Protein-altering germline mutations implicate novel genes related to lung cancer development.
Ontology highlight
ABSTRACT:
SUBMITTER: Ji X
PROVIDER: S-EPMC7214407 | biostudies-literature | 2020 May
REPOSITORIES: biostudies-literature
Publications
Protein-altering germline mutations implicate novel genes related to lung cancer development.
Ji Xuemei X Mukherjee Semanti S Landi Maria Teresa MT Bosse Yohan Y Joubert Philippe P Zhu Dakai D Gorlov Ivan I Xiao Xiangjun X Han Younghun Y Gorlova Olga O Hung Rayjean J RJ Brhane Yonathan Y Carreras-Torres Robert R Christiani David C DC Caporaso Neil N Johansson Mattias M Liu Geoffrey G Bojesen Stig E SE Le Marchand Loic L Albanes Demetrios D Bickeböller Heike H Aldrich Melinda C MC Bush William S WS Tardon Adonina A Rennert Gad G Chen Chu C Byun Jinyoung J Dragnev Konstantin H KH Field John K JK Kiemeney Lambertus Fa LF Lazarus Philip P Zienolddiny Shan S Lam Stephen S Schabath Matthew B MB Andrew Angeline S AS Bertazzi Pier A PA Pesatori Angela C AC Diao Nancy N Su Li L Song Lei L Zhang Ruyang R Leighl Natasha N Johansen Jakob S JS Mellemgaard Anders A Saliba Walid W Haiman Christopher C Wilkens Lynne L Fernandez-Somoano Ana A Fernandez-Tardon Guillermo G Heijden Erik H F M van der EHFMV Kim Jin Hee JH Davies Michael P A MPA Marcus Michael W MW Brunnström Hans H Manjer Jonas J Melander Olle O Muller David C DC Overvad Kim K Trichopoulou Antonia A Tumino Rosario R Goodman Gary E GE Cox Angela A Taylor Fiona F Woll Penella P Wichmann Erich E Muley Thomas T Risch Angela A Rosenberger Albert A Grankvist Kjell K Johansson Mikael M Shepherd Frances F Tsao Ming-Sound MS Arnold Susanne M SM Haura Eric B EB Bolca Ciprian C Holcatova Ivana I Janout Vladimir V Kontic Milica M Lissowska Jolanta J Mukeria Anush A Ognjanovic Simona S Orlowski Tadeusz M TM Scelo Ghislaine G Swiatkowska Beata B Zaridze David D Bakke Per P Skaug Vidar V Butler Lesley M LM Offit Kenneth K Srinivasan Preethi P Bandlamudi Chaitanya C Hellmann Matthew D MD Solit David B DB Robson Mark E ME Rudin Charles M CM Stadler Zsofia K ZK Taylor Barry S BS Berger Michael F MF Houlston Richard R McLaughlin John J Stevens Victoria V Nickle David C DC Obeidat Ma'en M Timens Wim W Artigas María Soler MS Shete Sanjay S Brenner Hermann H Chanock Stephen S Brennan Paul P McKay James D JD Amos Christopher I CI
Nature communications 20200511 1
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<sup>-15</sup>) and replication (adjusted OR = 2.93, P = 2.22 × 10<sup>-3</sup>) that is more pronounced in females (adjusted OR = 6.81 and 3.19 an ...[more]
Similar Datasets
Project description:The omnigenic model of complex disease stipulates that the majority of the heritability will be explained by the effects of common variation on genes in the periphery of core disease pathways. Rare variant associations, expected to explain far less of the heritability, may be enriched in core disease genes and thus will be instrumental in the understanding of complex disease pathogenesis and their potential therapeutic targets. Here, using complementary whole-exome sequencing, high-density imputation, and in vitro cellular assays, we identify candidate core genes in the pathogenesis of systemic lupus erythematosus (SLE). Using extreme-phenotype sampling, we sequenced the exomes of 30 SLE parent-affected-offspring trios and identified 14 genes with missense de novo mutations (DNM), none of which are within the >80 SLE susceptibility loci implicated through genome-wide association studies. In a follow-up cohort of 10, 995 individuals of matched European ancestry, we imputed genotype data to the density of the combined UK10K-1000 genomes Phase III reference panel across the 14 candidate genes. Gene-level analyses indicate three functional candidates: DNMT3A, PRKCD, and C1QTNF4. We identify a burden of rare variants across PRKCD associated with SLE risk (P = 0.0028), and across DNMT3A associated with two severe disease prognosis sub-phenotypes (P = 0.0005 and P = 0.0033). We further characterise the TNF-dependent functions of the third candidate gene C1QTNF4 on NF-κB activation and apoptosis, which are inhibited by the p.His198Gln DNM. Our results identify three novel genes in SLE susceptibility and support extreme-phenotype sampling and DNM gene discovery to aid the search for core disease genes implicated through rare variation.
| S-EPMC5886157 | biostudies-literature
Project description:Autism spectrum disorder (ASD) has a strong but complex genetic component. Here we report on the resequencing of 64 candidate neurodevelopmental disorder risk genes in 5,979 individuals: 3,486 probands and 2,493 unaffected siblings. We find a strong burden of de novo point mutations for these genes and specifically implicate nine genes. These include CHD2 and SYNGAP1, genes previously reported in related disorders, and novel genes TRIP12 and PAX5. We also show that mutation carriers generally have lower IQs and enrichment for seizures. These data begin to distinguish genetically distinct subtypes of autism important for aetiological classification and future therapeutics.
| S-EPMC4249945 | biostudies-literature
Project description:Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ?5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.
| S-EPMC6560635 | biostudies-literature
Project description:IntroductionAlthough lung cancer is generally thought to be environmentally provoked, anecdotal familial clustering has been reported, suggesting that there may be genetic susceptibility factors. We systematically tested whether germline mutations in eight candidate genes may be risk factors for lung adenocarcinoma.MethodsWe studied lung adenocarcinoma cases for which germline sequence data had been generated as part of The Cancer Genome Atlas project but had not been previously analyzed. We selected eight genes, ATM serine/threonine kinase gene (ATM), BRCA2, DNA repair associated gene (BRCA2), checkpoint kinase 2 gene (CHEK2), EGFR, parkin RBR E3 ubiquitin protein ligase gene (PARK2), telomerase reverse transcriptase gene (TERT), tumor protein p53 gene (TP53), and Yes associated protein 1 gene (YAP1), on the basis of prior anecdotal association with lung cancer or genome-wide association studies.ResultsAmong 555 lung adenocarcinoma cases, we detected 14 pathogenic mutations in five genes; they occurred at a frequency of 2.5% and represented an OR of 66 (95% confidence interval: 33-125, p < 0.0001 [chi-square test]). The mutations fell most commonly in ATM (50%), followed by TP53, BRCA2, EGFR, and PARK2. Most (86%) of these variants had been reported in other familial cancer syndromes. Another 12 cases (2%) carried ultrarare variants that were predicted to be deleterious by three protein prediction programs; these most frequently involved ATM and BRCA2.ConclusionsA subset of patients with lung adenocarcinoma, at least 2.5% to 4.5%, carry germline variants that have been linked to cancer risk in Mendelian syndromes. The genes fall most frequently in DNA repair pathways. Our data indicate that patients with lung adenocarcinoma, similar to other solid tumors, include a subset of patients with inherited susceptibility.
| S-EPMC5659909 | biostudies-literature
Project description:BackgroundEmerging evidence implicates the correlation of embryonic germline genes with the tumor progress and patient's outcome. However, the prognostic value of these genes in lung adenocarcinoma (LUAD) has not been fully studied. Here we systematically evaluated this issue, and constructed a novel signature and a nomogram associated with embryonic germline genes for predicting the outcomes of lung adenocarcinoma.MethodsThe LUAD cohorts retrieved from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database were used as training set and testing set, respectively. The embryonic germline genes were downloaded from the website https://venn.lodder.dev. Then, the differentially expressed embryonic germline genes (DEGGs) between the tumor and normal samples were identified by limma package. The functional enrichment and pathway analyses were also performed by clusterProfiler package. The prognostic model was constructed by the least absolute shrinkage and selection operator (LASSO)-Cox regression method. Survival and Receiver Operating Characteristic (ROC) analyses were performed to validate the model using training set and four testing GEO datasets. Finally, a prognostic nomogram based on the signature genes was constructed using multivariate regression method.ResultsAmong the identified 269 DEGGs, 249 were up-regulated and 20 were down-regulated. GO and KEGG analyses revealed that these DEGGs were mainly enriched in the process of cell proliferation and DNA damage repair. Then, 103 DEGGs with prognostic value were identified by univariate Cox regression and further filtered by LASSO method. The resulting sixteen DEGGs were included in step multivariate Cox regression and an eleven embryonic germline gene related signature (EGRS) was constructed. The model could robustly stratify the LUAD patients into high-risk and low-risk groups in both training and testing sets, and low-risk patients had much better outcomes. The multi-ROC analysis also showed that the EGRS model had the best predictive efficacy compared with other common clinicopathological factors. The EGRS model also showed robust predictive ability in four independent external datasets, and the area under curve (AUC) was 0.726 (GSE30219), 0.764 (GSE50081), 0.657 (GSE37745) and 0.668 (GSE72094). More importantly, the expression level of some genes in EGRS has a significant correlation with the progression of LUAD clinicopathology, suggesting these genes might play an important role in the progression of LUAD. Finally, based on EGRS genes, we built and calibrated a nomogram for conveniently evaluating patients' outcomes.
| S-EPMC8542372 | biostudies-literature
Project description:BackgroundGermline variations may contribute to lung cancer susceptibility besides environmental factors. The influence of germline mutations on lung cancer susceptibility and their correlation with somatic mutations has not been systematically investigated.MethodsIn this study, germline mutations from 1,026 non-small cell lung cancer (NSCLC) patients were analyzed with a 58-gene next-generation sequencing (NGS) panel containing known hereditary cancer-related genes, and were categorized based on American College of Medical Genetics and Genomics (ACMG) guidelines in pathogenicity, and the corresponding somatic mutations were analyzed using a 605-gene NGS panel containing known cancer-related genes.ResultsPlausible genetic susceptibility was found in 4.7% of lung cancer patients, in which 14 patients with pathogenic mutations (P group) and 34 patients with likely-pathogenic mutations (LP group) were identified. The ratio of the first degree relatives with lung cancer history of the P groups was significantly higher than the Non-P group (P=0.009). The ratio of lung cancer patients with history of other cancers was higher in P (P=0.0007) or LP (P=0.017) group than the Non-P group. Pathogenic mutations fell most commonly in BRCA2, followed by CHEK2 and ATM. Likely-pathogenic mutations fell most commonly in NTRK1 and EXT2, followed by BRIP1 and PALB2. These genes are involved in DNA repair, cell cycle regulation and tumor suppression. By comparing the germline mutation frequency from this study with that from the whole population or East Asian population (gnomAD database), we found that the overall odds ratio (OR) for P or LP group was 17.93 and 15.86, respectively, when compared with the whole population, and was 2.88 and 3.80, respectively, when compared with the East Asian population, suggesting the germline mutations of the P and LP groups were risk factors for lung cancer. Somatic mutation analysis revealed no significant difference in tumor mutation burden (TMB) among the groups, although a trend of lower TMB in the pathogenic group was found. The SNV/INDEL mutation frequency of TP53 in the P group was significantly lower than the other two groups, and the copy number variation (CNV) mutation frequency of PIK3CA and MET was significantly higher than the Non-P group. Pathway enrichment analysis found no significant difference in aberrant pathways among the three groups.ConclusionsA proportion of 4.7% of patients carrying germline variants may be potentially linked to increased susceptibility to lung cancer. Patients with pathogenic germline mutations exhibited stronger family history and higher lung cancer risk.
| S-EPMC7354149 | biostudies-literature
Project description:The Saccharomyces cerevisiae MOD5 gene encodes proteins that function in three subcellular locations: mitochondria, the cytoplasm, and nuclei (M. Boguta, L.A. Hunter, W.-C. Shen, E. C. Gillman, N. C. Martin, and A. K. Hopper, Mol. Cell. Biol. 14:2298-2306, 1994; E. C. Gillman, L. B. Slusher, N. C. Martin, and A. K. Hopper, Mol. Cell. Biol. 11:2382-2390, 1991). A mutant allele of MOD5 encoding a protein (Mod5p-I,KR6) located predominantly in mitochondria was constructed. Mutants defective in delivering Mod5p-I,KR6 to mitochondria were sought by selecting cells with increased cytosolic activity of this protein. Twenty-five mutants defining four complementation groups, mdp1, mdp2, mdp3, and mdp4, were found. They are unable to respire at 34 degrees C or to grow on glucose medium at 38 degrees C. Cell fractionation studies showed that mdp1, mdp2, and mdp3 mutants have an altered mitochondrial-cytoplasmic distribution of Mod5p. mdp2 can be suppressed by ACT1, the actin-encoding gene. The actin cytoskeleton organization is also aberrant in mdp2 cells. MDP2 is the same as VRP1 (S. F. H. Donnelly, M. J. Picklington, D. Pallotta, and E. Orr, Mol. Microbiol. 10:585-596, 1993). MDP3 is identical to PAN1, which encodes a protein that interacts with mRNA 3' ends and affects initiation of protein synthesis (A. B. Sachs and J. A. Deardoff, Cell 70:961-973, 1992). These results implicate the actin cytoskeleton and mRNA 3' ends and/or protein synthesis as being as important for protein distribution in S. cerevisiae as they are for distribution of cytosolic proteins in higher eukaryotes. This provides the potential to apply genetic and molecular approaches to study gene products and mechanisms involved in this type of protein distribution. The selection strategy also offers a new approach for identifying gene products involved in the distribution of proteins to their subscellular destinations.
| S-EPMC230943 | biostudies-other
Project description:The development of cancer is driven by the accumulation of many oncogenesis-related genetic alterations and 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.
| S-EPMC6442994 | biostudies-literature
Project description:This study aimed to assess the effects of hexavalent chromium on zebrafish (Danio rerio) embryo development. The zebrafish embryos were treated with solutions containing chromium at different concentrations (0.1, 1, 3.125, 6.25, 12.5, 50, and 100 µg/mL). The development of zebrafish embryos was estimated by the determination of survival rate, heart rate, and the measurement of larvae body length. Real time RT-PCR and Western blot were performed to assess the expression of apoptosis- and antioxidant-related genes. The results showed that the reduced survival rate of zebrafish embryos and larvae was associated with an increase in chromium concentration. The exposure of higher concentrations resulted in a decrease in body length of zebrafish larvae. In addition, a marked increase in heart rate was observed in the zebrafish larvae under chromium treatment, especially at high concentrations. The real-time RT-PCR analysis showed that the transcript expressions for cell-cycle-related genes (cdk4 and cdk6) and antioxidant-related genes (sod1 and sod2) were downregulated in the zebrafish embryos treated with chromium. Western blot analysis revealed the upregulation of Caspase 3 and Bax, while a downregulation was observed in Bcl2. These results indicated that hexavalent chromium induced changes in zebrafish embryo development by altering apoptosis- and antioxidant-related genes.
| S-EPMC10453199 | biostudies-literature
Project description:BackgroundGermline mutations of breast cancer susceptibility gene BRCA1 and BRCA2 (gBRCA1/2) are associated with elevated risk of breast cancer in young women in Asia. BRCA1 and BRCA2 proteins contribute to genomic stability through homologous recombination (HR)-mediated double-strand DNA break repair in cooperation with other HR-related proteins. In this study, we analyzed the targeted sequencing data of Korean breast cancer patients with gBRCA1/2 mutations to investigate the alterations in HR-related genes and their clinical implications.Materials and methodsData of the breast cancer patients with pathogenic gBRCA1/2 mutations and qualified targeted next-generation sequencing, SNUH FiRST cancer panel, were analyzed. Single nucleotide polymorphisms, small insertions, and deletions were analyzed with functional annotations using ANNOVAR. HR-related genes were defined as ABL1, ATM, ATR, BARD1, BRCA1, BRCA2, CDKN1A, CDKN2A, CHEK1, CHEK2, FANCA, FANCD2, FANCG, FANCI, FANCL, KDR, MUTYH, PALB2, POLE, POLQ, RAD50, RAD51, RAD51D, RAD54L, and TP53. Mismatch-repair genes were MLH1, MSH2, and MSH6. Clinical data were analyzed with cox proportional hazard models and survival analyses.ResultsFifty-five Korean breast cancer patients with known gBRCA1/2 mutations and qualified targeted NGS data were analyzed. Ethnically distinct mutations in gBRCA1/2 genes were noted, with higher frequencies of Val1833Ser (14.8%), Glu1210Arg (11.1%), and Tyr130Ter (11.1%) in gBRCA1 and Arg2494Ter (25.0%) and Lys467Ter (14.3%) in gBRCA2. Considering subtypes, gBRCA1 mutations were associated with triple-negative breast cancers (TNBC), while gBRCA2 mutations were more likely hormone receptor-positive breast cancers. At least one missense mutation of HR-related genes was observed in 44 cases (80.0%). The most frequently co-mutated gene was TP53 (38.1%). In patients with gBRCA1/2 mutations, however, genetic variations of TP53 occurred in locations different from the known hotspots of those with sporadic breast cancers. The patients with both gBRCA1/2 and TP53 mutations were more likely to have TNBC, high Ki-67 values, and increased genetic mutations, especially of HR-related genes. Survival benefit was observed in the TP53 mutants of patients with gBRCA2 mutations, compared to those with TP53 wild types.ConclusionOur study showed genetic heterogeneity of breast cancer patients with gBRCA1 and gBRCA2 mutations in the Korean populations. Further studies on precision medicine are needed for tailored treatments of patients with genetic diversity among different ethnic groups.
| S-EPMC9817339 | biostudies-literature