mouse strains, we conducted a genome-wide association study to identify loci that accounted for liver-related phenotypes between C57BL/6J and A/J fed a Paigen diet. We confirmed genome-wide significant associations for hepatic cholesterol (chromosome 10A2) and serum total bile acid concentration (chromosome 12E) and identified a new locus for liver inflammation (chromosome 7C). Analysis of consomic mice confirmed that chromosome 12 A/J alleles accounted for the variance in serum total bile acid concentrations and also had pleiotropic effects on liver mass, serum cholesterol and serum alanine aminotransferase activity. Using an affected-only haplotype analysis among strains, we refined the chromosome 12E signal to a 1.95 Mb linkage disequilibrium block containing only one gene, Sel1l. RNA-seq and immunoblotting demonstrated that the risk allele locally conferred reduced expression of SEL1L in liver and distantly downregulates pathways associa...

British journal of cancer, Jan 21, 2014

Cutaneous squamous cell carcinoma (cSCC) is one of the most common malignancies in fair-skinned p... more Cutaneous squamous cell carcinoma (cSCC) is one of the most common malignancies in fair-skinned populations worldwide and its incidence is increasing. Despite previous observations of multiple genetic abnormalities in cSCC, the oncogenic process remains elusive. The purpose of this study was to elucidate key molecular events associated with progression from premalignant actinic keratoses (AKs) to invasive cSCC by transcriptome profiling. We combined laser capture microdissection with the Affymetrix HGU133 Plus 2.0 microarrays to profile 30 cSCC and 10 AKs. We identified a core set of 196 genes that are differentially expressed between AK and cSCC, and are enriched for processes including epidermal differentiation, cell migration, cell-cycle regulation and metabolism. Gene set enrichment analysis highlighted a key role for the mitogen activated protein kinase (MAPK) pathway in cSCC compared with AK. Furthermore, the histological subtype of the tumour was shown to influence the expres...

Ultrasound Quarterly, 2011

Although upper gastrointestinal (GI) tract endoscopy is the investigation of choice for patients ... more Although upper gastrointestinal (GI) tract endoscopy is the investigation of choice for patients with suspected gastroesophageal reflux disease (GERD)-induced esophagitis, it is associated with complications and significant patient discomfort. The aim of the current study was to compare the accuracy of transabdominal ultrasonography with upper GI tract endoscopy in the detection of GERD-induced esophagitis. In this descriptive study, 350 patients (mean age, 41.41 ± 14.52 years) referred to a gastroenterologist with symptoms suggestive of GERD were enrolled. The esophageal wall thickness was measured with transabdominal ultrasonography, and patients were subsequently assessed by upper GI endoscopy, representing the criterion standard in the diagnostic evaluation for GERD-induced esophagitis. Endoscopic evaluation identified 100 patients with esophagitis (case group), and 250 subjects were reported to have normal endoscopic findings (control group). The wall thickness was significantly higher in the case group compared with the control (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001).In the receiver operating characteristic analysis, only 2 cutoff points had a positive predictive value (PPV) greater than 50%. The cutoff point of 2.7 mm had 38% sensitivity, 91% specificity, 63% PPV, and 79% negative predictive value in the detection of GERD. Its positive and negative likelihood ratios were 4.32 and 0.68, respectively. According to the identified sensitivity/specificity, low PPV and positive likelihood ratio, and relatively high negative likelihood ratio, we failed to find the transabdominal ultrasound effective in the detection of GERD-induced esophagitis.

Current Oncology Reports, 2008

The purpose of this review is to provide an upto-date summary of the current knowledge and unders... more The purpose of this review is to provide an upto-date summary of the current knowledge and understanding of the molecular alterations and pathways relevant to the clinical outcome of glioblastoma patients and their potential use in designing personalized treatment for these patients. This article also discusses the potential of molecular profi ling as a diagnostic modality, possible therapeutic implications of MGMT promoter methylation, the targeted inhibition of angiogenesis, and assessment of the tumor's molecular background with respect to PI3K/ AKT pathway activation and associated molecules (EGFR, EGFRvIII, PTEN).

Skeletal Radiology, 2012

Introduction Spondyloarthropathies including ankylosing spondylitis (AS) require early diagnosis ... more Introduction Spondyloarthropathies including ankylosing spondylitis (AS) require early diagnosis to prevent irreversible changes. Sacroiliitis is a common initial manifestation of AS and is frequently diagnosed by magnetic resonance imaging (MRI). The goal of our study was to assess color Doppler ultrasonography as a potential diagnostic tool in suspected sacroiliitis in comparison with MRI representing the gold standard. Materials and methods Fifty-one consecutive patients with AS and sacroiliitis and 30 control subjects underwent contrast-enhanced MRI and high resolution color Doppler and duplex ultrasonography of both sacroiliac joints (SIJ) for the detection of vascularization and blood flow spectral Doppler waveform analysis. Results MRI demonstrated active disease in 27 and inactive disease in 24 patients. CDUS detected pulsatile monophasic wave spectral waveform flow in 22 patients with the active disease, and triphasic in 7 patients with inactive disease and in 8 control patients. The sensitivity, specificity, positive predictive value and negative predictive value for active sacroiliitis detection with CDUS were 82 % (95 % CI, 68-91 %), 92 % (95 % CI, 85-96 %), 91 % (95 % CI, 84-96 %), and 84 % (95 % CI, 70-92 %), respectively, for pulsatile monophasic wave spectral waveform Doppler sonography. MRI of SIJ was negative in all 30 (60 SIJ) control participants. Conclusions Our results show that CDUS is a practical and useful tool in the diagnosis of active sacroiliitis.

BMC Cancer

Background Immune checkpoint inhibitors (ICI) treatment in recurrent/metastatic (R/M) head and ne... more Background Immune checkpoint inhibitors (ICI) treatment in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) offers new therapeutic venues. We have previously developed a predictive survival model in this patient population based on clinical parameters, and the purpose of this study was to expand the study cohort and internally validate the model. Methods A single institutional retrospective analysis of R/M HNSCC patients treated with ICI. Clinical parameters collected included p-16 status, hemoglobin (Hb), albumin (Alb), lactate dehydrogenase (LDH), neutrophil, lymphocyte and platelet counts. Cox proportional hazard regression was used to assess the impact of patient characteristics and clinical variables on survival. A nomogram was created using the rms package to generate individualized survival prediction. Results 201 patients were included, 47 females (23%), 154 males (77%). Median age was 61 years (IQR: 55-68). P-16 negative (66%). Median OS was 12 month...

Journal of Clinical Oncology, 2021

6038 Background: Immune checkpoint inhibitors (ICI) are currently approved in the treatment of pa... more 6038 Background: Immune checkpoint inhibitors (ICI) are currently approved in the treatment of patients (pts) with recurrent-metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). The majority of pts will progress on ICI. Little is known regarding the best treatment approach for this patient population. We previously showed that the combination of weekly carboplatin, paclitaxel and cetuximab was associated with reduced risk of grade 3/4 toxicities, which makes it an ideal regimen in this setting. Here; we report the outcomes of pts with R/M HNSCC who were treated with chemotherapy alone vs weekly chemotherapy plus cetuximab after progression on ICI. Methods: Between January 15th 2016 and April 9th 2020, 154 pts who progressed on ICI were analyzed. Among these pts, 64 had received subsequent systemic therapy and met the inclusion criteria. Progression Free Survival (PFS) was defined as the time elapsed between initiation of subsequent chemotherapy and tumor progression or de...

Journal of Clinical Oncology, 2021

6030 Background: Immune checkpoint inhibitors (ICI) therapy is approved for patients (pts) with r... more 6030 Background: Immune checkpoint inhibitors (ICI) therapy is approved for patients (pts) with recurrent-metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). The majority of pts will die within two years of diagnosis. We have shown that pretreatment clinical characteristics may predict overall survival (OS). Here, we expand our analysis to a total of 201 pts. Methods: Between January 15,2016 and April 9, 2020, 201 pts with R/M HNSCC were treated with ICI as first, second line and beyond. Data on p16 status, hemoglobin (Hb), albumin, lactate dehydrogenase (LDH), neutrophil, platelet and lymphocyte count was recorded initially. OS was defined from the start of ICI to death. Progression Free Survival (PFS) was defined from the start of ICI to disease progression (PD) or death. A nomogram was created using the rms package to generate individualized survival prediction. Results: 201 pts were analyzed, sex: 154 male (77%), 47 female (23%), median age 61 (IQR: 55-68). ICI drug:...

ABSTRACTIgA nephropathy (IgAN) is a progressive form of kidney disease defined by glomerular depo... more ABSTRACTIgA nephropathy (IgAN) is a progressive form of kidney disease defined by glomerular deposition of IgA. We performed a genome-wide association study involving 10,146 kidney biopsy-diagnosed IgAN cases and 28,751 matched controls across 17 international cohorts. We defined 30 independent genome-wide significant risk loci jointly explaining 11% of disease risk. A total of 16 loci were novel, including TNFSF4, REL, CD28, CXCL8/PF4V1, LY86, LYN, ANXA3, TNFSF8/15, REEP3, ZMIZ1, RELA, ETS1, IGH, IRF8, TNFRSF13B and FCAR. The SNP-based heritability of IgAN was estimated at 23%. We observed a positive genetic correlation between IgAN and total serum IgA levels, allergy, tonsillectomy, and several infections, and a negative correlation with inflammatory bowel disease. All significant non-HLA loci shared with serum IgA levels had a concordant effect on the risk of IgAN. Moreover, IgAN loci were globally enriched in gene orthologs causing abnormal IgA levels when genetically manipulate...

International Journal of Radiation Oncology*Biology*Physics, 2021

PURPOSE/OBJECTIVE(S) Olfactory neuroblastoma (ONB) and sinonasal undifferentiated carcinoma (SNUC... more PURPOSE/OBJECTIVE(S) Olfactory neuroblastoma (ONB) and sinonasal undifferentiated carcinoma (SNUC) are rare sinonasal cancers with distinct clinical courses. Methylomic differences between these entities have not been previously explored. The aims of this study were to compare genome-wide methylomes of ONB and SNUC, and to explore candidate tissue of origin of SNUC using a comparative methylomics approach. MATERIALS/METHODS We included a total of 87 sinonasal malignancy samples. Genome-wide methylome data were obtained with an SNP-based human microarray for 71 ONB-like samples (44 "definitive" ONB samples, 27 ONB-resembling samples) and 10 IDH2-mutatnt SNUC samples. RNA sequencing data for a further 3 ONB and 3 SNUC samples were included. Methylomes were compared between ONB and SNUC samples and to publicly available methylation data for 195 tissue samples representing an array of tumors and normal tissues using R. Strict quality control was performed. RESULTS A total of 41 ONB and 9 SNUC samples passed QC and were included in the final analysis. A total of 89,016 differentially methylated probes had adjusted P-value < 0.01, the majority (90.4%) of which were hypermethylated in SNUC and located predominantly in regulatory regions, likely reflecting IDH2 mutation. The remaining 9.6% were hypomethylated in SNUC samples and were commonly located in intergenic regions. Top differentially methylated regions were GATA3, IGF2, LSP1, NKX6-2 and UNCX. NKX6-2 and UNCX were not expressed in SNUC RNAseq data. Gene set enrichment analysis (GSEA) of differentially hypermethylated CpG-island associated probes with at least 2.5-fold-decrease in SNUC RNA-seq data showed enrichment of EZH2 targets, H3K27 bound genes consistent with previous GSEA in IDH2-mutat sarcomas, in addition to WNT pathway, olfactory transduction, lipid & carbohydrate metabolism and genes pertaining to the nervous system (P < 0.0001). On Pearson's correlation-based analysis, ONB clustered with neuronal samples while SNUC clustered with medulloblastoma (MB) and malignant peripheral nerve sheath tumor (MPNST). On separate correlation, SNUC clustered with T-cell lymphoma, MPNST and MB. On examination of the top 300 differentially methylated probes, SNUC again clustered with MPNST and MB and with a neural crest cluster. On deconvolution analysis, both ONB and SNUC samples showed a predominant T-cell presence, which was significantly higher in SNUC (P < 0.001). CONCLUSION ONB and SNUC possess distinct methylomes. PRC2 complex dysregulation may represent a key driver of a genome-wide repressive phenotype in IDH2-mutant SNUC samples leading to a dedifferentiated phenotype and may be a potential avenue for targeted therapies in the future. The presence of T-cell infiltration in both tumors represents a potential avenue for exploration of therapeutic checkpoint inhibition. Genome-wide methylomics suggests SNUC may be derived from neuronal tissue and we are currently involved in further transomic approaches to independently validate this hypothesis.

International Journal of Radiation Oncology*Biology*Physics, 2021

Laryngoscope Investigative Otolaryngology, 2021

Background: Olfactory neuroblastoma (ONB) or esthesioneuroblastoma (ENB) is a rare malignancy of ... more Background: Olfactory neuroblastoma (ONB) or esthesioneuroblastoma (ENB) is a rare malignancy of the nasal cavity believed to arise from the olfactory epithelium. The goal of this study was to systematically review the genomics, epigenetics, and cytogenetics of ONB and to understand the potential clinical implications of these studies. Methods: A systematic literature review was performed for articles published before May 2020 using Cochrane, Embase, Pubmed, and Scopus databases. Inclusion criteria included genomics, cytogenetics, and epigenetics studies on ONB. Exclusion criteria included studies not in English or systematic reviews. Articles and abstracts were reviewed by two independent reviewers to reduce bias during article selection and synthesis of results. Of the 36 studies included in this review, 24 were research articles and 12 were abstracts. Results: Although recurrent mutations among ONB tumors are uncommon, alterations in TP53,

Asian Pacific Journal of Cancer Care, 2020

The COVID-19 global pandemic represents a unique challenge affecting all aspects of current life ... more The COVID-19 global pandemic represents a unique challenge affecting all aspects of current life including the delivery of healthcare around the globe. Radiation treatment is an integral part in the management of many pediatric malignancies, and the aim is to provide our institutional experience and trainee perspective on the delivery of radiation treatment during this era to facilitate further discussion regarding the practical impact of the pandemic on the treatment of childhood cancers and trainee education. Overall, the effect of the virus on the population of children with malignancies and its possible impact on their overall outcome is uncertain. The impact on trainee education is inevitable but can be mitigated in the context of adequate personal safety measures and online education. The authors strongly advocate for data sharing among facilities to determine the optimal safety measures that decrease the likelihood of COVID-19 transmission yet do not compromise the delivery o...

Nature Communications, 2020

Membranous Nephropathy (MN) is a rare autoimmune cause of kidney failure. Here we report a genome... more Membranous Nephropathy (MN) is a rare autoimmune cause of kidney failure. Here we report a genome-wide association study (GWAS) for primary MN in 3,782 cases and 9,038 controls of East Asian and European ancestries. We discover two previously unreported loci, NFKB1 ( rs230540, OR = 1.25, P = 3.4 × 10−12) and IRF4 ( rs9405192, OR = 1.29, P = 1.4 × 10−14), fine-map the PLA2R1 locus ( rs17831251, OR = 2.25, P = 4.7 × 10−103) and report ancestry-specific effects of three classical HLA alleles: DRB1*1501 in East Asians (OR = 3.81, P = 2.0 × 10−49), DQA1*0501 in Europeans (OR = 2.88, P = 5.7 × 10−93), and DRB1*0301 in both ethnicities (OR = 3.50, P = 9.2 × 10−23 and OR = 3.39, P = 5.2 × 10−82, respectively). GWAS loci explain 32% of disease risk in East Asians and 25% in Europeans, and correctly re-classify 20–37% of the cases in validation cohorts that are antibody-negative by the serum anti-PLA2R ELISA diagnostic test. Our findings highlight an unusual genetic architecture of MN, with ...

International Journal of Molecular Sciences, 2019

Background: Cutaneous squamous cell carcinoma (cSCC) incidence continues to rise with increasing ... more Background: Cutaneous squamous cell carcinoma (cSCC) incidence continues to rise with increasing morbidity and mortality, with limited treatment options for advanced disease. Future improvements in targeted therapy will rely on advances in genomic/transcriptomic understanding and the use of model systems for basic research. We describe here the panel of 16 primary and metastatic cSCC cell lines developed and characterised over the past three decades in our laboratory in order to provide such a resource for future preclinical research and drug screening. Methods: Primary keratinocytes were isolated from cSCC tumours and metastases, and cell lines were established. These were characterised using short tandem repeat (STR) profiling and genotyped by whole exome sequencing. Multiple in vitro assays were performed to document their morphology, growth characteristics, migration and invasion characteristics, and in vivo xenograft growth. Results: STR profiles of the cSCC lines allow the con...

Journal of Clinical Oncology, 2019

e17546 Background: Head and neck cancers represent a diverse group of tumors linked with HPV infe... more e17546 Background: Head and neck cancers represent a diverse group of tumors linked with HPV infection, alcohol and smoking that contribute to cancer morbidity and mortality globally. Sox2 and Nanog are transcription factors that maintain pluripotency in embryonic stem cells, and their individual expression has been associated with prognosis in head and neck tumors previously. Methods: TCGA dataset containing 522 tumor samples with RNAseq data, clinical information (anatomically classified as 133 oral tongue, 117 laryngeal, 73 oral cavity, 63 floor of mouth, 45 tonsillar, 27 base of tongue and 70 other samples) and 44 normal samples with RNAseq data available was used to detect differentially expressed genes in head and neck tumors. The levels of each gene were then transformed to z-score per patient and classified as over- or under-expressed if those were 2 SD away from the mean. The expression levels were then correlated with survival in individual patients for all tumor combined....

Oncogene, 2018

Glioblastomas (GBMs) are the most aggressive primary brain tumors, with an average survival of le... more Glioblastomas (GBMs) are the most aggressive primary brain tumors, with an average survival of less than 15 months. Therefore, there is a critical need to develop novel therapeutic strategies for GBM. This study aimed to assess the prognostic value of miR-4516 and investigate its oncogenic functions and the underlying cellular and molecular mechanisms in GBM. To determine the correlation between miR-4516 expression and overall survival of patients with GBM, total RNAs were isolated from 268 FFPE tumor samples, miR expression was assayed (simultaneously) using the nCounter human miRNA v3a assay followed by univariable and multivariable survival analyses. Further, in vitro and in vivo studies were conducted to define the role of miR-4516 in GBM tumorigenesis and the underlying molecular mechanisms. Upon multivariable analysis, miR-4516 was correlated with poor prognosis in GBM patients (HR=1.49, 95%CI: 1.12-1.99, p=0.01). Interestingly, the significance of miR-4516 was retained including MGMT methylation status. Overexpression of miR-4516 significantly enhanced cell proliferation and invasion of GBM cells both in vitro and in vivo. While conducting downstream targeting studies, we found that the

Aberrant O-glycosylation of serum immunoglobulin A1 (IgA1) represents a heritable pathogenic defe... more Aberrant O-glycosylation of serum immunoglobulin A1 (IgA1) represents a heritable pathogenic defect in IgA nephropathy, the most common form of glomerulonephritis worldwide, but specific genetic factors involved in its determination are not known. We performed a quantitative GWAS for serum levels of galactose-deficient IgA1 (Gd-IgA1) in 2,633 subjects of European and East Asian ancestry and discovered two genome-wide significant loci, in C1GALT1 (rs13226913, P = 3.2 x 10-11) and C1GALT1C1 (rs5910940, P = 2.7 x 10-8). These genes encode molecular partners essential for enzymatic O-glycosylation of IgA1. We demonstrated that these two loci explain approximately 7% of variability in circulating Gd-IgA1 in Europeans, but only 2% in East Asians. Notably, the Gd-IgA1-increasing allele of rs13226913 is common in Europeans, but rare in East Asians. Moreover, rs13226913 represents a strong cis-eQTL for C1GALT1, which encodes the key enzyme responsible for the transfer of galactose to O-linke...

Journal of the American Society of Nephrology : JASN, Jan 3, 2016

An intronic variant at the complement factor H (CFH) gene on chromosome 1q32 (rs6677604) associat... more An intronic variant at the complement factor H (CFH) gene on chromosome 1q32 (rs6677604) associates with risk of IgA nephropathy (IgAN), but the association signal has not been uniformly replicated in Han Chinese populations. We investigated whether the causal sequence variant resides in the CFH gene or the neighboring complement factor H-related 1 (CFHR1) gene and CFHR3, which harbor an 84-kb combined deletion (CFHR3,1Δ) in linkage disequilibrium with rs6677604. Imputation of 1000 Genomes Project data did not suggest new causal single-nucleotide variants within the CFH cluster. We next performed copy number analysis across the CFH locus in two independent Han Chinese case-control cohorts (combined n=3581). The CFHR3,1Δ and rs6677604-A alleles were rare (4.4% in patients and 7.1% in controls) and in strong linkage disequilibrium with each other (r(2)=0.95); of these alleles, CFHR3,1Δ associated more significantly with decreased risk of IgAN (odds ratio [OR], 0.56; 95% confidence int...

Hepatology (Baltimore, Md.), Jun 9, 2016

Using publicly available data from inbred mouse strains, we conducted a genome-wide association s... more Using publicly available data from inbred mouse strains, we conducted a genome-wide association study to identify loci that accounted for liver-related phenotypes between C57BL/6J and A/J fed a Paigen diet. We confirmed genome-wide significant associations for hepatic cholesterol (chromosome 10A2) and serum total bile acid concentration (chromosome 12E) and identified a new locus for liver inflammation (chromosome 7C). Analysis of consomic mice confirmed that chromosome 12 A/J alleles accounted for the variance in serum total bile acid concentrations and also had pleiotropic effects on liver mass, serum cholesterol and serum alanine aminotransferase activity. Using an affected-only haplotype analysis among strains, we refined the chromosome 12E signal to a 1.95 Mb linkage disequilibrium block containing only one gene, Sel1l. RNA-seq and immunoblotting demonstrated that the risk allele locally conferred reduced expression of SEL1L in liver and distantly downregulates pathways associa...

British journal of cancer, Jan 21, 2014

Cutaneous squamous cell carcinoma (cSCC) is one of the most common malignancies in fair-skinned p... more Cutaneous squamous cell carcinoma (cSCC) is one of the most common malignancies in fair-skinned populations worldwide and its incidence is increasing. Despite previous observations of multiple genetic abnormalities in cSCC, the oncogenic process remains elusive. The purpose of this study was to elucidate key molecular events associated with progression from premalignant actinic keratoses (AKs) to invasive cSCC by transcriptome profiling. We combined laser capture microdissection with the Affymetrix HGU133 Plus 2.0 microarrays to profile 30 cSCC and 10 AKs. We identified a core set of 196 genes that are differentially expressed between AK and cSCC, and are enriched for processes including epidermal differentiation, cell migration, cell-cycle regulation and metabolism. Gene set enrichment analysis highlighted a key role for the mitogen activated protein kinase (MAPK) pathway in cSCC compared with AK. Furthermore, the histological subtype of the tumour was shown to influence the expres...

Ultrasound Quarterly, 2011

Although upper gastrointestinal (GI) tract endoscopy is the investigation of choice for patients ... more Although upper gastrointestinal (GI) tract endoscopy is the investigation of choice for patients with suspected gastroesophageal reflux disease (GERD)-induced esophagitis, it is associated with complications and significant patient discomfort. The aim of the current study was to compare the accuracy of transabdominal ultrasonography with upper GI tract endoscopy in the detection of GERD-induced esophagitis. In this descriptive study, 350 patients (mean age, 41.41 ± 14.52 years) referred to a gastroenterologist with symptoms suggestive of GERD were enrolled. The esophageal wall thickness was measured with transabdominal ultrasonography, and patients were subsequently assessed by upper GI endoscopy, representing the criterion standard in the diagnostic evaluation for GERD-induced esophagitis. Endoscopic evaluation identified 100 patients with esophagitis (case group), and 250 subjects were reported to have normal endoscopic findings (control group). The wall thickness was significantly higher in the case group compared with the control (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001).In the receiver operating characteristic analysis, only 2 cutoff points had a positive predictive value (PPV) greater than 50%. The cutoff point of 2.7 mm had 38% sensitivity, 91% specificity, 63% PPV, and 79% negative predictive value in the detection of GERD. Its positive and negative likelihood ratios were 4.32 and 0.68, respectively. According to the identified sensitivity/specificity, low PPV and positive likelihood ratio, and relatively high negative likelihood ratio, we failed to find the transabdominal ultrasound effective in the detection of GERD-induced esophagitis.

Current Oncology Reports, 2008

The purpose of this review is to provide an upto-date summary of the current knowledge and unders... more The purpose of this review is to provide an upto-date summary of the current knowledge and understanding of the molecular alterations and pathways relevant to the clinical outcome of glioblastoma patients and their potential use in designing personalized treatment for these patients. This article also discusses the potential of molecular profi ling as a diagnostic modality, possible therapeutic implications of MGMT promoter methylation, the targeted inhibition of angiogenesis, and assessment of the tumor's molecular background with respect to PI3K/ AKT pathway activation and associated molecules (EGFR, EGFRvIII, PTEN).

Skeletal Radiology, 2012

Introduction Spondyloarthropathies including ankylosing spondylitis (AS) require early diagnosis ... more Introduction Spondyloarthropathies including ankylosing spondylitis (AS) require early diagnosis to prevent irreversible changes. Sacroiliitis is a common initial manifestation of AS and is frequently diagnosed by magnetic resonance imaging (MRI). The goal of our study was to assess color Doppler ultrasonography as a potential diagnostic tool in suspected sacroiliitis in comparison with MRI representing the gold standard. Materials and methods Fifty-one consecutive patients with AS and sacroiliitis and 30 control subjects underwent contrast-enhanced MRI and high resolution color Doppler and duplex ultrasonography of both sacroiliac joints (SIJ) for the detection of vascularization and blood flow spectral Doppler waveform analysis. Results MRI demonstrated active disease in 27 and inactive disease in 24 patients. CDUS detected pulsatile monophasic wave spectral waveform flow in 22 patients with the active disease, and triphasic in 7 patients with inactive disease and in 8 control patients. The sensitivity, specificity, positive predictive value and negative predictive value for active sacroiliitis detection with CDUS were 82 % (95 % CI, 68-91 %), 92 % (95 % CI, 85-96 %), 91 % (95 % CI, 84-96 %), and 84 % (95 % CI, 70-92 %), respectively, for pulsatile monophasic wave spectral waveform Doppler sonography. MRI of SIJ was negative in all 30 (60 SIJ) control participants. Conclusions Our results show that CDUS is a practical and useful tool in the diagnosis of active sacroiliitis.