Browsing by Subject "Mutation"

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  • Drug-Induced Liver Injury Network; Int DILI Consortium iDILIC; Cirulli, Elizabeth T.; Nicoletti, Paola; Laitinen, Tarja (2019)
    BACKGROUND & AIMS: We performed genetic analyses of a multiethnic cohort of patients with idiosyncratic drug-induced liver injury (DILI) to identify variants associated with susceptibility. METHODS: We performed a genome-wide association study of 2048 individuals with DILI (cases) and 12,429 individuals without (controls). Our analysis included subjects of European (1806 cases and 10,397 controls), African American (133 cases and 1,314 controls), and Hispanic (109 cases and 718 controls) ancestry. We analyzed DNA from 113 Icelandic cases and 239,304 controls to validate our findings. RESULTS: We associated idiosyncratic DILI with rs2476601, a nonsynonymous polymorphism that encodes a substitution of tryptophan with arginine in the protein tyrosine phosphatase, nonreceptor type 22 gene (PTPN22) (odds ratio [OR] 1.44; 95% confidence interval [CI] 1.28-1.62; P = 1.2 x 10(-9) and replicated the finding in the validation set (OR 1.48; 95% CI 1.09-1.99; P =.01). The minor allele frequency showed the same effect size (OR > 1) among ethnic groups. The strongest association was with amoxicillin and clavulanate-associated DILI in persons of European ancestry (OR 1.62; 95% CI 1.32-1.98; P = 4.0 x 10(-6); allele frequency = 13.3%), but the polymorphism was associated with DILI of other causes (OR 1.37; 95% CI 1.21-1.56; P = 1.5 x 10(-6); allele frequency = 11.5%). Among amoxicillin-and clavulanate-associated cases of European ancestry, rs2476601 doubled the risk for DILI among those with the HLA risk alleles A* 02: 01 and DRB1* 15: 01. CONCLUSIONS: In a genome-wide association study, we identified rs2476601 in PTPN22 as a non-HLA variant that associates with risk of liver injury caused by multiple drugs and validated our finding in a separate cohort. This variant has been associated with increased risk of autoimmune diseases, providing support for the concept that alterations in immune regulation contribute to idiosyncratic DILI.
  • Esterhuizen, Karien; Lindeque, J. Zander; Mason, Shayne; van der Westhuizen, Francois H.; Suomalainen, Anu; Hakonen, Anna H.; Carroll, Christopher J.; Rodenburg, Richard J.; de Laat, Paul B.; Janssen, Mirian C. H.; Smeitink, Jan A. M.; Louw, Roan (2019)
    We used a comprehensive metabolomics approach to study the altered urinary metabolome of two mitochondrial myopathy, encephalopathy lactic acidosis and stroke like episodes (MELAS) cohorts carrying the m.3243A > G mutation. The first cohort were used in an exploratory phase, identifying 36 metabolites that were significantly perturbed by the disease. During the second phase, the 36 selected metabolites were able to separate a validation cohort of MELAS patients completely from their respective control group, suggesting usefulness of these 36 markers as a diagnostic set. Many of the 36 perturbed metabolites could be linked to an altered redox state, fatty acid catabolism and one-carbon metabolism. However, our evidence indicates that, of all the metabolic perturbations caused by MELAS, stalled fatty acid oxidation prevailed as being particularly disturbed. The strength of our study was the utilization of five different analytical platforms to generate the robust metabolomics data reported here. We show that urine may be a useful source for disease-specific metabolomics data, linking, amongst others, altered one-carbon metabolism to MELAS. The results reported here are important in our understanding of MELAS and might lead to better treatment options for the disease.
  • Ylikallio, Emil; Rahikkala, Elisa; Keski-Filppula, Riikka; Auranen, Mari; Tyynismaa, Henna (2017)
  • Sagath, L.; Lehtokari, V.-L.; Välipakka, S.; Udd, B.; Wallgren-Pettersson, C.; Pelin, K.; Kiiski, K. (2018)
    Background: Our previous array, the Comparative Genomic Hybridisation design (CGH-array) for nemaline myopathy (NM), named the NM-CGH array, revealed pathogenic copy number variation (CNV) in the genes for nebulin (NEB) and tropomyosin 3 (TPM3), as well as recurrent CNVs in the segmental duplication (SD), i.e. triplicate, region of NEB (TRI, exons 82-89, 90-97, 98-105). In the light of this knowledge, we have designed and validated an extended CGH array, which includes a selection of 187 genes known to cause neuromuscular disorders (NMDs). Objective: Our aim was to develop a reliable method for CNV detection in genes related to neuromuscular disorders for routine mutation detection and analysis, as a much-needed complement to sequencing methods. Methods: We have developed a novel custom-made 4×180 k CGH array for the diagnostics of NMDs. It includes the same tiled ultra-high density coverage of the 12 known or putative NM genes as our 8×60 k NM-CGH-array but also comprises a selection of 175 additional genes associated with NMDs, including titin (TTN), at a high to very high coverage. The genes were divided into three coverage groups according to known and potential pathogenicity in neuromuscular disorders. Results: The array detected known and putative CNVs in all three gene coverage groups, including the repetitive regions of NEB and TTN. Conclusions: The targeted neuromuscular disorder 4×180 k array-CGH (NMD-CGH-array v1.0) design allows CNV detection for a broader spectrum of neuromuscular disorders at a high resolution. © 2018 - IOS Press and the authors. All rights reserved.
  • Pasanen, Leo; Meriranta, Leo; Leppä, Sirpa (2017)
  • Qadri, Sami; Anttonen, Olli; Viikilä, Juho; Seppälä, Eija H; Myllykangas, Samuel; Alastalo, Tero-Pekka; Holmström, Miia; Heliö, Tiina; Koskenvuo, Juha W (BioMed Central, 2017)
    Abstract Background Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disease, involving changes in ventricular myocardial tissue and leading to fatal arrhythmias. Mutations in desmosomal genes are thought to be the main cause of ARVC. However, the exact molecular genetic etiology of the disease still remains largely inconclusive, and this along with large variabilities in clinical manifestations complicate clinical diagnostics. Case presentation We report two families (n = 20) in which a desmoglein-2 (DSG2) missense variant c.1003A > G, p.(Thr335Ala) was discovered in the index patients using next-generation sequencing panels. The presence of this variant in probands’ siblings and children was studied by Sanger sequencing. Five homozygotes and nine heterozygotes were found with the mutation. Participants were evaluated clinically where possible, and available medical records were obtained. All patients homozygous for the variant fulfilled the current diagnostic criteria for ARVC, whereas none of the heterozygous subjects had symptoms suggestive of ARVC or other cardiomyopathies. Conclusions The homozygous DSG2 variant c.1003A > G co-segregated with ARVC, indicating autosomal recessive inheritance and complete penetrance. More research is needed to establish a detailed understanding of the relevance of rare variants in ARVC associated genes, which is essential for informative genetic counseling and rational family member testing.
  • Qadri, Sami; Anttonen, Olli; Viikila, Juho; Seppälä, Eija H.; Myllykangas, Samuel; Alastalo, Tero-Pekka; Holmström, Miia; Helio, Tiina; Koskenvuo, Juha W. (2017)
    Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disease, involving changes in ventricular myocardial tissue and leading to fatal arrhythmias. Mutations in desmosomal genes are thought to be the main cause of ARVC. However, the exact molecular genetic etiology of the disease still remains largely inconclusive, and this along with large variabilities in clinical manifestations complicate clinical diagnostics. Case presentation: We report two families (n = 20) in which a desmoglein-2 (DSG2) missense variant c. 1003A > G, p.(Thr335Ala) was discovered in the index patients using next-generation sequencing panels. The presence of this variant in probands' siblings and children was studied by Sanger sequencing. Five homozygotes and nine heterozygotes were found with the mutation. Participants were evaluated clinically where possible, and available medical records were obtained. All patients homozygous for the variant fulfilled the current diagnostic criteria for ARVC, whereas none of the heterozygous subjects had symptoms suggestive of ARVC or other cardiomyopathies. Conclusions: The homozygous DSG2 variant c. 1003A > G co-segregated with ARVC, indicating autosomal recessive inheritance and complete penetrance. More research is needed to establish a detailed understanding of the relevance of rare variants in ARVC associated genes, which is essential for informative genetic counseling and rational family member testing.
  • Cai, Shuang; Gao, Mingshi; Xi, Jianying; Liu, Zhuo; Yue, Dongyue; Wu, Hui; Bi, Haixia; Li, Jing; Liang, Zonghui; Zhao, Chongbo; Udd, Bjarne; Luo, Sushan; Lu, Jiahong (2019)
    Recessive mutations in anoctamin-5 (ANO5) are causative for limb-girdle muscular dystrophy (LGMD) 2L and non-dysferlin Miyoshi-like distal myopathy (MMD3). ANDS mutations are highly prevalent in European countries; however it is not common in patients of Asian origin, and there is no data regarding the Chinese population. We retrospectively reviewed the clinical manifestations and gene mutations of Chinese patients with anoctaminopathy. A total of five ANDS mutations including four novel mutations and one reported mutation were found in four patients from three families. No hotspot mutation was found. Three patients presented with presymptomatic hyperCKemia and one patient had limb muscle weakness. Muscle imaging of lower limbs showed preferential adductor magnus and medial gastrocnemius involvement. No hotspot mutation has been identified in Chinese patients to date. (C) 2019 Elsevier B.V. All rights reserved.
  • Mäki-Nevala, Satu; Valo, Satu; Ristimaki, Ari; Sarhadi, Virinder; Knuutila, Sakari; Nyström, Minna; Renkonen-Sinisalo, Laura; Lepistö, Anna; Mecklin, Jukka-Pekka; Peltomäki, Päivi (2019)
    Background: DNA mismatch repair (MMR) defects are a major factor in colorectal tumorigenesis in Lynch syndrome (LS) and 15% of sporadic cases. Some adenomas from carriers of inherited MMR gene mutations have intact MMR protein expression implying other mechanisms accelerating tumorigenesis. We determined roles of DNA methylation changes and somatic mutations in cancer-associated genes as tumorigenic events in LS-associated colorectal adenomas with intact MMR. Methods: We investigated 122 archival colorectal specimens of normal mucosae, adenomas and carcinomas from 57 LS patients. MMR-deficient (MMR-D, n 49) and MMR-proficient (MMR-P, n 18) adenomas were of particular interest and were interrogated by methylation-specific multiplex ligation-dependent probe amplification and Ion Torrent sequencing. Findings: Promoter methylation of CpG island methylator phenotype (CIMP)-associated marker genes and selected colorectal cancer (CRC)-associated tumor suppressor genes (TSGs) increased and LINE-1 methylation decreased from normal mucosa to MMR-P adenomas to MMR-D adenomas. Methylation differences were statistically significant when either adenoma group was compared with normal mucosa, but not between MMR-P and MMR-D adenomas. Significantly increased methylation was found in multiple CIMP marker genes (1612, NEUROGI,CRABP1, and CDKN2A) and TSGs (SERPI and SFRP2) in MMR-P adenomas already. Furthermore, certain CRC-associated somatic mutations, such as KRAS, were prevalent in MMR-P adenomas. Interpretation: We conclude that DNA methylation changes and somatic mutations of cancer-associated genes might serve as an alternative pathway accelerating LS-associated tumorigenesis in the presence of proficient MMR. Fund: Jane and Aatos Erkko Foundation, Academy of Finland, Cancer Foundation Finland, Sigrid juselius Foundation, and HiL1FE. (C) 2019 Published by Elsevier B.V.
  • Maki-Nevala, Satu; Sarhadi, Virinder Kaur; Knuuttila, Aija; Scheinin, Ilari; Ellonen, Pekka; Lagstrom, Sonja; Ronty, Mikko; Kettunen, Eeva; Husgafvel-Pursiainen, Kirsti; Wolff, Henrik; Knuutila, Sakari (2016)
    Background Asbestos is a carcinogen linked to malignant mesothelioma (MM) and lung cancer. Some gene aberrations related to asbestos exposure are recognized, but many associated mutations remain obscure. We performed exome sequencing to determine the association of previously known mutations (driver gene mutations) with asbestos and to identify novel mutations related to asbestos exposure in lung adenocarcinoma (LAC) and MM. MethodsExome sequencing was performed on DNA from 47 tumor tissues of MM (21) and LAC (26) patients, 27 of whom had been asbestos-exposed (18 MM, 9 LAC). In addition, 9 normal lung/blood samples of LAC were sequenced. Novel mutations identified from exome data were validated by amplicon-based deep sequencing. Driver gene mutations in BRAF, EGFR, ERBB2, HRAS, KRAS, MET, NRAS, PIK3CA, STK11, and ephrin receptor genes (EPHA1-8, 10 and EPHB1-4, 6) were studied for both LAC and MM, and in BAP1, CUL1, CDKN2A, and NF2 for MM. ResultsIn asbestos-exposed MM patients, previously non-described NF2 frameshift mutation (one) and BAP1 mutations (four) were detected. Exome data mining revealed some genes potentially associated with asbestos exposure, such as MRPL1 and SDK1. BAP1 and COPG1 mutations were seen exclusively in MM. Pathogenic KRAS mutations were common in LAC patients (42 %), both in non-exposed (n = 5) and exposed patients (n = 6). Pathogenic BRAF mutations were found in two LACs. ConclusionBAP1 mutations occurred in asbestos-exposed MM. MRPL1, SDK1, SEMA5B, and INPP4A could possibly serve as candidate genes for alterations associated with asbestos exposure. KRAS mutations in LAC were not associated with asbestos exposure.
  • Heliö, Krista; Kangas-Kontio, Tiia; Weckström, Sini; Vanninen, Sari U M; Aalto-Setälä, Katriina; Alastalo, Tero-Pekka; Myllykangas, Samuel; Heliö, Tiina M; Koskenvuo, Juha W (BioMed Central, 2020)
    Abstract Background Dilated cardiomyopathy (DCM) is a condition characterized by dilatation and systolic dysfunction of the left ventricle in the absence of severe coronary artery disease or abnormal loading conditions. Mutations in the titin (TTN) and lamin A/C (LMNA) genes are the two most significant contributors in familial DCM. Previously mutations in the desmoplakin (DSP) gene have been associated with arrhythmogenic right ventricular cardiomyopathy (ARVC) and more recently with DCM. Methods We describe the cardiac phenotype related to a DSP mutation which was identified in ten unrelated Finnish index patients using next-generation sequencing. Sanger sequencing was used to verify the presence of this DSP variant in the probands’ relatives. Medical records were obtained, and clinical evaluation was performed. Results We identified DSP c.6310delA, p.(Thr2104Glnfs*12) variant in 17 individuals of which 11 (65%) fulfilled the DCM diagnostic criteria. This pathogenic variant presented with left ventricular dilatation, dysfunction and major ventricular arrhythmias. Two patients showed late gadolinium enhancement (LGE) and myocardial edema on cardiac magnetic resonance imaging (MRI) that may suggest inflammatory process at myocardium. Conclusions The patients diagnosed with DCM showed an arrhythmogenic phenotype as well as SCD at young age supporting the recently proposed concept of arrhythmogenic cardiomyopathy. This study also demonstrates relatively low penetrance of truncating DSP variant in the probands’ family members by the age of 40. Further studies are needed to elucidate the possible relations between myocardial inflammation and pathogenic DSP variants.
  • Heliö, Krista; Kangas-Kontio, Tiia; Weckström, Sini; Vanninen, Sari U. M.; Aalto-Setälä, Katriina; Alastalo, Tero-Pekka; Myllykangas, Samuel; Heliö, Tiina M.; Koskenvuo, Juha W. (2020)
    Background Dilated cardiomyopathy (DCM) is a condition characterized by dilatation and systolic dysfunction of the left ventricle in the absence of severe coronary artery disease or abnormal loading conditions. Mutations in the titin (TTN) and lamin A/C (LMNA) genes are the two most significant contributors in familial DCM. Previously mutations in the desmoplakin (DSP) gene have been associated with arrhythmogenic right ventricular cardiomyopathy (ARVC) and more recently with DCM. Methods We describe the cardiac phenotype related to a DSP mutation which was identified in ten unrelated Finnish index patients using next-generation sequencing. Sanger sequencing was used to verify the presence of this DSP variant in the probands' relatives. Medical records were obtained, and clinical evaluation was performed. Results We identified DSP c.6310delA, p.(Thr2104Glnfs*12) variant in 17 individuals of which 11 (65%) fulfilled the DCM diagnostic criteria. This pathogenic variant presented with left ventricular dilatation, dysfunction and major ventricular arrhythmias. Two patients showed late gadolinium enhancement (LGE) and myocardial edema on cardiac magnetic resonance imaging (MRI) that may suggest inflammatory process at myocardium. Conclusions The patients diagnosed with DCM showed an arrhythmogenic phenotype as well as SCD at young age supporting the recently proposed concept of arrhythmogenic cardiomyopathy. This study also demonstrates relatively low penetrance of truncating DSP variant in the probands' family members by the age of 40. Further studies are needed to elucidate the possible relations between myocardial inflammation and pathogenic DSP variants.
  • EORP Cardiomyopathy Registry Inves; Heliö, Tiina; Elliott, Perry; Koskenvuo, Juha W.; Charron, Philippe (2020)
    Aims Cardiomyopathies comprise a heterogeneous group of diseases, often of genetic origin. We assessed the current practice of genetic counselling and testing in the prospective European Society of Cardiology EURObservational Research Programme Cardiomyopathy Registry. Methods and results A total of 3208 adult patients from 69 centres in 18 countries were enrolled. Genetic counselling was performed in 60.8% of all patients [75.4% in hypertrophic cardiomyopathy (HCM), 39.2% in dilated cardiomyopathy (DCM), 70.8% in arrhythmogenic right ventricular cardiomyopathy (ARVC), and 49.2% in restrictive cardiomyopathy (RCM),P <0.001]. Comparing European geographical areas, genetic counselling was performed from 42.4% to 83.3% (P <0.001). It was provided by a cardiologist (85.3%), geneticist (15.1%), genetic counsellor (11.3%), or a nurse (7.5%) (P <0.001). Genetic testing was performed in 37.3% of all patients (48.8% in HCM, 18.6% in DCM, 55.6% in ARVC, and 43.6% in RCM,P <0.001). Index patients with genetic testing were younger at diagnosis and had more familial disease, family history of sudden cardiac death, or implanted cardioverter defibrillators but less co-morbidities than those not tested (P <0.001 for each comparison). At least one disease-causing variant was found in 41.7% of index patients with genetic testing (43.3% in HCM, 33.3% in DCM, 51.4% in ARVC, and 42.9% in RCM,P = 0.13). Conclusions This is the first detailed report on the real-life practice of genetic counselling and testing in cardiomyopathies in Europe. Genetic counselling and testing were performed in a substantial proportion of patients but less often than recommended by European guidelines and much less in DCM than in HCM and ARVC, despite evidence for genetic background.
  • Kuchenbaecker, K.B.; McGuffog, L.; Barrowdale, D.; Lee, Andrew; Soucy, P.; Dennis, J.; Domchek, S.M.; Robson, M.; Spurdle, A.B.; Ramus, S.J.; Mavaddat, N.; Terry, M.B.; Neuhausen, S.L.; Schmutzler, R.K.; Simard, J.; Pharoah, P.D.P.; Offit, K.; Couch, F.J.; Chenevix-Trench, G.; Easton, D.F.; Antoniou, A.C.; Healey, S.; Lush, M.; Hamann, U.; Southey, M.; John, E.M.; Chung, W.K.; Daly, M. B.; Buys, S.S.; Goldgar, D.E.; Dorfling, C.M.; van Rensburg, E.J.; Ding, Y.C.; Ejlertsen, B.; Gerdes, A.-M.; Hansen, T.V.O.; Slager, S.; Hallberg, E.; Benitez, J.; Osorio, A.; Cohen, N.; Lawler, W.; Weitzel, J.N.; Peterlongo, P.; Pensotti, V.; Dolcetti, R.; Barile, M.; Aittomäki, K.; Nevanlinna, H.; Rantala, J. (2017)
    Background: Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates. Methods: We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]-positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS. Results: The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P = 8.2 × 10-53). InBRCA2 carriers, the strongest association with BC risk was seen for the overall BCPRS (HR = 1.22, 95% CI = 1.17 to 1.28, P = 7.2 × 10-20). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS. Conclusions: BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management. © The Author 2017.
  • Koskenvuo, Laura; Pöyhönen, Minna; Lepistö, Anna (2020)
  • FinHCM Study Grp; Jääskeläinen, Pertti; Vangipurapu, Jagadish; Raivo, Joose; Kuulasmaa, Teemu; Helio, Tiina; Aalto-Setala, Katriina; Kaartinen, Maija; Ilveskoski, Erkki; Vanninen, Sari; Hämäläinen, Liisa; Melin, John; Kokkonen, Jorma; Nieminen, Markku S.; Laakso, Markku; Kuusisto, Johanna; Kervinen, Helena; Mustonen, Juha; Juvonen, Jukka; Niemi, Mari; Uusimaa, Paavo; Junttila, Juhani; Kotila, Matti; Pietila, Mikko; Jyrkila, Heini; Mahonen, Ilkka; Vartia, Paula (2019)
    Aims Nationwide large-scale genetic and outcome studies in cohorts with hypertrophic cardiomyopathy (HCM) have not been previously published. Methods and results We sequenced 59 cardiomyopathy-associated genes in 382 unrelated Finnish patients with HCM and found 24 pathogenic or likely pathogenic mutations in six genes in 38.2% of patients. Most mutations were located in sarcomere genes (MYBPC3, MYH7, TPM1, and MYL2). Previously reported mutations by our study group (MYBPC3-Gln1061Ter, MYH7-Arg1053Gln, and TPM1-Asp175Asn) and a fourth major mutation MYH7-Val606Met accounted for 28.0% of cases. Mutations in GLA and PRKAG2 were found in three patients. Furthermore, we found 49 variants of unknown significance in 31 genes in 20.4% of cases. During a 6.7 +/- 4.2 year follow-up, annual all-cause mortality in 482 index patients and their relatives with HCM was higher than that in the matched Finnish population (1.70 vs. 0.87%; P <0.001). Sudden cardiac deaths were rare (n = 8). Systolic heart failure (hazard ratio 17.256, 95% confidence interval 3.266-91.170, P = 0.001) and maximal left ventricular wall thickness (hazard ratio 1.223, 95% confidence interval 1.098-1.363, P <0.001) were independent predictors of HCM-related mortality and life-threatening cardiac events. The patients with a pathogenic or likely pathogenic mutation underwent an implantable cardioverter defibrillator implantation more often than patients without a pathogenic or likely pathogenic mutation (12.9 vs. 3.5%, P <0.001), but there was no difference in all-cause or HCM-related mortality between the two groups. Mortality due to HCM during 10 year follow-up among the 5.2 million population of Finland was studied from death certificates of the National Registry, showing 269 HCM-related deaths, of which 32% were sudden. Conclusions We identified pathogenic and likely pathogenic mutations in 38% of Finnish patients with HCM. Four major sarcomere mutations accounted for 28% of HCM cases, whereas HCM-related mutations in non-sarcomeric genes were rare. Mortality in patients with HCM exceeded that of the general population. Finally, among 5.2 million Finns, there were at least 27 HCM-related deaths annually.
  • Maki-Nevala, Satu; Sarhadi, Virinder Kaur; Ronty, Mikko; Kettunen, Eeva; Husgafvel-Pursiainen, Kirsti; Wolff, Henrik; Knuuttila, Aija; Knuutila, Sakari (2016)
    Objectives: Non-small cell lung cancer (NSCLC) is a common cancer with a poor prognosis. The aim of this study was to screen Finnish NSCLC tumor samples for common cancer-related mutations by targeted next generation sequencing and to determine their concurrences and associations with clinical features. Materials and methods: Sequencing libraries were prepared from DNA isolated from formalin-fixed, paraffin-embedded tumor material of 425 patients using the AmpliSeq Colon and Lung panel covering mutational hot spot regions of 22 cancer genes. Sequencing was performed with the Ion Torrent Personal Genome Machine (PGM). Results: Data analysis of the hot spot mutations revealed mutations in 77% of the patients, with 7% having 3 or more mutations reported in the Catalogue of Somatic Mutations in Cancer (COSMIC) database. Two of the most frequently mutated genes were TP53 (46%) and KRAS (25%). KRAS codon 12 mutations were the most recurrently occurring mutations. EGFR mutations were significantly associated with adenocarcinoma, female gender and never/light-smoking history; CTNNB1 mutations with light ex-smokers, PlIC3CA and TP53 mutations with squamous cell carcinoma, and KRAS with adenocarcinoma. TP53 mutations were most prevalent in current smokers and ERBB2, ERBB4, PIK3CA, NRAS, NOTCH1, FBWX7, PTEN and STK11 mutations occurred exclusively in a group of ever-smokers, however the association was not statistically significant. No mutation was found that associated with asbestos exposure. Conclusion: Finnish NSCLC patients have a similar mutation profile as other Western patients, however with a higher frequency of BRAF mutations but a lower frequency of STK11 and ERBB2 mutations. Moreover, TP53 mutations occurred frequently with other gene mutations, most commonly with KRAS, MET, EGFR and PIK3CA mutations. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
  • Lukaszewicz, German; Iturburu, Fernando G.; Garanzini, Daniela S.; Menone, Mirta L.; Pflugmacher, Stephan (2019)
    Imidacloprid (IMI) is a neonicotinoid insecticide widely used in agricultural activities all around the world. This compound is transported from croplands to surrounding freshwater ecosystems, producing adverse effects on non-target organisms. Because of the relevance of aquatic macrophytes in the above-mentioned environments and the lack of studies of potential effects of IMI on them, this work aimed to assess the mitotic process and potential genotoxicity in the aquatic macrophyte Bidens laevis L. Although the analysis of the Mitotic Index (MI) showed that IMI was not cytotoxic, the Cell Proliferation Kinetics (CPK) frequencies evidenced modifications in the kinetics of the mitotic process. Indeed, the anaphases ratio decreased at 10 and 100 mu g/L IMI, while at 1000 mu g/L an increase of prophases ratio and a decrease of metaphases ratio were observed. Regarding genotoxicity, IMI produced an increase of the abnormal metaphases frequency from 10 mu g/L to 1000 mu g/L as well as an increase in clastogenic anaphases-telophases frequency at 100 and 1000 mu g/L. In addition, aneugenic anaphases-telophases and C-mitosis frequencies also increased at 1000 mu g/L, confirming the effects on the mitotic spindle. Considering the genotoxic effects on B. laevis through two different mechanisms (aneugenic and clastogenic) and the wide spread use of IMI in agriculture, these mechanisms of toxicity on macrophytes should be considered among other recognized effects of this insecticide on aquatic biota.
  • Lal, Dennis; Steinbruecker, Sandra; Schubert, Julian; Sander, Thomas; Becker, Felicitas; Weber, Yvonne; Lerche, Holger; Thiele, Holger; Krause, Roland; Lehesjoki, Anna-Elina; Nuernberg, Peter; Palotie, Aarno; Neubauer, Bernd A.; Muhle, Hiltrud; Stephani, Ulrich; Helbig, Ingo; Becker, Albert J.; Schoch, Susanne; Hansen, Joerg; Dorn, Thomas; Hohl, Christin; Luescher, Nicole; von Spiczak, Sarah; Lemke, Johannes R.; Epicure Consortium; EuroEPINOMICS-CoGIE Consortium (2015)
    Recently, mutations and deletions in the GRIN2A gene have been identified to predispose to benign and severe idiopathic focal epilepsies (IFE), revealing a higher incidence of GRIN2A alterations among the more severe phenotypes. This study aimed to explore the phenotypic boundaries of GRIN2A mutations by investigating patients with the two most common epilepsy syndromes: (i) idiopathic generalized epilepsy (IGE) and (ii) temporal lobe epilepsy (TLE). Whole exome sequencing data of 238 patients with IGE as well as Sanger sequencing of 84 patients with TLE were evaluated for GRIN2A sequence alterations. Two additional independent cohorts comprising 1469 IGE and 330 TLE patients were screened for structural deletions (>40 kb) involving GRIN2A. Apart from a presumably benign, non-segregating variant in a patient with juvenile absence epilepsy, neither mutations nor deletions were detected in either cohort. These findings suggest that mutations in GRIN2A preferentially are involved in genetic variance of pediatric IFE and do not contribute significantly to either adult focal epilepsies as TLE or generalized epilepsies. (C) 2015 Elsevier B.V. All rights reserved.