Genetic Interaction Analysis Among Oncogenesis-Related Genes Revealed Novel Genes and Networks in Lung Cancer Development

The development of cancer is driven by the accumulation of many oncogenesis-related genetic alterationsand tumorigenesis is triggered by complex networks of involved genes rather than independent actions. To explore the epistasis existing among oncogenesis-related genes in lung cancer development, we conducted pairwise genetic interaction analyses among 35,031 SNPs from 2027 oncogenesis-related genes. The genotypes from three independent genome-wide association studies including a total of 24,037 lung cancer patients and 20,401 healthy controls with Caucasian ancestry were analyzed in the study. Using a two-stage study design including discovery and replication studies, and stringent Bonferroni correction for multiple statistical analysis, we identified significant genetic interactions between SNPs in RGL1:RAD51B (OR=0.44, p value=3.27x10-11 in overall lung cancer and OR=0.41, p value=9.71x10-11 in non-small cell lung cancer), SYNE1:RNF43 (OR=0.73, p value=1.01x10-12 in adenocarcinoma) and FHIT:TSPAN8 (OR=1.82, p value=7.62x10-11 in squamous cell carcinoma) in our analysis. None of these genes have been identified from previous main effect association studies in lung cancer. Further eQTL gene expression analysis in lung tissues provided information supporting the functional role of the identified epistasis in lung tumorigenesis. Gene set enrichment analysis revealed potential pathways and gene networks underlying molecular mechanisms in overall lung cancer as well as histology subtypes development. Our results provide evidence that genetic interactions between oncogenesis-related genes play an important role in lung tumorigenesis and epistasis analysis, combined with functional annotation, provides a valuable tool for uncovering functional novel susceptibility genes that contribute to lung cancer development by interacting with other modifier genes

Protein-altering germline mutations implicate novel genes related to lung cancer development

Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio = 8.82, P = 1.18 × 10−15) and replication (adjusted OR = 2.93, P = 2.22 × 10−3) that is more pronounced in females (adjusted OR = 6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR = 2.61, P = 7.98 × 10−22) and replication datasets (adjusted OR = 1.55, P = 0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930. Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk

Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes.

Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genome-wide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, with four loci associated with lung cancer overall and six loci associated with lung adenocarcinoma. Gene expression quantitative trait locus (eQTL) analysis in 1,425 normal lung tissue samples highlights RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer

Multi-Omics Analysis Reveals a HIF Network and Hub Gene EPAS1 Associated with Lung Adenocarcinoma

Recent technological advancements have permitted high-throughput measurement of the human genome, epigenome, metabolome, transcriptome, and proteome at the population level. We hypothesized that subsets of genes identified from omic studies might have closely related biological functions and thus might interact directly at the network level. Therefore, we conducted an integrative analysis of multi-omic datasets of non-small cell lung cancer (NSCLC) to search for association patterns beyond the genome and transcriptome. A large, complex, and robust gene network containing well-known lung cancer-related genes, including EGFR and TERT, was identified from combined gene lists for lung adenocarcinoma. Members of the hypoxia-inducible factor (HIF) gene family were at the center of this network. Subsequent sequencing of network hub genes within a subset of samples from the Transdisciplinary Research in Cancer of the Lung-International Lung Cancer Consortium (TRICL-ILCCO) consortium revealed a SNP (rs12614710) in EPAS1 associated with NSCLC that reached genome-wide significance (OR = 1.50; 95% CI: 1.31–1.72; p = 7.75 × 10−9). Using imputed data, we found that this SNP remained significant in the entire TRICL-ILCCO consortium (p = .03). Additional functional studies are warranted to better understand interrelationships among genetic polymorphisms, DNA methylation status, and EPAS1 expression

Sähköinen kirjaaminen heräämön hoitotyössä

Opinnäytetyön tarkoituksena on tehdä Nokian terveyskeskuksen leikkausosaston heräämön sairaanhoitajille kirjaamisrunko sähköiseen potilastietojärjestelmään, jonka avulla osaston sairaanhoitajat jäsentävät hoitotyön kirjaamistaan heräämöhoidon aikana. Opinnäytetyön tehtävänä on selvittää, mitkä asiat ovat olennaisia sairaanhoitajan kirjata potilaan päiväkirurgisen heräämöhoidon aikana hyvän hoidon jatkuvuuden kannalta. Tavoitteena on saada yhtenäistettyä kirjaamiskäytäntöjä kyseisessä yksikössä, sekä auttaa sairaanhoitajia kirjaamaan tehokkaasti, mutta laadukkaasti. Työ toteutettiin kirjallisuuden pohjalta, sekä työelämäyhteyttä haastatellen teemahaastattelulla ja heidän aikai-simpia materiaalejaan hyväksikäyttäen. Työssä käsitellään postoperatiivista hoitoa, päiväkirurgisen potilaan heräämöhoidon erityispiirteitä, kirjaamista sekä potilasturvallisuutta. Potilaan välitön leikkauksen jälkeinen hoito tapahtuu erityisvalvonnassa eli heräämössä, jossa päiväkirurgiset potilaat toipuvat anestesiasta ja lopulta kuntoutuvat kotikuntoisiksi. Tällöin hoitosuhde on lyhyt, ja sairaanhoitajan vuorovaikutustaidot sekä kirjaamisen merkitys korostuvat potilasturvallisuuden kannalta. Hyvä tiedonkulku on tärkeä perustekijä turvallisessa ja laadukkaassa hoidossa. Omaan tuotokselliseen lopputulokseemme valitsimme kirjauksen pääkohdiksi postoperatiivisen hoidon seitsemän tärkeintä osa-aluetta, joita sairaanhoitaja heräämöhoitotyössä seuraa. Liitimme mukaan myös päiväkirurgisen potilaan kotiutumiskriteerit, joita sairaanhoitaja voi kirjaamisen yhteydessä hyödyntää tarkistuslistan tyyppisesti.The purpose of this thesis was to create a template for electronic documentation of nursing work for nurses in the postoperative care unit in Nokia. The aim was to standardize documentation of nursing work in the unit. Information for this thesis was gathered from recent literature and by interviewing the nurses of the postoperative care unit. The theoretical section discusses postoperative nursing, day surgery, electronic nursing documentation and patient safety. Immediate postoperative care takes place in a postop-erative care unit, from where outpatients are discharged. The care outpatients receive is very short-term, thus nursing documentation and the communication skills of the nurse are very important. The seven most important points of postoperative nursing were chosen as the main titles in the template, under which the nurse can document all the important information of the care the patient has received. The discharge criteria of an outpatient was also included in the template, enabling it to simultaneously act as a checking list for the nurse responsible of the discharging

Genetic interaction analysis among oncogenesis-related genes revealed novel genes and networks in lung cancer development

The development of cancer is driven by the accumulation of many oncogenesis-related genetic alterationsand tumorigenesis is triggered by complex networks of involved genes rather than independent actions. To explore the epistasis existing among oncogenesis-related genes in lung cancer development, we conducted pairwise genetic interaction analyses among 35,031 SNPs from 2027 oncogenesis-related genes. The genotypes from three independent genome-wide association studies including a total of 24,037 lung cancer patients and 20,401 healthy controls with Caucasian ancestry were analyzed in the study. Using a two-stage study design including discovery and replication studies, and stringent Bonferroni correction for multiple statistical analysis, we identified significant genetic interactions between SNPs in RGL1:RAD51B (OR=0.44, p value=3.27x10-11 in overall lung cancer and OR=0.41, p value=9.71x10-11 in non-small cell lung cancer), SYNE1:RNF43 (OR=0.73, p value=1.01x10-12 in adenocarcinoma) and FHIT:TSPAN8 (OR=1.82, p value=7.62x10-11 in squamous cell carcinoma) in our analysis. None of these genes have been identified from previous main effect association studies in lung cancer. Further eQTL gene expression analysis in lung tissues provided information supporting the functional role of the identified epistasis in lung tumorigenesis. Gene set enrichment analysis revealed potential pathways and gene networks underlying molecular mechanisms in overall lung cancer as well as histology subtypes development. Our results provide evidence that genetic interactions between oncogenesis-related genes play an important role in lung tumorigenesis and epistasis analysis, combined with functional annotation, provides a valuable tool for uncovering functional novel susceptibility genes that contribute to lung cancer development by interacting with other modifier genes