Monogenic Autoinflammatory Diseases with Mendelian Inheritance: Genes, Mutations, and Genotype/Phenotype Correlations.

Front Immunol. 2017;8:344

Authors: Martorana D, Bonatti F, Mozzoni P, Vaglio A, Percesepe A

Abstract
Autoinflammatory diseases (AIDs) are a genetically heterogeneous group of diseases caused by mutations of genes encoding proteins, which play a pivotal role in the regulation of the inflammatory response. In the pathogenesis of AIDs, the role of the genetic background is triggered by environmental factors through the modulation of the innate immune system. Monogenic AIDs are characterized by Mendelian inheritance and are caused by highly penetrant genetic variants in single genes. During the last years, remarkable progress has been made in the identification of disease-associated genes by using new technologies, such as next-generation sequencing, which has allowed the genetic characterization in undiagnosed patients and in sporadic cases by means of targeted resequencing of a gene panel and whole exome sequencing. In this review, we delineate the genetics of the monogenic AIDs, report the role of the most common gene mutations, and describe the evidences of the most sound genotype/phenotype correlations in AID.

PMID: 28421071 [PubMed - in process]

Application and progress of high-throughput sequencing technologies in the research of hereditary hearing loss.

Yi Chuan. 2017 Mar 20;39(3):208-219

Authors: Cuicui W, Huijun Y

Abstract
Hearing loss (HL) is the most common birth defect. Elucidating the genetic basis of hereditary deafness can not only assist diagnosis, provide the basis for genetic counseling and the prevention of deafness, but also bring a deeper understanding of the disease pathogenesis. In the genomic era, high-throughput sequencing technologies, represented by whole genome sequencing (WGS), whole exome sequencing (WES) or target region sequencing, have been widely used in the studies of hereditary HL. Here, we summarize the application and progress of WES and target region sequencing in the research of causative genes and clinical molecular diagnosis of hereditary HL, hoping to be helpful for the development and improvement of clinical genetic diagnosis of deafness in China.

PMID: 28420617 [PubMed - in process]

Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden.

Genome Med. 2017 Apr 19;9(1):34

Authors: Chalmers ZR, Connelly CF, Fabrizio D, Gay L, Ali SM, Ennis R, Schrock A, Campbell B, Shlien A, Chmielecki J, Huang F, He Y, Sun J, Tabori U, Kennedy M, Lieber DS, Roels S, White J, Otto GA, Ross JS, Garraway L, Miller VA, Stephens PJ, Frampton GM

Abstract
BACKGROUND: High tumor mutational burden (TMB) is an emerging biomarker of sensitivity to immune checkpoint inhibitors and has been shown to be more significantly associated with response to PD-1 and PD-L1 blockade immunotherapy than PD-1 or PD-L1 expression, as measured by immunohistochemistry (IHC). The distribution of TMB and the subset of patients with high TMB has not been well characterized in the majority of cancer types.
METHODS: In this study, we compare TMB measured by a targeted comprehensive genomic profiling (CGP) assay to TMB measured by exome sequencing and simulate the expected variance in TMB when sequencing less than the whole exome. We then describe the distribution of TMB across a diverse cohort of 100,000 cancer cases and test for association between somatic alterations and TMB in over 100 tumor types.
RESULTS: We demonstrate that measurements of TMB from comprehensive genomic profiling are strongly reflective of measurements from whole exome sequencing and model that below 0.5 Mb the variance in measurement increases significantly. We find that a subset of patients exhibits high TMB across almost all types of cancer, including many rare tumor types, and characterize the relationship between high TMB and microsatellite instability status. We find that TMB increases significantly with age, showing a 2.4-fold difference between age 10 and age 90 years. Finally, we investigate the molecular basis of TMB and identify genes and mutations associated with TMB level. We identify a cluster of somatic mutations in the promoter of the gene PMS2, which occur in 10% of skin cancers and are highly associated with increased TMB.
CONCLUSIONS: These results show that a CGP assay targeting ~1.1 Mb of coding genome can accurately assess TMB compared with sequencing the whole exome. Using this method, we find that many disease types have a substantial portion of patients with high TMB who might benefit from immunotherapy. Finally, we identify novel, recurrent promoter mutations in PMS2, which may be another example of regulatory mutations contributing to tumorigenesis.

PMID: 28420421 [PubMed - in process]

Novel Genetic Variants Associated with Child Refractory Esophageal Stricture with Food Allergy by Exome Sequencing.

Nutrients. 2017 Apr 15;9(4):

Authors: Yang M, Xiong M, Chen H, Geng L, Chen P, Xie J, Ye SQ, Li DY, Gong S

Abstract
BACKGROUND: Refractory esophageal stricture (RES) may be attributed to food allergy. Its etiology and pathogenesis are not fully understood. Identification of novel genetic variants associated with this disease by exome sequencing (exome-seq) may provide new mechanistic insights and new therapeutic targets.
METHODS: To identify new and novel disease-associating variants, whole-exome sequencing was performed on an Illumina NGS platform in three children with RES as well as food allergy.
RESULTS: A total of 91,024 variants were identified. By filtering out 'normal variants' against those of the 1000 Genomes Project, we identified 12,741 remaining variants which are potentially associated with RES plus food allergy. Among these variants, there are 11,539 single nucleotide polymorphisms (SNPs), 627 deletions, 551 insertions and 24 mixture variants. These variants are located in 1370 genes. They are enriched in biological processes or pathways such as cell adhesion, digestion, receptor metabolic process, bile acid transport and the neurological system. By the PubMatrix analysis, 50 out of the top 100 genes, which contain most variants, have not been previously associated with any of the 17 allergy-associated diseases. These 50 genes represent newly identified allergy-associated genes. Those variants of 627 deletions and 551 insertions have also not been reported before in RES with food allergy.
CONCLUSIONS: Exome-seq is potentially a powerful tool to identify potential new biomarkers for RES with food allergy. This study has identified a number of novel genetic variants, opening new avenues of research in RES plus food allergy. Additional validation in larger and different patient populations and further exploration of the underlying molecular mechanisms are warranted.

PMID: 28420126 [PubMed - in process]

Molecular classification of pulmonary sarcomatoid carcinomas suggests new therapeutic opportunities.

Ann Oncol. 2017 Apr 13;:

Authors: Pécuchet N, Vieira T, Rabbe N, Antoine M, Blons H, Cadranel J, Laurent-Puig P, Wislez M

Abstract
Background: Pulmonary sarcomatoid carcinoma (SC) is a rare disease with poor prognosis and with strong inter- and intratumor heterogeneity. However, molecular classification is currently focused on activating MET mutations. We sought to better characterize the molecular diversity of SC using mutational signatures that reflect different mutational processes, such as tobacco-associated adducts (signature 4), BRCA1/BRCA2 deficiency (signature 3) or APOBEC enzyme deamination (signatures 2&13).
Patients and methods: Whole-exome sequencing was performed in 15 SC patients and on data from 10 previously-published cases. Hierarchical clustering and consensus non-negative matrix factorization (NMF) were performed for classification, based on mutational signatures.
Results: In the two series, we identified two clusters (C): C sig4 (characterized by signature 4) and C sig2-3-13 (signatures 2, 3, and 13). C sig4 exhibited more frequent MAPK pathway mutations than C sig2-3-13 (pooled series: n = 10/14 vs. 2/11, P <.05 , respectively) and stronger PD-L1 expression (our series: n = 6/9 vs. 1/6, P =.12). MET alterations were only found in C sig2-3-13 (pooled series: n = 5/11 vs. 0/14, P =.009), as well as BRCA1 / BRCA2 (n = 3/11 vs. 0/15), EGFR (n = 1), and IDH1 ( n = 1 ) mutations. C sig2-3-13 patients had better overall survival than C sig4 patients (median: >45 months vs. 7 months, respectively, P=.001).
Conclusions: Our study suggests that SC presents at least two clusters comprising different mutational processes, gene alterations, and PD-L1 expression. New potential treatment possibilities are immune checkpoint inhibitors in C sig4 and specific targeted agents in C sig2-3-13 . These findings should encourage clinicians to conduct broad molecular and immunological testing in SC patients beyond MET exon 14 alterations.

PMID: 28419182 [PubMed - as supplied by publisher]

Atypical juvenile presentation of GM2 gangliosidosis AB in a patient compound-heterozygote for c.259G > T and c.164C > T mutations in the GM2A gene.

Mol Genet Metab Rep. 2017 Jun;11:24-29

Authors: Martins C, Brunel-Guitton C, Lortie A, Gauvin F, Morales CR, Mitchell GA, Pshezhetsky AV

Abstract
GM2-gangliosidosis, AB variant is an extremely rare autosomal recessive inherited disorder caused by mutations in the GM2A gene that encodes GM2 ganglioside activator protein (GM2AP). GM2AP is necessary for solubilisation of GM2 ganglioside in endolysosomes and its presentation to β-hexosaminidase A. Conversely GM2AP deficiency impairs lysosomal catabolism of GM2 ganglioside, leading to its storage in cells and tissues. We describe a 9-year-old child with an unusual juvenile clinical onset of GM2-gangliosidosis AB. At the age of 3 years he presented with global developmental delay, progressive epilepsy, intellectual disability, axial hypertonia, spasticity, seizures and ataxia, but without the macular cherry-red spots typical for GM2 gangliosidosis. Brain MRI detected a rapid onset of diffuse atrophy, whereas whole exome sequencing showed that the patient is a compound heterozygote for two mutations in GM2A: a novel nonsense mutation, c.259G > T (p.E87X) and a missense mutation c.164C > T (p.P55L) that was recently identified in homozygosity in patients of a Saudi family with a progressive chorea-dementia syndrome. Western blot analysis showed an absence of GM2AP in cultured fibroblasts from the patient, suggesting that both mutations interfere with the synthesis and/or folding of the protein. Finally, impaired catabolism of GM2 ganglioside in the patient's fibroblasts was demonstrated by metabolic labeling with fluorescently labeled GM1 ganglioside and by immunohistochemistry with anti-GM2 and anti-GM3 antibodies. Our observation expands the molecular and clinical spectrum of molecular defects linked to GM2-gangliosidosis and suggests novel diagnostic approach by whole exome sequencing and perhaps ganglioside analysis in cultured patient's cells.

PMID: 28417072 [PubMed - in process]

A phase 2 study of vorinostat in locally advanced, recurrent, or metastatic adenoid cystic carcinoma.

Oncotarget. 2017 Mar 22;:

Authors: Goncalves PH, Heilbrun LK, Barrett MT, Kummar S, Hansen AR, Siu LL, Piekarz RL, Sukari AW, Chao J, Pilat MJ, Smith DW, Casetta L, Boerner SA, Chen A, Lenkiewicz E, Malasi S, LoRusso PM

Abstract
PURPOSE: Vorinostat is a histone deacetylase inhibitor (HDACi). Based on a confirmed partial response (PR) in an adenoid cystic carcinoma (ACC) patient treated with vorinostat in a prior phase 1 trial, we initiated this phase 2 trial.
METHODS: Vorinostat was administered orally 400 mg daily, 28 day cycles. The primary objective was to evaluate response rate (RR). Exploratory studies included whole exome sequencing (WES) of selected patients.
RESULTS: Thirty patients were enrolled. Median age of patients was 53 years (range 21-73). Median number of cycles was 5 (range 1-66). Lymphopenia (n = 5), hypertension (n = 3), oral pain (n = 2), thromboembolic events (n = 2) and fatigue (n = 2) were the only grade 3 adverse events (AEs) that occurred in more than 1 patient. Eleven patients were dose reduced secondary to drug-related AEs. Two patients had a partial response (PR), with response durations of 53 and 7.2 months. One patient had a minor response with a decrease in ascites (for 19 cycles). Stable disease was the best response in 27 patients. Targeted and WES of 8 patients in this trial identified mutations in chromatin remodeling genes highlighting the role of the epigenome in ACC.
CONCLUSION: Vorinostat demonstrated efficacy in patients with ACC supporting the inclusion of HDACi in future studies to treat ACC.

PMID: 28415633 [PubMed - as supplied by publisher]

Semantic prioritization of novel causative genomic variants.

PLoS Comput Biol. 2017 Apr 17;13(4):e1005500

Authors: Boudellioua I, Mahamad Razali RB, Kulmanov M, Hashish Y, Bajic VB, Goncalves-Serra E, Schoenmakers N, Gkoutos GV, Schofield PN, Hoehndorf R

Abstract
Discriminating the causative disease variant(s) for individuals with inherited or de novo mutations presents one of the main challenges faced by the clinical genetics community today. Computational approaches for variant prioritization include machine learning methods utilizing a large number of features, including molecular information, interaction networks, or phenotypes. Here, we demonstrate the PhenomeNET Variant Predictor (PVP) system that exploits semantic technologies and automated reasoning over genotype-phenotype relations to filter and prioritize variants in whole exome and whole genome sequencing datasets. We demonstrate the performance of PVP in identifying causative variants on a large number of synthetic whole exome and whole genome sequences, covering a wide range of diseases and syndromes. In a retrospective study, we further illustrate the application of PVP for the interpretation of whole exome sequencing data in patients suffering from congenital hypothyroidism. We find that PVP accurately identifies causative variants in whole exome and whole genome sequencing datasets and provides a powerful resource for the discovery of causal variants.

PMID: 28414800 [PubMed - as supplied by publisher]

The role of GLI1 for 5-Fu resistance in colorectal cancer.

Cell Biosci. 2017;7:17

Authors: Zhang L, Song R, Gu D, Zhang X, Yu B, Liu B, Xie J

Abstract
Colorectal cancer is a leading cause of cancer-related mortality worldwide, with Fluorouracil (5-FU)-based chemotherapy as the major treatment for advanced disease. Many patients with advanced colorectal cancer eventually succumb to the disease despite some patients responded initially to chemotherapy. Thus, identifying molecular mechanisms responsible for chemotherapy resistance will help design novel strategies to treat colorectal cancer. In this study, we established an acquired 5-FU resistant cell line, LoVo-R, from LoVo cells. Through exome sequencing, we discovered that elevated GLI1 signaling axis is a major genetic alteration in the 5-FU resistant cells. Hh signaling, a pathway essential for embryonic development, is an important regulator for residual cancer cells. We demonstrated that knockdown of GLI1 or GLI2 sensitized LoVo-R cells to 5-FU treatment, reduced cell invasiveness. The relevance of our studies to colorectal cancer patients is reflected by our discovery that high expression of GLI1 signaling molecules was associated with a high incidence of cancer relapse and a shorter survival in a larger cohort of colorectal cancer patients who underwent chemotherapy (containing 5-FU). Taken together, our data demonstrate the critical role of the GLI1 signaling axis for 5-FU resistance in colorectal cancer.

PMID: 28413604 [PubMed]

A SLC24A2 Gene Variant Uncovered in Pancreatic Ductal Adenocarcinoma by Whole Exome Sequencing.

Tohoku J Exp Med. 2017;241(4):287-295

Authors: Wang L, Shao Z, Chen S, Shi L, Li Z

Abstract
Pancreatic ductal adenocarcinoma (PDAC) presents as an aggressive malignancy caused by environmental and genetic factors. In order to identify causal genes for PDAC, we performed whole exome sequencing (WES) to detect gene mutations in seven pairs of PDAC tissue and adjacent non-tumor tissue samples. Finally, we found a new nonsynonymous single nucleotide variant (nsSNV) in solute carrier 24 family member 2 (SLC24A2) gene resulting in the substitution of native glutamic acid (E) into aspartic acid (D) at position of 287 amino acid (E287D) in SLC24A2 protein, and confirmed this variant by Sanger gene sequencing. SLC24A2 is a potassium-dependent sodium-calcium exchanger and can transport metal ion across cell membrane. Multiple in silico variants' effects analyses methods including SIFT, PolyPhen, PROVEAN, and PANTHER demonstrated this variant had probably damaging effects, which was consistent with the results obtained from Mutation Taster software analysis with a probability of 0.99999997 to be "disease causing." The three dimension (3D) structure analysis results suggested this variant had little effects on the solubility and hydrophobicity of the protein; but it could decrease the protein stability by increasing the total protein structure energy (-8874.33 kJ/mol for the mutant and -8963.54 kJ/mol for the native) and by causing the mutant protein decreasing three stabilizing residues. Less stability of the mutant 287D protein than the native E287 protein was also supported by I-Mutant and Western-blotting analysis results. Overall, a new mutation in SLC24A2 gene was identified to decrease the stability of SLC24A2, which may have potential clinical usages.

PMID: 28413183 [PubMed - in process]

Childhood leukodystrophies: A literature review of updates on new definitions, classification, diagnostic approach and management.

Brain Dev. 2017 May;39(5):369-385

Authors: Ashrafi MR, Tavasoli AR

Abstract
Childhood leukodystrophies are a growing category of neurological disorders in pediatric neurology practice. With the help of new advanced genetic studies such as whole exome sequencing (WES) and whole genome sequencing (WGS), the list of childhood heritable white matter disorders has been increased to more than one hundred disorders. During the last three decades, the basic concepts and definitions, classification, diagnostic approach and medical management of these disorders much have changed. Pattern recognition based on brain magnetic resonance imaging (MRI), has played an important role in this process. We reviewed the last Global Leukodystrophy Initiative (GLIA) expert opinions in definition, new classification, diagnostic approach and medical management including emerging treatments for pediatric leukodystrophies.

PMID: 28117190 [PubMed - indexed for MEDLINE]

Whole-exome sequencing identifies SGCD and ACVRL1 mutations associated with total anomalous pulmonary venous return (TAPVR) in Chinese population.

Oncotarget. 2017 Feb 17;:

Authors: Li J, Yang S, Pu Z, Dai J, Jiang T, Du F, Jiang Z, Cheng Y, Dai G, Wang J, Qi J, Cao L, Cheng X, Ren C, Li X, Qin Y

Abstract
As a rare type of Congenital Heart Defects (CHD), the genetic mechanism of Total Anomalous Pulmonary Venous Return (TAPVR) remains unknown, although previous studies have revealed potential disease-driving regions/genes. Blood samples collected from the 6 sporadic TAPVR cases and 81 non-TAPVR controls were subjected to whole exome sequencing. All detected variations were confirmed by direct Sanger sequencing. Here, we identified 2 non-synonymous missense mutations: c.C652T, p.R218W in activin A receptor type II-like 1 (ACVRL1), c.C717G, p.D239E in sarcoglycan delta (SGCD). Our results offered the landscape of mutations for TAPVR in Chinese population firstly and are valuable in the mutation-based pre- and post-natal screening and genetic diagnosis for TAPVR.

PMID: 28412737 [PubMed - as supplied by publisher]

Whole-Exome Sequencing Identifies Biallelic IDH3A Variants as a Cause of Retinitis Pigmentosa Accompanied by Pseudocoloboma.

Ophthalmology. 2017 Apr 12;:

Authors: Pierrache LHM, Kimchi A, Ratnapriya R, Roberts L, Astuti GDN, Obolensky A, Beryozkin A, Tjon-Fo-Sang MJH, Schuil J, Klaver CCW, Bongers EMHF, Haer-Wigman L, Schalij N, Breuning MH, Fischer GM, Banin E, Ramesar RS, Swaroop A, van den Born LI, Sharon D, Cremers FPM

Abstract
PURPOSE: To identify the genetic cause of and describe the phenotype in 4 families with autosomal recessive retinitis pigmentosa (arRP) that can be associated with pseudocoloboma.
DESIGN: Case series.
PARTICIPANTS: Seven patients from 4 unrelated families with arRP, among whom 3 patients had bilateral early-onset macular pseudocoloboma.
METHODS: We performed homozygosity mapping and whole-exome sequencing in 5 probands and 2 unaffected family members from 4 unrelated families. Subsequently, Sanger sequencing and segregation analysis were performed in additional family members. We reviewed the medical history of individuals carrying IDH3A variants and performed additional ophthalmic examinations, including full-field electroretinography, fundus photography, fundus autofluorescence imaging, and optical coherence tomography.
MAIN OUTCOME MEASURES: IDH3A variants, age at diagnosis, visual acuity, fundus appearance, visual field, and full-field electroretinography, fundus autofluorescence, and optical coherence tomography findings.
RESULTS: We identified 7 different variants in IDH3A in 4 unrelated families, that is, 5 missense, 1 nonsense, and 1 frameshift variant. All participants showed symptoms early in life, ranging from night blindness to decreased visual acuity, and were diagnosed between the ages of 1 and 11 years. Four participants with biallelic IDH3A variants displayed a typical arRP phenotype and 3 participants were diagnosed with arRP and pseudocoloboma of the macula.
CONCLUSIONS: IDH3A variants were identified as a novel cause of typical arRP in some individuals associated with macular pseudocoloboma. We observed both phenotypes in 2 siblings carrying the same compound heterozygous variants, which could be explained by variable disease expression and warrants caution when making assertions about genotype-phenotype correlations.

PMID: 28412069 [PubMed - as supplied by publisher]

The Molecular Revolution in Cutaneous Biology: The Era of Genome-Wide Association Studies and Statistical, Big Data, and Computational Topics.

J Invest Dermatol. 2017 May;137(5):e113-e118

Authors: Anbunathan H, Bowcock AM

Abstract
The investigation of biological systems involving all organs of the body including the skin is in era of big data. This requires heavy-duty computational tools, and novel statistical methods. Microarrays have allowed the interrogation of thousands of common genetic markers in thousands of individuals from the same population (termed genome wide association studies or GWAS) to reveal common variation associated with disease or phenotype. These markers are usually single nucleotide polymorphisms (SNPs) that are relatively common in the population. In the case of dermatological diseases such as alopecia areata, vitiligo, psoriasis and atopic dermatitis, common variants have been identified that are associated with disease, and these provide insights into biological pathways and reveal possible novel drug targets. Other skin phenotypes such as acne, color and skin cancers are also being investigated with GWAS. Analyses of such large GWAS datasets require a consideration of a number of statistical issues including the testing of multiple markers, population substructure, and ultimately a requirement for replication. There are also issues regarding the missing heritability of disease that cannot be entirely explained with current GWAS approaches. Next generation sequencing technologies such as exome and genome sequencing of similar patient cohorts will reveal additional variants contributing to disease susceptibility. However, the data generated with these approaches will be orders of magnitude greater than that those generated with arrays, with concomitant challenges in the identification of disease causing variants.

PMID: 28411841 [PubMed - in process]

Genetic Variation at the Sulfonylurea Receptor, Type 2 Diabetes, and Coronary Heart Disease.

Diabetes. 2017 Apr 14;:

Authors: Emdin CA, Klarin D, Natarajan P, CARDIOGRAM Exome consortium, Florez JC, Kathiresan S, Khera AV

Abstract
Despite widespread clinical use in the treatment of type 2 diabetes, the impact of sulfonylurea therapy on cardiovascular outcomes remains uncertain. Studies of naturally occurring genetic variation can be used to anticipate the expected clinical consequences of a pharmacologic therapy. A common missense variant in the gene encoding a component of the sulfonylurea receptor (ABCC8 p.A1369S) promotes closure of the target channel of sulfonylurea therapy and is associated with increased insulin secretion, thus mimicking the effects of sulfonylurea therapy. Using individual-level data from 120 286 participants in the UK Biobank and summary association results from four large-scale genome wide association studies, we examined the impact of this variant on cardiometabolic traits, type 2 diabetes and coronary heart disease. The p.A1369S variant was associated with a significantly lower risk of type 2 diabetes (OR 0.93 95%CI 0.91, 0.95; p=1.2×10(-11)). The variant was associated with increased body mass index (0.062 CI 0.037, 0.086 kg/m(2); p=8.1×10(-7)) but lower waist-to-hip ratio adjusted for body mass index, a marker of abdominal fat distribution. Furthermore, p.A1369S was associated with a reduced risk of coronary heart disease (OR 0.98 CI 0.96, 0.99; p=5.9×10(-4)). These results suggest that, despite a known association with increased weight, long-term sulfonylurea therapy may reduce the risk of coronary heart disease.

PMID: 28411266 [PubMed - as supplied by publisher]

Identification of C21orf59 and ATG2A as novel determinants of renal function-related traits in Japanese by exome-wide association studies.

Oncotarget. 2017 Mar 30;:

Authors: Yamada Y, Sakuma J, Takeuchi I, Yasukochi Y, Kato K, Oguri M, Fujimaki T, Horibe H, Muramatsu M, Sawabe M, Fujiwara Y, Taniguchi Y, Obuchi S, Kawai H, Shinkai S, Mori S, Arai T, Tanaka M

Abstract
We have performed exome-wide association studies to identify genetic variants that influence renal function-related traits or confer susceptibility to chronic kidney disease or hyperuricemia in Japanese. Exome-wide association studies for estimated glomerular filtration rate and the serum concentration of creatinine were performed with 12,565 individuals, that for the serum concentration of uric acid with 9934 individuals, and those for chronic kidney disease or hyperuricemia with 5161 individuals (3270 cases, 1891 controls) or 11,686 individuals (2045 cases, 9641 controls), respectively. The relation of genotypes of single nucleotide polymorphisms to estimated glomerular filtration rate or the serum concentrations of creatinine or uric acid was examined by linear regression analysis, and that of allele frequencies of single nucleotide polymorphisms to chronic kidney disease or hyperuricemia was examined with Fisher's exact test. The exome-wide association studies revealed that 25, seven, and six single nucleotide polymorphisms were significantly (P <1.21 × 10-6) associated with estimated glomerular filtration rate or the serum concentrations of creatinine or uric acid, respectively, and that 49 and 35 polymorphisms were significantly associated with chronic kidney disease or hyperuricemia, respectively. Subsequent multivariable logistic regression analysis with adjustment for covariates revealed that four and three single nucleotide polymorphisms were related (P < 0.05) to chronic kidney disease or hyperuricemia, respectively. Among polymorphisms identified in the present study, rs76974938 [C/T (D67N)] of C21orf59 and rs188780113 [G/A (R478C)] of ATG2A may be novel determinants of estimated glomerular filtration rate and chronic kidney disease or of the serum concentration of uric acid, respectively.

PMID: 28410202 [PubMed - as supplied by publisher]

Genetic Effects on the Correlation Structure of CVD Risk Factors: Exome-Wide Data From a Ghanaian Population.

Glob Heart. 2017 Apr 10;:

Authors: Kodaman N, Sobota RS, Asselbergs FW, Oetjens MT, Moore JH, Brown NJ, Aldrich MC, Williams SM

Abstract
Plasma concentration of plasminogen activator inhibitor-1 (PAI-1) is highly correlated with several cardiovascular disease (CVD) risk factors. It also plays a direct role in CVD, including myocardial infarction and stroke, by impeding the dissolution of thrombi in the blood. Insofar as PAI-1 links CVD's risk factors to its endpoints, genetic variants modulating the relationship between PAI-1 and risk factors may be of particular clinical and biological interest. The high heritability of PAI-1, which has not been explained by genetic association studies, may also, in large part, be due to this relationship with CVD risk factors. Using exome-wide data from 1,032 Ghanaian study participants, we tested for heterogeneity of correlation by genotype between PAI-1 and 4 CVD risk factors (body mass index, triglycerides, mean arterial pressure, and fasting glucose) under the hypothesis that loci involved in the relationship between PAI-1 and other risk factors will also modify their correlational structure. We found more significant heterogeneities of correlation by genotype than we found marginal effects, with no evidence of type I inflation. The most significant result among all univariate and multivariate tests performed in this study was the heterogeneity of correlation between PAI-1 and mean arterial pressure at rs10738554, near SLC24A2, a gene previously associated with high blood pressure in African Americans.

PMID: 28408189 [PubMed - as supplied by publisher]

Deleterious Protein-altering Mutations in the SCN10A Voltage-gated Sodium Channel Gene are Associated with Prolonged QT.

Clin Genet. 2017 Apr 13;:

Authors: Abou Ziki MD, Seidelmann SB, Smith E, Atteya G, Jiang Y, Fernandes RG, Marieb MA, Akar JG, Mani A

Abstract
Long QT syndrome (LQT) is a pro-arrhythmogenic condition with life threatening complications. Fifteen genes have been associated with congenital LQT however, the genetic causes remain unknown in more than 20% of cases. Eighteen patients with history of palpitations, presyncope, syncope and prolonged QT were referred to the Yale Cardiovascular Genetics Program. All subjects underwent whole exome sequencing (WES) followed by confirmatory Sanger sequencing. Mutation burden analysis was carried out using WES data from sixteen subjects with no identifiable cause of LQT. Deleterious and novel SCN10A mutations were identified in three of the sixteen patients (19%) with idiopathic LQT. These included two frameshifts and one missense variants (p.G810fs, p.R1259Q, and p.P1877fs). Further analysis identified two damaging SCN10A mutations with allele frequencies of ~0.2% (p.R14L, p.R1268Q) in two independent cases. None of the SCN10A mutation carriers had mutations in known arrhythmia genes. Damaging SCN10A mutations (p.R209H, p.R485C) were also identified in the two subjects on QT prolonging medications. Our findings implicate SCN10A in LQT. The presence of frameshift mutations suggests loss of function as the underlying disease mechanism. The common association with AF suggests a unique mechanism of disease for this LQT gene.

PMID: 28407228 [PubMed - as supplied by publisher]

Tumor Immune Microenvironment and Nivolumab Efficacy in EGFR Mutation-Positive Non-Small Cell Lung Cancer Based on T790M Status after Disease Progression During EGFR-TKI Treatment.

Ann Oncol. 2017 Apr 12;:

Authors: Haratani K, Hayashi H, Tanaka T, Kaneda H, Togashi Y, Sakai K, Hayashi K, Tomida S, Chiba Y, Yonesaka K, Nonagase Y, Takahama T, Tanizaki J, Tanaka K, Yoshida T, Tanimura K, Takeda M, Yoshioka H, Ishida T, Mitsudomi T, Nishio K, Nakagawa K

Abstract
Background.: The efficacy of programmed death-1 (PD-1) blockade in epidermal growth factor receptor gene ( EGFR ) mutation-positive non-small cell lung cancer (NSCLC) patients with different mechanisms of acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) is unknown. We retrospectively evaluated nivolumab efficacy and immune-related factors in such patients according to their status for the T790M resistance mutation of EGFR .
Patients and Methods.: We identified 25 patients with EGFR mutation-positive NSCLC who were treated with nivolumab after disease progression during EGFR-TKI treatment (cohort A). Programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocyte (TIL) density in tumor specimens obtained after acquisition of EGFR-TKI resistance were determined by immunohistochemistry. Whole-exome sequencing of tumor DNA was performed to identify gene alterations. The relation of T790M status to PD-L1 expression or TIL density was also examined in an independent cohort of 60 patients (cohort B).
Results.: In cohort A, median progression-free survival (PFS) was 2.1 and 1.3 months for T790M-negative and T790M-positive patients, respectively ( P = 0.099; hazard ratio [HR] of 0.48 with a 95% confidence interval [CI] of 0.20-1.24). Median PFS was 2.1 and 1.3 months for patients with a PD-L1 expression level of ≥ 1% or < 1%, respectively ( P = 0.084; HR of 0.37, 95% CI of 0.10-1.21). PFS tended to increase as the PD-L1 expression level increased with cutoff values of ≥ 10% and ≥50%. The proportion of tumors with a PD-L1 level of ≥ 10% or ≥ 50% was higher among T790M-negative patients than among T790M-positive patients of both cohorts A and B. Nivolumab responders had a significantly higher CD8 + TIL density and nonsynonymous mutation burden.
Conclusion.: T790M-negative patients with EGFR mutation-positive NSCLC are more likely to benefit from nivolumab after EGFR-TKI treatment, possibly as a result of a higher PD-L1 expression level, than are T790M-positive patients.

PMID: 28407039 [PubMed - as supplied by publisher]

Germline whole exome sequencing and large-scale replication identifies FANCM as a likely high grade serous ovarian cancer susceptibility gene.

Oncotarget. 2017 Mar 03;:

Authors: Dicks E, Song H, Ramus SJ, Van Oudenhove E, Tyrer JP, Intermaggio MP, Kar S, Harrington P, Bowtell DD, Study Group A, Cicek MS, Cunningham JM, Fridley BL, Alsop J, Jimenez-Linan M, Piskorz A, Goranova T, Kent E, Siddiqui N, Paul J, Crawford R, Poblete S, Lele S, Sucheston-Campbell L, Moysich KB, Sieh W, McGuire V, Lester J, Odunsi K, Whittemore AS, Bogdanova N, Dürst M, Hillemanns P, Karlan BY, Gentry-Maharaj A, Menon U, Tischkowitz M, Levine D, Brenton JD, Dörk T, Goode EL, Gayther SA, Pharoah PD

Abstract
We analyzed whole exome sequencing data in germline DNA from 412 high grade serous ovarian cancer (HGSOC) cases from The Cancer Genome Atlas Project and identified 5,517 genes harboring a predicted deleterious germline coding mutation in at least one HGSOC case. Gene-set enrichment analysis showed enrichment for genes involved in DNA repair (p = 1.8x10-3). Twelve DNA repair genes - APEX1, APLF, ATX, EME1, FANCL, FANCM, MAD2L2, PARP2, PARP3, POLN, RAD54L and SMUG1 - were prioritized for targeted sequencing in up to 3,107 HGSOC cases, 1,491 cases of other epithelial ovarian cancer (EOC) subtypes and 3,368 unaffected controls of European origin. We estimated mutation prevalence for each gene and tested for associations with disease risk. Mutations were identified in both cases and controls in all genes except MAD2L2, where we found no evidence of mutations in controls. In FANCM we observed a higher mutation frequency in HGSOC cases compared to controls (29/3,107 cases, 0.96 percent; 13/3,368 controls, 0.38 percent; P=0.008) with little evidence for association with other subtypes (6/1,491, 0.40 percent; P=0.82). The relative risk of HGSOC associated with deleterious FANCM mutations was estimated to be 2.5 (95% CI 1.3 - 5.0; P=0.006). In summary, whole exome sequencing of EOC cases with large-scale replication in case-control studies has identified FANCM as a likely novel susceptibility gene for HGSOC, with mutations associated with a moderate increase in risk. These data may have clinical implications for risk prediction and prevention approaches for high-grade serous ovarian cancer in the future and a significant impact on reducing disease mortality.

PMID: 28404948 [PubMed - as supplied by publisher]