Suscettibilità genetica al cancro al polmone: analisi di polimorfismi in geni candidati

Il cancro al polmone è una neoplasia maligna toracica molto comune. È noto che solo il 15% dei fumatori longevi sviluppano cancro al polmone entro l’età di 70 anni. Una possibile spiegazione è che fattori genetici possano essere alla base delle variazioni della dose interna di cancerogeni attivi. Questo potrebbe giustificare differenze nel rischio per individui che fumano un numero simile di sigarette. Un’altra spiegazione è che esista una variabilita’ genetica dei sistemi di riparazione del DNA, che porti a differenze nelle capacità di rimuovere le lesioni causate dai cancerogeni attivati, sottoponendo individui con simili dosi interne a differenti livelli di rischio per lo sviluppo della patologia. Molti geni coinvolti nel metabolismo degli xenobiotici, nei sistemi di riparazione e nei checkpoint del ciclo cellulare sono polimorfici. A tale scopo è stato messo punto un micro-array per la genotipizzazione di polimorfismi a singolo nucleotide (SNPs) potenzialmente implicati nella suscettibilita’ genetica al tumore polmonare. La metodica utilizzata, definita APEX (arrayed primer extention), ha permesso una genotipizzazione parallela di 233 SNPs in 99 geni del metabolismo di xenobiotici, ciclo cellulare e riparazione del DNA. E’ stato effettuato uno studio di associazione caso-controllo su 300 soggetti affetti da tumore polmonare, provenienti dall’Est Europeo di eta’ inferiore a 50 anni e 317 controlli. Le frequenze genotipiche relative a ciascun polimorfismo sono state analizzate mediante regressione logistica per identificare quali varianti sono associate con il rischio di contrarre la malattia. Sono stati identificati alcuni fattori genetici di suscettibilità al cancro al polmone coinvolti nel metabolismo degli xenobiotici quali: CYP1B1 Val432Leu (OR=1.74; 1.05-3.3), CYP1A2 A-164C (OR=1.61; 1.12-2,32), CYP2A6 T-48G (OR=0.56; 0,34-0,94), EPHX1 His139Arg (OR= 0,66; 0,45-0,97), GSTA2 S111T (OR=1,78; 1,05-3,02), GSTM3 Val224Ile (OR=0.55; 0.31-0.99). Inoltre, i polimorfismi in ATM IVS48+238 (OR= 0.61; 0.41-0.90) e MLH1 Ile219Val (OR: 0.51; 0.27-0.99) sono associati con un diminuito rischio, mentre polimorfismi in XRCC1 Arg194Trp (OR:0.64; 0.39-0.94), MSH6 D180D (OR= 1.99; 1.03-3.85), LIGI –7 C>T (OR= 1.49; 1.03-2.17); IVS9-21 (OR= 1.65; 1.06-2.57) e XRCC4 Asn298Ser (OR= 1.62; 1.04-2.53), sono associati con un aumento del rischio della neoplasia

Homo sapiens natriuretic peptide precursor type C (NPPC) mRNA,partial cds and 3\u27 UTR.

LOCUS HQ419060 318 bp mRNA linear PRI 24-NOV-2010 DEFINITION Homo sapiens natriuretic peptide precursor type C (NPPC) mRNA, partial cds and 3\u27 UTR. ACCESSION HQ419060 VERSION HQ419060.1 GI:312261407 KEYWORDS . SOURCE Homo sapiens (human) ORGANISM Homo sapiens Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo. REFERENCE 1 (bases 1 to 318) AUTHORS Landi,S., Melaiu,O., Cabiati,M., Landi,D., Caselli,C., Prescimone,T., Giannessi,D., Gemignani,F. and Del Ry,S. TITLE Direct Submission JOURNAL Submitted (20-OCT-2010) Laboratory of Cardiovascular Biochemistry, Institute of Clinical Physiology, Via Moruzzi 1, Pisa, PI 56100, Italy FEATURES Location/Qualifiers source 1..318 /organism="Homo sapiens" /mol_type="mRNA" /db_xref="taxon:9606" /cell_line="SKNBE" /PCR_primers="fwd_seq: gtcagaagaagggcgacaag, rev_seq: gcgtttaaacgcgcacgcgt" gene <1..318 /gene="NPPC" CDS <1..188 /gene="NPPC" /codon_start=3 /product="natriuretic peptide precursor type C" /protein_id="ADQ54381.1" /db_xref="GI:312261408" /translation="GDRSRLLRDLRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKG CFGLKLDRIGSMSGLGC" 3\u27UTR 189..318 /gene="NPPC" ORIGIN 1 agggcgaccg gtcgcgactg ctccgggacc tgcgcgtgga caccaagtcg cgggcagcgt 61 gggctcgcct tctgcaagag caccccaacg cgcgcaaata caaaggagcc aacaagaagg 121 gcttgtccaa gggctgcttc ggcctcaagc tggaccgaat cggctccatg agcggcctgg 181 gatgttagtg cggcgccccc tggcggcggg agaagaatga ttctgacact tggggaccag 241 ccttcagtag ctacccttgg aatgcctttg ctctcttctc tcctgtctaa acaacaaaga 301 gacggagtct gaggcct

The genetic susceptibility in the development of malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is a cancer of the pleural cavity whose main risk factor is exposure to asbestos. However, it has been shown that only a minority of exposed people develops MPM. In fact, the incidence among professionally exposed workers was shown to vary between 0.5% and 18.0%. Various hints suggested that other important cofactors could play a role, in particular the genetic susceptibility. Impressive is the case of Cappadocians families exposed to erionite and affected by an "epidemic" of MPM with about half of the inhabitants dying for the disease. However, no results for a "Cappadocia" gene of susceptibility to MPM have been obtained yet and more studies are needed. Among asbestos-exposed workers, several studies reported familial cases of MPM, suggesting that heredity could be important in the tumor development. However, large studies on familial clusters showed only weak increased risks that could be attributable also to indirect exposures in a contaminated household. Moreover, the risk of developing MPM is increased of a limited extent among people exposed to asbestos with a positive history of familial cancers. A particular is represented by carriers of germline mutations within BAP1 gene. In families and in animal models, mutations within BAP1 are strongly predisposing to develop MPM. However, also other types of cancer (such as uveal melanoma) are present, thus BAP1 mutations are considered as responsible for a hereditary form of a multi-cancer syndrome. In any case, among sporadic MPM, the prevalence of germline BAP1 mutations is negligible. Finally, genetic studies highlighted the presence of low-risk susceptibility alleles, such as those within XRCC3, NAT2 or GSTM1. Two different genome-wide association studies could not find positive associations reaching the genome-wide statistical significance threshold, however, both were concordant in showing a weak signal within the SDK1 gene region. Overall, it could be concluded that, as for other types of sporadic cancers, the susceptibility to develop MPM following asbestos exposure is modulated moderately by the individual genetic background. Further studies on larger series could help in a better characterization of more genes predisposing to MPM, being this tumor a rare disease

More targets, more pathways and more clues for mutant p53.

Mutations in the transcription factor p53 are among the most common genetic alterations in human cancer, and missense p53 mutations in cancer cells can lead to aggressive phenotypes. So far, only few studies investigated transcriptional reprogramming under mutant p53 expression as a means to identify deregulated targets and pathways. A review of the literature was carried out focusing on mutant p53-dependent transcriptome changes with the aims of (i) verifying whether different p53 mutations can be equivalent for their effects, or whether there is a mutation-specific transcriptional reprogramming of target genes, (ii) understanding what is the main mechanism at the basis of upregulation or downregulation of gene expression under the p53 mutant background, (iii) identifying novel candidate target genes of WT and/or mutant p53 and (iv) defining cellular pathways affected by the mutant p53-dependent gene expression reprogramming. Nearly 600 genes were consistently found upregulated or downregulated upon ectopic expression of mutant p53, regardless of the specific p53 mutation studied. Promoter analysis and the use of ChIP-seq data indicate that, for most genes, the expression changes could be ascribed to a loss both of WT p53 transcriptional activation and repressor functions. Pathway analysis indicated changes in the metabolism/catabolism of amino acids such as aspartate, glutamate, arginine and proline. Novel p53 candidate target genes were also identified, including ARID3B, ARNT2, CLMN, FADS1, FTH1, KPNA2, LPHN2, PARD6B, PDE4C, PIAS2, PRPF40A, PYGL and RHOBTB2, involved in the metabolism, xenobiotic responses and cell differentiation

Genetics and molecular epidemiology of multiple myeloma : the rationale for the IMMEnSE consortium (review)

There is strong evidence suggesting the presence of a genetic component in the aetiology of multiple myeloma (MM). However no genetic risk factors have been unequivocally established so far. To further our understanding of the genetic determinants of MM risk, a promising strategy is to collect a large set of patients in a consortium, as successfully done for other cancers. In this article, we review the main findings in the genetic susceptibility and pharmacogenetics of MM and present the strategy of the IMMEnSE (International Multiple Myeloma rESEarch) consortium in contributing to determine the role of genetic variation in pharmacogenetics and in MM risk.We acknowledge support by the recruiting hospitals and physicians of the study regions as well as their collaborating nurses and technicians. Collection of blood samples from Spain, patients from Granada area and DNA extraction was partially supported by grants P08-CVI-4116 from Consejeria de Salud de la Junta de Andalucia (Sevilla, Spain) and PI081051 from Fondo de Investigaciones Sanitarias (Madrid, Spain). Collection of blood samples from Polish patients and controls from Lodz area and DNA extraction was supported by a grant from Polish Ministry of Science and Higher Education (No. N N402178334)

Integrative Organelle-Based Functional Proteomics: In Silico Prediction of Impaired Functional Annotations in SACS KO Cell Model

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an inherited neurodegenerative disease characterized by early-onset spasticity in the lower limbs, axonal-demyelinating sensorimotor peripheral neuropathy, and cerebellar ataxia. Our understanding of ARSACS (genetic basis, protein function, and disease mechanisms) remains partial. The integrative use of organelle-based quantitative proteomics and whole-genome analysis proposed in the present study allowed identifying the affected disease-specific pathways, upstream regulators, and biological functions related to ARSACS, which exemplify a rationale for the development of improved early diagnostic strategies and alternative treatment options in this rare condition that currently lacks a cure. Our integrated results strengthen the evidence for disease-specific defects related to bioenergetics and protein quality control systems and reinforce the role of dysregulated cytoskeletal organization in the pathogenesis of ARSACS.Peer reviewe

Integrative Organelle-Based Functional Proteomics: In Silico Prediction of Impaired Functional Annotations in SACS KO Cell Model

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an inherited neurodegenerative disease characterized by early-onset spasticity in the lower limbs, axonal-demyelinating sensorimotor peripheral neuropathy, and cerebellar ataxia. Our understanding of ARSACS (genetic basis, protein function, and disease mechanisms) remains partial. The integrative use of organelle-based quantitative proteomics and whole-genome analysis proposed in the present study allowed identifying the affected disease-specific pathways, upstream regulators, and biological functions related to ARSACS, which exemplify a rationale for the development of improved early diagnostic strategies and alternative treatment options in this rare condition that currently lacks a cure. Our integrated results strengthen the evidence for disease-specific defects related to bioenergetics and protein quality control systems and reinforce the role of dysregulated cytoskeletal organization in the pathogenesis of ARSACS

Integrative Organelle-Based Functional Proteomics: In Silico Prediction of Impaired Functional Annotations in SACS KO Cell Model

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an inherited neurodegenerative disease characterized by early-onset spasticity in the lower limbs, axonal-demyelinating sensorimotor peripheral neuropathy, and cerebellar ataxia. Our understanding of ARSACS (genetic basis, protein function, and disease mechanisms) remains partial. The integrative use of organelle-based quantitative proteomics and whole-genome analysis proposed in the present study allowed identifying the affected disease-specific pathways, upstream regulators, and biological functions related to ARSACS, which exemplify a rationale for the development of improved early diagnostic strategies and alternative treatment options in this rare condition that currently lacks a cure. Our integrated results strengthen the evidence for disease-specific defects related to bioenergetics and protein quality control systems and reinforce the role of dysregulated cytoskeletal organization in the pathogenesis of ARSACS

Type 2 diabetes-related variants influence the risk of developing multiple myeloma: results from the IMMEnSE consortium

Type 2 diabetes (T2D) has been suggested to be a risk factor for multiple myeloma (MM), but the relationship between the two traits is still not well understood. The aims of this study were to evaluate whether 58 genome-wide-association-studies (GWAS)-identified common variants for T2D influence the risk of developing MM and to determine whether predictive models built with these variants might help to predict the disease risk. We conducted a case–control study including 1420 MM patients and 1858 controls ascertained through the International Multiple Myeloma (IMMEnSE) consortium. Subjects carrying the KCNQ1rs2237892T allele or the CDKN2A-2Brs2383208G/G, IGF1rs35767T/T and MADDrs7944584T/T genotypes had a significantly increased risk of MM (odds ratio (OR)=1.32–2.13) whereas those carrying the KCNJ11rs5215C, KCNJ11rs5219T and THADArs7578597C alleles or the FTOrs8050136A/A and LTArs1041981C/C genotypes showed a significantly decreased risk of developing the disease (OR=0.76–0.85). Interestingly, a prediction model including those T2D-related variants associated with the risk of MM showed a significantly improved discriminatory ability to predict the disease when compared to a model without genetic information (area under the curve (AUC)=0.645 vs AUC=0.629; P=4.05×10-06). A gender-stratified analysis also revealed a significant gender effect modification for ADAM30rs2641348 and NOTCH2rs10923931 variants (Pinteraction=0.001 and 0.0004, respectively). Men carrying the ADAM30rs2641348C and NOTCH2rs10923931T alleles had a significantly decreased risk of MM whereas an opposite but not significant effect was observed in women (ORM=0.71 and ORM=0.66 vs ORW=1.22 and ORW=1.15, respectively). These results suggest that TD2-related variants may influence the risk of developing MM and their genotyping might help to improve MM risk prediction models.This work was supported by grants from the FIBAO foundation (Granada, Spain) and the CRIS foundation against cancer, from the Cancer Network of Excellence (RD12/10 Red de Cancer) and from the Instituto de Salud Carlos III (Madrid, Spain; PI12/02688)

A common variant within the HNF1B gene is associated with overall survival of multiple myeloma patients: results from the IMMEnSE consortium and meta-analysis

Diabetogenic single nucleotide polymorphisms (SNPs) have recently been associated with multiple myeloma (MM) risk but their impact on overall survival (OS) of MM patients has not been analysed yet. In order to investigate the impact of 58 GWAS-identified variants for type 2 diabetes (T2D) on OS of patients with MM, we analysed genotyping data of 936 MM patients collected by the International Multiple Myeloma rESEarch (IMMENSE) consortium and an independent set of 700 MM patients recruited by the University Clinic of Heidelberg. A meta-analysis of the cox regression results of the two sets showed that rs7501939 located in the HNF1B gene negatively impacted OS (HRRec = 1.44, 95% CI = 1.18-1.76, P = 0.0001). The meta-analysis also showed a noteworthy gender-specific association of the SLC30A8(rs13266634) SNP with OS. The presence of each additional copy of the minor allele at rs13266634 was associated with poor OS in men whereas no association was seen in women (HRMen-Add = 1.32, 95% CI 1.13-1.54, P = 0.0003). In conclusion, these data suggest that the HNF1B(rs7501939) SNP confers poor OS in patients with MM and that a SNP in SLC30A8 affect OS in men.This work was supported by grants from the FIBAO foundation (Granada, Spain), from the CRIS foundation against cancer, from the Cancer Network of Excellence (RD12/10 Red de Cáncer), from the Instituto de Salud Carlos III (Madrid, Spain; PI12/02688) and from the Dietmar Hopp Foundation and the German Ministry of Education and Science (BMBF: CLIOMMICS [01ZX1309]).FIBAO foundation (Granada, Spain), from the CRIS foundation against cancer, from the Cancer Network of Excellence (RD12/10 Red de Cáncer), from the Instituto de Salud Carlos III (Madrid, Spain; PI12/02688) and from the Dietmar Hopp Foundation and the German Ministry of Education and Science (BMBF: CLIOMMICS [01ZX1309]info:eu-repo/semantics/publishedVersio