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
) and IRF4 (rs9405192, OR = 1.29, P = 1.4 × 10
), fine-map the PLA2R1 locus (rs17831251, OR = 2.25, P = 4.7 × 10
) and report ancestry-specific effects of three classical HLA alleles: DRB1*1501 in East Asians (OR = 3.81, P = 2.0 × 10
), DQA1*0501 in Europeans (OR = 2.88, P = 5.7 × 10
), and DRB1*0301 in both ethnicities (OR = 3.50, P = 9.2 × 10
and OR = 3.39, P = 5.2 × 10
, 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 four loci and their interactions accounting for nearly one-third of the disease risk.
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 that encodes the key enzyme responsible for the transfer of galactose to O-linked glycans on IgA1. By in vitro siRNA knock-down studies, we confirmed that mRNA levels of both C1GALT1 and C1GALT1C1 determine the rate of secretion of Gd-IgA1 in IgA1-producing cells. Our findings provide novel insights into the genetic regulation of O-glycosylation and are relevant not only to IgA nephropathy, but also to other complex traits associated with O-glycosylation defects, including inflammatory bowel disease, hematologic disease, and cancer.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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 months (95% CI: 9.4, 14.9). Updated OS model included age, sex, absolute neutrophil count, absolute lymphocyte count, albumin, hemoglobin, LDH, and p-16 status. We stratified patients into three risk groups based on this model at the 0.33 and 0.66 quantiles. Median OS in the optimal risk group reached 23.7 months (CI: 18.5, NR), 13.8 months (CI: 11.1, 20.3) in the average risk group, and 2.3 months (CI: 1.7, 4.4) in the high-risk group. Following internal validation, the discriminatory power of the model reached a c-index of 0.72 and calibration slope of 0.79. Conclusions Our updated nomogram could assist in the precise selection of patients for which ICI could be beneficial and cost-effective. Keywords: Head and neck cancer, Head and neck squamous cell carcinoma, Immunotherpay, Immune checkpoint inhibitors, Survival in head and neck cancer
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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.
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.
STR profiles of the cSCC lines allow the confirmation of their unique identity. Phylogenetic trees derived from exome sequence analysis of the matched primary and metastatic lines provide insight into the genetic basis of disease progression. The results of in vivo and in vitro analyses allow researchers to select suitable cell lines for specific experimentation.
There are few well-characterised cSCC lines available for widespread preclinical experimentation and drug screening. The described cSCC cell line panel provides a critical tool for in vitro and in vivo experimentation.
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 s 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 s.
Results
Although recurrent mutations among ONB tumors are uncommon, alterations in TP53, DMD, PIK3CA, NF1, CDKN2A, CDKN2C, CTNNB1, EGFR, APC, cKIT, cMET, PDGFRA, CDH1, FH, SMAD4, FGFR3 and IDH2 genes have been reported in several recent studies. In addition, cytogenetic studies revealed that the landscape of chromosomal aberrations varies widely amongst ONB tumors.
Conclusions
The rare character of ONB has limited the sample size available for cytogenetic, genomic, and epigenetic studies and contributes to the limitations of this systematic review. Comprehensive genomic and epigenomic studies with larger cohorts are warranted to validate the initial reports summarized in this review and to identify potential therapeutic targets for ONB.
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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. Subgroup analysis of oral tongue, laryngeal, oral cavity, floor of mouth, tonsillar cancers was carried out separately. Results: A total of 233 genes were significantly correlated with survival in head and neck tumors ( < 0.01). This geneset was subsequently analyzed for enrichment of common pathway dysregulation or for enrichment of shared regulatory elements. The expression level of a set of a total of 15 genes that represent targets of Nanog and Sox2 was shown to either increase or decrease survival directly dependent on either up- or down-regulated expression levels. Of note, neither Nanog nor Sox2 expression levels individually impacted survival. Subgroup analysis revealed individualized prognostic signatures in each anatomic location, with an overlap of individual genes with Nanog and Sox2 targets signature ranging from 6.25-20%. Conclusions: We describe a prognostic signature in head and neck tumors derived from a TCGA data consisting of genes that represent targets of critical stem cell regulators Sox2 and Nanog. On a subgroup analysis, we also derived prognostic signatures for five anatomic locations and head&neck tumors with various ranges of overlap with Sox2 and Nanog targets signature. Pending validation in additional datasets, those represent an attractive target for further mechanistic evaluation in tumorigenesis in this group of tumors.
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e18504
Background: External Beam Radiotherapy (EBRT) has a well-established role in palliation of metastatic bone disease, yet the adherence to evidence based palliative EBRT doses and ...fractionation schemes is not universal across United States outpatient treatment facilities. We aimed to explore potential disparities in palliative EBRT quality in relation to Medicare visit payments and population demographics. Methods: Centers for Medicare & Medicaid Services (CMS) EBRT for Bone Metastases process measure score for 2018 included in the Hospital Outpatient Quality Reporting Program (Hospital OQR) was available for a total of 824 facilities across the US. The score represents the percentage of evaluated patients that received an acceptable palliative dose/fractionation regimen. Radiation Oncology Office Visit Costs per zip code for new and established patients were obtained from CMS. Demographics (percentage of total population representing males, females, 5 years or younger, under 18 years, 65 or older, white, black or African American, Latino) were obtained from US census. Linear regression analysis was carried out with score representing the dependent variable. Results: The median score was 95% (range 5-100%), average 88.86%. In the final multivariate model, the score was significantly positively associated with the percentage of white population (p = 0.04) and negatively associated with the percentage of population under 18 (p = 0.03), and there was a trend toward association with the mode of Medicare pricing for a new patient visit (p = 0.06). Of note, the percentage of population under 18 was positively correlated with percentage of Latino population (p = 3.155e-09) but not black population (p = 0.9.) There was no association with gender, or with the percentage of those patients who were very young (under 5) or over the age of 65 years. Conclusions: The quality of palliative EBRT in US outpatient facilities is associated with demographic diversity of a given area, with predominantly nondiverse neighborhoods generally receiving higher quality EBRT-based palliative care. Additionally, it appears to be negatively affected by Medicare payments. This data suggests that disparities in healthcare quality are directly mediated by race and partially by geography.
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 of radiation treatment to children.
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