Publications by authors named "Antonella Galvan"

35 Publications

Identification of genetic polymorphisms modulating nausea and vomiting in two series of opioid-treated cancer patients.

Sci Rep 2020 01 17;10(1):542. Epub 2020 Jan 17.

Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.

Nausea and vomiting are often associated with opioid analgesia in cancer patients; however, only a subset of patients develop such side effects. Here, we tested the hypothesis that the occurrence of nausea and vomiting is modulated by the genetic background of the patients. Whole exome sequencing of DNA pools from patients with either low (n = 937) or high (n = 557) nausea and vomiting intensity, recruited in the European Pharmacogenetic Opioid Study, revealed a preliminary association of 53 polymorphisms. PCR-based genotyping of 45 of these polymorphisms in the individual patients of the same series confirmed the association for six SNPs in AIM1L, CLCC1, MUC16, PDE3A, POM121L2, and ZNF165 genes. Genotyping of the same 45 polymorphisms in 264 patients of the Italian CERP study, also treated with opioids for cancer pain, instead confirmed the association for two SNPs in ZNF568 and PDE3A genes. Only one SNP, rs12305038 in PDE3A, was confirmed in both series, although with opposite effects of the minor allele on the investigated phenotype. Overall, our findings suggest that genetic factors are indeed associated with nausea and vomiting in opioid-treated cancer patients, but the role of individual polymorphisms may be weak.
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http://dx.doi.org/10.1038/s41598-019-57358-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6969029PMC
January 2020

Pharmacogenetic study of seven polymorphisms in three nicotinic acetylcholine receptor subunits in smoking-cessation therapies.

Sci Rep 2017 12 1;7(1):16730. Epub 2017 Dec 1.

Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Smoking-cessation therapy reduces the risk of smoking-related diseases, but is successful only in a fraction of smokers. There is growing evidence that genetic variations in nicotinic acetylcholine receptor (nAChR) subunits influence the risk of nicotine dependence and the ability to quit smoking. To investigate the role of polymorphisms in nAChR genes on smoking quantity and the outcome of smoking-cessation therapies, we carried out an association study on 337 smokers who underwent pharmacotherapy with varenicline, bupropion, nicotine replacement therapy (NRT) alone, or NRT plus bupropion. Smoking habit and abstention were assessed from the number of cigarettes smoked per day (CPD) and the exhaled CO (eCO), at baseline and up to 12 months. We genotyped seven polymorphisms in genes encoding the nAChR subunits CHRNA4, CHRNA5, and CHRNB2. At baseline, both CPD and eCO were associated with polymorphisms in the CHRNA5 locus (rs503464, rs55853698, rs55781567 and rs16969968; P < 0.01). rs503464, a variant in the 5'-UTR of CHRNA5, was also associated with short-, mid- and long-term responses to therapy (P = 0.011, P = 0.0043, P = 0.020, respectively), although after correction for multiple testing only the association at the mid-term assessment remained significant (FDR = 0.03). These data support the role of individual genetic makeup in the ability to quit smoking.
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http://dx.doi.org/10.1038/s41598-017-16946-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5711795PMC
December 2017

Genetic susceptibility variants for lung cancer: replication study and assessment as expression quantitative trait loci.

Sci Rep 2017 02 9;7:42185. Epub 2017 Feb 9.

Department of Predictive and Preventive Medicine, Milan, Italy.

Many single nucleotide polymorphisms (SNPs) have been associated with lung cancer but lack confirmation and functional characterization. We retested the association of 56 candidate SNPs with lung adenocarcinoma risk and overall survival in a cohort of 823 Italian patients and 779 healthy controls, and assessed their function as expression quantitative trait loci (eQTLs). In the replication study, eight SNPs (rs401681, rs3019885, rs732765, rs2568494, rs16969968, rs6495309, rs11634351, and rs4105144) associated with lung adenocarcinoma risk and three (rs9557635, rs4105144, and rs735482) associated with survival. Five of these SNPs acted as cis-eQTLs, being associated with the transcription of IREB2 (rs2568494, rs16969968, rs11634351, rs6495309), PSMA4 (rs6495309) and ERCC1 (rs735482), out of 10,821 genes analyzed in lung. For these three genes, we obtained experimental evidence of differential allelic expression in lung tissue, pointing to the existence of in-cis genomic variants that regulate their transcription. These results suggest that these SNPs exert their effects on cancer risk/outcome through the modulation of mRNA levels of their target genes.
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http://dx.doi.org/10.1038/srep42185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5299838PMC
February 2017

Read-through transcripts in normal human lung parenchyma are down-regulated in lung adenocarcinoma.

Oncotarget 2016 May;7(19):27889-98

Department of Predictive and Prevention Medicine, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy.

Read-through transcripts result from the continuous transcription of adjacent, similarly oriented genes, with the splicing out of the intergenic region. They have been found in several neoplastic and normal tissues, but their pathophysiological significance is unclear. We used high-throughput sequencing of cDNA fragments (RNA-Seq) to identify read-through transcripts in the non-involved lung tissue of 64 surgically treated lung adenocarcinoma patients. A total of 52 distinct read-through species was identified, with 24 patients having at least one read-through event, up to a maximum of 17 such transcripts in one patient. Sanger sequencing validated 28 of these transcripts and identified an additional 15, for a total of 43 distinct read-through events involving 35 gene pairs. Expression levels of 10 validated read-through transcripts were measured by quantitative PCR in pairs of matched non-involved lung tissue and lung adenocarcinoma tissue from 45 patients. Higher expression levels were observed in normal lung tissue than in the tumor counterpart, with median relative quantification ratios between normal and tumor varying from 1.90 to 7.78; the difference was statistically significant (P < 0.001, Wilcoxon's signed-rank test for paired samples) for eight transcripts: ELAVL1-TIMM44, FAM162B-ZUFSP, IFNAR2-IL10RB, INMT-FAM188B, KIAA1841-C2orf74, NFATC3-PLA2G15, SIRPB1-SIRPD, and SHANK3-ACR. This report documents the presence of read-through transcripts in apparently normal lung tissue, with inter-individual differences in patterns and abundance. It also shows their down-regulation in tumors, suggesting that these chimeric transcripts may function as tumor suppressors in lung tissue.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5053695PMC
http://dx.doi.org/10.18632/oncotarget.8556DOI Listing
May 2016

Germline polymorphisms and survival of lung adenocarcinoma patients: a genome-wide study in two European patient series.

Int J Cancer 2015 Mar 19;136(5):E262-71. Epub 2014 Sep 19.

Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy.

In lung cancer, the survival of patients with the same clinical stage varies widely for unknown reasons. In this two-phase study, we examined the hypothesis that germline variations influence the survival of patients with lung adenocarcinoma. First, we analyzed existing genotype and clinical data from 289 UK-resident patients with lung adenocarcinoma, identifying 86 single nucleotide polymorphisms (SNPs) that associated with survival (p < 0.01). We then genotyped these candidate SNPs in a validation series of 748 patients from Italy that resulted genetically compatible with the UK series based on principal component analysis. In a Cox proportional hazard model adjusted for age, sex and clinical stage, four SNPs were confirmed on the basis of their having a hazard ratio (HR) indicating the same direction of effect in the two series and p < 0.05. The strongest association was provided by rs2107561, an intronic SNP of PTPRG, protein tyrosine phosphatase, receptor type, G; the C allele was associated with poorer survival in both patient series (pooled analysis loge HR = 0.31; 95% CI: 0.15-0.46, p = 8.5 × 10(-5) ). PTPRG mRNA levels in 43 samples of lung adenocarcinoma were 40% of those observed in noninvolved lung tissue from the same patients. PTPRG overexpression significantly inhibited the clonogenicity of A549 lung carcinoma cells and the anchorage-independent growth of the NCI-H460 large cell lung cancer line. These four germline variants represent promising candidates that, with further study, may help predict clinical outcome. In addition, the PTPRG locus may have a role in tumor progression.
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http://dx.doi.org/10.1002/ijc.29195DOI Listing
March 2015

Mouse pulmonary adenoma susceptibility 1 locus is an expression QTL modulating Kras-4A.

PLoS Genet 2014 Apr 17;10(4):e1004307. Epub 2014 Apr 17.

Department of Predictive and Preventive Medicine, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy.

Pulmonary adenoma susceptibility 1 (Pas1) is the major locus responsible for lung tumor susceptibility in mice; among the six genes mapping in this locus, Kras is considered the best candidate for Pas1 function although how it determines tumor susceptibility remains unknown. In an (A/J × C57BL/6)F4 intercross population treated with urethane to induce lung tumors, Pas1 not only modulated tumor susceptibility (LOD score = 48, 69% of phenotypic variance explained) but also acted, in lung tumor tissue, as an expression quantitative trait locus (QTL) for Kras-4A, one of two alternatively spliced Kras transcripts, but not Kras-4B. Additionally, Kras-4A showed differential allelic expression in lung tumor tissue of (A/J × C57BL/6)F4 heterozygous mice, with significantly higher expression from the A/J-derived allele; these results suggest that cis-acting elements control Kras-4A expression. In normal lung tissue from untreated mice of the same cross, Kras-4A levels were also highly linked to the Pas1 locus (LOD score = 23.2, 62% of phenotypic variance explained) and preferentially generated from the A/J-derived allele, indicating that Pas1 is an expression QTL in normal lung tissue as well. Overall, the present findings shed new light on the genetic mechanism by which Pas1 modulates the susceptibility to lung tumorigenesis, through the fine control of Kras isoform levels.
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http://dx.doi.org/10.1371/journal.pgen.1004307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3990522PMC
April 2014

Unique microRNA-profiles in EGFR-mutated lung adenocarcinomas.

Int J Cancer 2014 Oct 14;135(8):1812-21. Epub 2014 Mar 14.

Department of Genetics Institute for Cancer Research, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway; Department of Oncology, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway.

The findings of mutations and the development of targeted therapies have improved lung cancer management. Still, the prognosis remains poor, and we need to know more about the genetic and epigenetic alterations in lung cancer. MicroRNAs are involved in crucial biological processes like carcinogenesis by regulating gene expression at the post-transcriptional level. In this project, we have studied the microRNA expression of lung adenocarcinomas and corresponding normal lung tissue and correlated the expression with clinical data and EGFR- and KRAS-mutational status. Agilent microarrays have been used, examining microRNA expression in 154 surgically resected lung adenocarcinomas and 20 corresponding normal lung tissue samples. Findings were confirmed by RT-qPCR in the same cohort and in an independent cohort of 103 lung cancer patients. EGFR and KRAS mutation analyses were also performed. 129 microRNAs were significantly differentially expressed in lung adenocarcinomas compared with normal lung tissue, and 17 microRNAs were differentially expressed between EGFR-mutated and EGFR wildtype tumors. We identified microRNAs associated with time to progression. We have identified several aberrantly expressed microRNAs that discriminate lung adenocarcinomas from normal lung tissue, and hence may be potential biomarkers for early detection. We have found microRNAs that are differentially expressed between EGFR-mutated and EGFR wildtype lung adenocarcinomas, suggesting that microRNAs can be used as molecular biomarkers in classification. We hypothesize that microRNA expression can be used as biomarkers for clinical course.
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http://dx.doi.org/10.1002/ijc.28828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4235315PMC
October 2014

Pristane-induced arthritis loci interact with the Slc11a1 gene to determine susceptibility in mice selected for high inflammation.

PLoS One 2014 5;9(2):e88302. Epub 2014 Feb 5.

Laboratório de Imunogenética, Instituto Butantan, São Paulo, Brazil.

AIRmax (maximal inflammation) and AIRmin (minimal inflammation) mice show distinct susceptibilities to pristane-induced arthritis (PIA). The Slc11a1 gene, which regulates macrophage and neutrophil activity, is involved in this infirmity. AIRmax (SS) mice homozygous for the non-functional Slc11a1 S (gly169asp) allele obtained by genotype-assisted crosses from AIRmax and AIRmin mice are more susceptible than mice homozygous for the Slc11a1 resistant (R) allele. The present work sought to identify the quantitative trait loci (QTL) regulating PIA and to examine the interactions of these QTL with Slc11a1 alleles in modulating PIA. Mice were given two ip injections of 0.5 mL pristane at 60 day intervals, and the incidence and severity of PIA was scored up to 160 days. Genome-wide linkage studies were performed to search for arthritis QTL in an F2 (AIRmax × AIRmin, n = 290) population. Significant arthritis QTL (LODscore>4) were detected on chromosomes 5 and 8, and suggestive QTL on chromosomes 7, 17 and 19. Global gene expression analyses performed on Affymetrix mouse 1.0 ST bioarrays (27k genes) using RNA from arthritic or control mice paws showed 419 differentially expressed genes between AIRmax and AIRmin mice and demonstrated significantly (P<0.001) over-represented genes related to inflammatory responses and chemotaxis. Up-regulation of the chemokine genes Cxcl1, Cxcl9, Cxcl5, Cxcl13 on chromosome 5 was higher in AIRmax(SS) than in the other lines. Macrophage scavenger receptor 1 and hemeoxigenase (decycling) 1 genes on chromosome 8 were also expressed at higher levels in AIRmax(SS) mice. Our results show that the gene expression profiles of the two arthritis QTL (on chromosomes 5 and 8) correlate with Slc11a1 alleles, resulting in enhanced AIRmax(SS) mice susceptibility to PIA.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0088302PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3914970PMC
September 2014

Genetic control of renal tumorigenesis by the mouse Rtm1 locus.

BMC Genomics 2013 Oct 22;14:724. Epub 2013 Oct 22.

Laboratory of Immunogenetics, Instituto Butantan, Avenida Dr, Vital Brazil, 1500, 05503-900 São Paulo, Brazil.

Background: The genetic basis of susceptibility to renal tumorigenesis has not yet been established in mouse strains. Mouse lines derived by bidirectional phenotypic selection on the basis of their maximal (AIRmax) or minimal (AIRmin) acute inflammatory responsiveness differ widely in susceptibility to spontaneous and urethane-induced renal tumorigenesis. To map the functional loci modulating renal tumor susceptibility in these mice, we carried out a genome-wide genetic linkage study, using SNP arrays, in an (AIRmax x AIRmin)F2 intercross population treated with a single urethane dose at 1 week of age and phenotyped for renal tumors at 35 weeks of age.

Results: AIRmax mice did not develop renal tumors spontaneously nor in response to urethane, whereas in AIRmin mice renal tumors formed spontaneously (in 52% of animals) and after urethane induction (89%). The tumors had a papillary morphology and were positive for alpha-methylacyl-CoA racemase and negative for CD10. By analysis of 879 informative SNPs in 662 mice, we mapped a single quantitative trait locus modulating the incidence of renal tumors in the (AIRmax x AIRmin)F2 intercross population. This locus, which we named Renal tumor modifier QTL 1 (Rtm1), mapped to chromosome 17 at 23.4 Mb (LOD score = 15.8), with SNPs rs3696835 and rs3719497 flanking the LOD score peak. The A allele of rs3719497 from AIRmin mice was associated with a 2.5-fold increased odds ratio for renal tumor development. The LOD score peak included the Tuberous sclerosis 2 (Tsc2) gene which has already been implicated in kidney disease: loss of function by germline retroviral insertion is associated with spontaneous renal tumorigenesis in the Eker rat, and heterozygous-null Tsc2(+/-) mice develop renal cystadenomas.

Conclusions: We mapped Rtm1 as a single major locus modulating renal tumorigenesis in a murine intercross population. Thus, the AIR mouse lines can be considered a new genetic model for studying the role of germline and somatic molecular alterations in kidney neoplastic disease.
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http://dx.doi.org/10.1186/1471-2164-14-724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4046818PMC
October 2013

Gene expression signature of non-involved lung tissue associated with survival in lung adenocarcinoma patients.

Carcinogenesis 2013 Dec 25;34(12):2767-73. Epub 2013 Aug 25.

Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Lung adenocarcinoma patients of similar clinical stage and undergoing the same treatments often have marked interindividual variations in prognosis. These clinical discrepancies may be due to the genetic background modulating an individual's predisposition to fighting cancer. Herein, we hypothesized that the lung microenvironment, as reflected by its expression profile, may affect lung adenocarcinoma patients' survival. The transcriptome of non-involved lung tissue, excised from a discovery series of 204 lung adenocarcinoma patients, was evaluated using whole-genome expression microarrays (with probes corresponding to 28 688 well-annotated coding sequences). Genes associated with survival status at 60 months were identified by Cox regression analysis (adjusted for gender, age and clinical stage) and retested in a validation series of 78 additional cases. RNA-Seq analysis from non-involved lung tissue of 12 patients was performed to characterize the different isoforms of candidate genes. Ten genes for which the loge-transformed hazard ratios expressed the same direction of effect in the discovery (P < 1.0 × 10(-3)) and validation series comprised the gene expression signature associated with survival: CNTNAP1, PKNOX1, FAM156A, FRMD8, GALNTL1, TXNDC12, SNTB1, PPP3R1, SNX10 and SERPINH1. RNA sequencing highlighted the complex expression pattern of these genes in non-involved lung tissue from different patients and permitted the detection of a read-through gene fusion between PPP3R1 and the flanking gene (CNRIP1) as well as a novel isoform of CNTNAP1. Our findings support the hypothesis that individual genetic characteristics, evidenced by the expression pattern of non-involved tissue, influence the outcome of lung adenocarcinoma patients.
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http://dx.doi.org/10.1093/carcin/bgt294DOI Listing
December 2013

Testing of human papillomavirus in lung cancer and non-tumor lung tissue.

BMC Cancer 2012 Nov 12;12:512. Epub 2012 Nov 12.

Department of Predictive and Preventive Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Via Amadeo 42, Milan 20133, Italy.

Background: Risk factors for lung cancer, such as cigarette smoking, environmental pollution, asbestos, and genetic determinants, are well-known, whereas involvement of the human papillomavirus (HPV) is still unclear.

Methods: We examined a series of 100 lung cancer patients from Italy and the UK for the presence of HPV DNA in both lung tumor specimens and adjacent non-tumoral specimens from the same patients. Thirty-five of the most clinically relevant HPV types were assayed using PCR amplification of the highly conserved L1 region of the viral genome followed by hybridization with specific probes.

Results: No HPV was detected in tumor specimens nor in normal lung tissue of any patient.

Conclusions: These data indicate that, in this Western series, HPV is not associated with the risk of lung cancer. Our findings will help refine estimates of lung cancer risk in patients affected by a common viral infection involved in other types of human cancer.
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http://dx.doi.org/10.1186/1471-2407-12-512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3537645PMC
November 2012

The Lsktm1 locus modulates lung and skin tumorigenesis in the mouse.

G3 (Bethesda) 2012 Sep 1;2(9):1041-6. Epub 2012 Sep 1.

Department of Predictive and Preventive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.

Alleles derived from skin tumor-resistant Car-R mice provide resistance to both skin and lung tumorigenesis over the susceptibility of the SWR/J strain. In an effort to map tumor modifier loci affecting both tumor types, we carried out a genetic linkage analysis in backcross SWR/J x (SWR/J x Car-R) mice and identified a locus (Lsktm1) on chromosome 1 linked to both skin (LOD score = 3.93) and lung (LOD score = 8.74) tumorigenesis. Two genes, Igfbp5 and Igfbp2, residing in this locus and belonging to the insulin-like growth factor binding protein family were expressed at significantly greater levels in normal lung tissue from cancer-resistant Car-R mice than in cancer-susceptible SWR/J mice. Overexpression of the recombinant Igfbp5 and Igfbp2 genes in two lung cancer cell lines significantly inhibited clonogenicity (P < 0.0001). Collectively, we have identified a single polymorphic locus that affects skin and lung tumorigenesis and identify Igfbp5 and Igfbp2 as candidate modifier genes of lung tumorigenesis.
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http://dx.doi.org/10.1534/g3.112.003525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3429918PMC
September 2012

Association of lung adenocarcinoma clinical stage with gene expression pattern in noninvolved lung tissue.

Int J Cancer 2012 Sep 28;131(5):E643-8. Epub 2012 Feb 28.

Department of Predictive and Preventive Medicine, Fondazione IRCCS, Istituto Nazionale Tumori, Milan, Italy.

Associations between clinical outcome of cancer patients and the gene expression signature in primary tumors at time of diagnosis have been reported. To test whether gene expression patterns in noninvolved lung tissue might correlate with clinical stage in lung adenocarcinoma (ADCA) patients, we compared the transcriptome of noninvolved lung samples from 60 ADCA smoker patients of clinical stage I versus 60 patients with stage>I. Quantitative PCR of 10 genes with the most significant differential expression confirmed the statistical association with clinical stage in eight genes, six of which were downregulated in high-stage patients. Five of these six genes were also downregulated in lung ADCA tissue as compared to noninvolved tissue. Studies in vitro indicated that four of the genes (SLC14A1, SMAD6, TMEM100 and TXNIP) inhibited colony formation of lung cancer cell lines transfected to overexpress the genes, suggesting their potential tumor-suppressor activity. Our findings suggest that individual variations in the transcriptional profile of noninvolved lung tissue may reflect the lung ADCA patient's predisposition to tumor aggressiveness.
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http://dx.doi.org/10.1002/ijc.27426DOI Listing
September 2012

A 5'-region polymorphism modulates promoter activity of the tumor suppressor gene MFSD2A.

Mol Cancer 2011 Jul 7;10:81. Epub 2011 Jul 7.

Department of Predictive and Preventive Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.

Background: The MFSD2A gene maps within a linkage disequilibrium block containing the MYCL1-EcoRI polymorphism associated with prognosis and survival in lung cancer patients. Survival discrepancies between Asians and Caucasians point to ethnic differences in allelic frequencies of the functional genetic variations.

Results: Analysis of three single-nucleotide polymorphisms (SNPs) mapping in the MFSD2A 5'-regulatory region using a luciferase reporter system showed that SNP rs12072037, in linkage disequilibrium with the MYCL1-EcoRI polymorphism and polymorphic in Asians but not in Caucasians, modulated transcriptional activity of the MFSD2A promoter in cell lines expressing AHR and ARNT transcription factors, which potentially bind to the SNP site.

Conclusion: SNP rs12072037 modulates MFSD2A promoter activity and thus might affect MFSD2A levels in normal lung and in lung tumors, representing a candidate ethnically specific genetic factor underlying the association between the MYCL1 locus and lung cancer patients' survival.
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http://dx.doi.org/10.1186/1476-4598-10-81DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3155907PMC
July 2011

Multiple Loci modulate opioid therapy response for cancer pain.

Clin Cancer Res 2011 Jul 27;17(13):4581-7. Epub 2011 May 27.

Department of Predictive and Preventive Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.

Purpose: Patients treated with opioid drugs for cancer pain experience different relief responses, raising the possibility that genetic factors play a role in opioid therapy outcome. In this study, we tested the hypothesis that genetic variations may control individual response to opioid drugs in cancer patients.

Experimental Design: We tested 1 million single-nucleotide polymorphisms (SNP) in European cancer patients, selected in a first series, for extremely poor (pain relief ≤40%; n = 145) or good (pain relief ≥90%; n = 293) responses to opioid therapy using a DNA-pooling approach. Candidate SNPs identified by SNP-array were genotyped in individual samples constituting DNA pools as well as in a second series of 570 patients.

Results: Association analysis in 1,008 cancer patients identified eight SNPs significantly associated with pain relief at a statistical threshold of P < 1.0 × 10⁻³, with rs12948783, upstream of the RHBDF2 gene, showing the best statistical association (P = 8.1 × 10⁻⁹). Functional annotation analysis of SNP-tagged genes suggested the involvement of genes acting on processes of the neurologic system.

Conclusion: Our results indicate that the identified SNP panel can modulate the response of cancer patients to opioid therapy and may provide a new tool for personalized therapy of cancer pain.
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http://dx.doi.org/10.1158/1078-0432.CCR-10-3028DOI Listing
July 2011

Multiple genetic loci modulate lung adenocarcinoma clinical staging.

Clin Cancer Res 2011 Apr 17;17(8):2410-6. Epub 2011 Jan 17.

Fondazione IRCCS Istituto Nazionale Tumori, Università degli Studi di Milano, Milan, Italy.

Purpose: The main prognostic factor of lung cancer patient outcome is clinical stage, a parameter of tumor aggressiveness. Our study was conducted to test whether germ line variations modulate individual differences in clinical stage.

Experimental Design: We conducted a case-only genome-wide association study (GWAS) using a 620,901 single-nucleotide polymorphism (SNP) array in a first series of 600 lung adenocarcinoma (ADCA) patients and in a replication series of 317 lung ADCA patients.

Results: GWAS identified 54 putatively associated SNPs, 3 of which were confirmed in the replication series. Joint analysis of the two series pointed to 22 statistically associated (P < 0.01) genetic variants that together explained about 20% of the phenotypic variation in clinical staging (P < 2 × 10(-16)) and showed a statistically significant difference in overall survival (P = 8.0 × 10(-8)). The strongest statistical association was observed at rs10278557 (P = 1.1 × 10(-5)), located in the mesenchyme homeobox 2 (MEOX2) gene.

Conclusion: These data point to the role of germ line variations involving multiple loci in modulating clinical stage and, therefore, prognosis in lung ADCA patients.
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http://dx.doi.org/10.1158/1078-0432.CCR-10-2394DOI Listing
April 2011

Promoter polymorphisms and transcript levels of nicotinic receptor CHRNA5.

J Natl Cancer Inst 2010 Sep 23;102(17):1366-70. Epub 2010 Aug 23.

Department of Predictive and Preventive Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Via G. Venezian 1, Milan, Italy.

Chromosomal locus 15q25, implicated in lung cancer risk and nicotine dependence, shows extensive linkage disequilibrium that complicates identification of causal variation. Cholinergic receptor nicotinic alpha5 (CHRNA5) has been identified as a lung cancer risk factor. We identified by sequence analysis three haplotypes (delTTC, insATC, and insTGG) in the 5' promoter region and three at the 3'-untranslated region of CHRNA5. Linkage disequilibrium analysis of the 5' variants showed that the insTGG haplotype is associated with three tightly linked risk alleles (nicotine dependence, lung cancer, and chronic obstructive pulmonary disease). The three CHRNA5 promoter haplotypes were statistically significantly associated with lung CHRNA5 transcript levels, determined by real-time polymerase chain reaction. In nontumor lung parenchyma from 68 patients who underwent lung lobectomy, the delTTC haplotype was associated with the highest CHRNA5 transcript levels (relative quantification units = 1.82), whereas the insTGG haplotype was associated with the lowest (0.88 units, P(diff) < .001, Welch t test; all statistical tests were two-sided). Luciferase reporter assays in human lung cancer cell lines A549, H460, H520, and H596 also showed that the 5' region haplotypes were statistically significantly associated with changes in CHRNA5 promoter activity, whereas the 3'-untranslated region variants were not.
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http://dx.doi.org/10.1093/jnci/djq264DOI Listing
September 2010

Genetic control of IL-1 beta production and inflammatory response by the mouse Irm1 locus.

J Immunol 2010 Aug 7;185(3):1616-21. Epub 2010 Jul 7.

Laboratório de Imunogenética, Instituto Butantan, São Paulo, Brazil.

Genome-wide linkage analysis using single nucleotide polymorphism arrays was carried out in pedigrees of mice differing in the extent of acute inflammatory response (AIRmax or AIRmin). The AIR phenotype was determined by quantifying the number of infiltrating cells in the 24-h exudate induced by Biogel P-100 s.c. injection and by ex vivo IL-1beta production by leukocytes stimulated with LPS and ATP. We mapped the major inflammatory response modulator 1 locus on chromosome 7, at the 1-logarithm of odds (LOD) confidence interval from 116.75 to 139.75 Mb, linked to the number of infiltrating cells (LOD = 3.61) through the production of IL-1beta (LOD = 9.35). Of several interesting candidate genes mapping to the inflammatory response modulator 1 locus, 28 of these were differentially expressed in the bone marrow of AIRmax and AIRmin mice. These findings represent a step toward the identification of the genes underlying this complex phenotype.
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http://dx.doi.org/10.4049/jimmunol.1000358DOI Listing
August 2010

Genetic heterogeneity of inflammatory response and skin tumorigenesis in phenotypically selected mouse lines.

Cancer Lett 2010 Sep 21;295(1):54-8. Epub 2010 Mar 21.

Department of Predictive and Preventive Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.

Non-inbred AIR (AIRmax, AIRmin) and Car (Car-S, Car-R) mouse lines were generated from the same eight inbred mice through bidirectional selective breeding for acute inflammatory response and for susceptibility to two-stage skin tumorigenesis, respectively. Because AIR lines also showed a differential predisposition to skin tumorigenesis and Car lines differed in the extent of inflammatory response, we carried out genome-wide association studies using SNP arrays to identify the genetic elements affecting skin tumor susceptibility and inflammatory response in AIR and Car lines. We found that the phenotypic outcome reflects a specific genetic profile in each mouse line, suggesting that distinct genetic elements, selected by differential genetic drifts, and exerting pleiotropic effects in each mouse population, control the skin tumor susceptibility and inflammatory response phenotypes. These findings point to the complex link between skin tumor susceptibility and inflammatory response in mice.
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http://dx.doi.org/10.1016/j.canlet.2010.02.013DOI Listing
September 2010

Transcriptome of normal lung distinguishes mouse lines with different susceptibility to inflammation and to lung tumorigenesis.

Cancer Lett 2010 Aug 1;294(2):187-94. Epub 2010 Mar 1.

Laboratory of Imunogenetics, Instituto Butantan, Avenida Dr. Vital Brazil, 1500, 05503-900, São Paulo, Brazil.

AIRmax and AIRmin mouse lines show a differential lung inflammatory response and differential lung tumor susceptibility after urethane treatment. The transcript profile of approximately 24,000 known genes was analyzed in normal lung tissue of untreated and urethane-treated AIRmax and AIRmin mice. In lungs of untreated mice, inflammation-associated genes involved in pathways such as "leukocyte transendothelial migration", "cell adhesion" and "tight junctions" were differentially expressed. Moreover, gene expression levels differed significantly in urethane-treated mice; in AIRmin mice, modulation of expression of genes involved in pathways associated with inflammatory response paralleled the previously observed persistent infiltration of inflammatory cells in the lung of these mice.
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http://dx.doi.org/10.1016/j.canlet.2010.01.038DOI Listing
August 2010

A locus on mouse chromosome 2 is involved in susceptibility to congenital hypothyroidism and contains an essential gene expressed in thyroid.

Endocrinology 2010 Apr 16;151(4):1948-58. Epub 2010 Feb 16.

Stazione Zoologica Anton Dohrn, Villa Comunale I, Naples 80121, Italy.

We report here the mapping of a chromosomal region responsible for strain-specific development of congenital hypothyroidism in mice heterozygous for null mutations in genes encoding Nkx2-1/Titf1 and Pax8. The two strains showing a differential predisposition to congenital hypothyroidism contain several single-nucleotide polymorphisms in this locus, one of which leads to a nonsynonymous amino acid change in a highly conserved region of Dnajc17, a member of the type III heat-shock protein-40 (Hsp40) family. We demonstrate that Dnajc17 is highly expressed in the thyroid bud and had an essential function in development, suggesting an important role of this protein in organogenesis and/or function of the thyroid gland.
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http://dx.doi.org/10.1210/en.2009-1240DOI Listing
April 2010

Beyond genome-wide association studies: genetic heterogeneity and individual predisposition to cancer.

Trends Genet 2010 Mar 26;26(3):132-41. Epub 2010 Jan 26.

Department of Predictive and for Prevention Medicine, Fondazione IRCCS, Istituto Nazionale Tumori, Via G. Venezian 1, 20133 Milan, Italy.

Genome-wide association studies (GWAS) using population-based designs have identified many genetic loci associated with risk of a range of complex diseases including cancer; however, each locus exerts a very small effect and most heritability remains unexplained. Family-based pedigree studies have also suggested tentative loci linked to increased cancer risk, often characterized by pedigree-specificity. However, comparison between the results of population- and family-based studies shows little concordance. Explanations for this unidentified genetic 'dark matter' of cancer include phenotype ascertainment issues, limited power, gene-gene and gene-environment interactions, population heterogeneity, parent-of-origin-specific effects, and rare and unexplored variants. Many of these reasons converge towards the concept of genetic heterogeneity that might implicate hundreds of genetic variants in regulating cancer risk. Dissecting the dark matter is a challenging task. Further insights can be gained from both population association and pedigree studies.
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http://dx.doi.org/10.1016/j.tig.2009.12.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2826571PMC
March 2010

Genome-wide association study in discordant sibships identifies multiple inherited susceptibility alleles linked to lung cancer.

Carcinogenesis 2010 Mar 18;31(3):462-5. Epub 2009 Dec 18.

Fondazione IRCCS, Istituto Nazionale Tumori, 20133 Milan, Italy.

We analyzed a series of young (median age = 52 years) non-smoker lung cancer patients and their unaffected siblings as controls, using a genome-wide 620 901 single-nucleotide polymorphism (SNP) array analysis and a case-control DNA pooling approach. We identified 82 putatively associated SNPs that were retested by individual genotyping followed by use of the sib transmission disequilibrium test, pointing to 36 SNPs associated with lung cancer risk in the discordant sibs series. Analysis of these 36 SNPs in a polygenic model characterized by additive and interchangeable effects of rare alleles revealed a highly statistically significant dosage-dependent association between risk allele carrier status and proportion of cancer cases. Replication of the same 36 SNPs in a population-based series confirmed the association with lung cancer for three SNPs, suggesting that phenocopies and genetic heterogeneity can play a major role in the complex genetics of lung cancer risk in the general population.
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http://dx.doi.org/10.1093/carcin/bgp315DOI Listing
March 2010

Nicotine dependence may link the 15q25 locus to lung cancer risk.

Carcinogenesis 2010 Mar 12;31(3):331-3. Epub 2009 Nov 12.

Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Via Giacomo Venezian 1, 20133 Milan, Italy.

The nicotinic 15q25 locus has been implicated in lung cancer risk, with an odds ratio of approximately 1.3. The same locus is associated with nicotine dependence due to cigarette smoking and with smoking-associated chronic obstructive pulmonary disease, which is a risk factor for lung cancer. Our meta-analysis of reported studies shows that this locus was not associated with lung cancer risk in >1000 never-smoker cases and >1800 controls. Review of exposure-response data for lung cancer risk showed that less than a half-cigarette per day may confer the same risk of lung cancer as that conferred by the 15q25 locus. Given the lack of effect in never-smokers and the known common and variable underreporting of smoking habit in studies on smoking-associated diseases, we cannot exclude that the association between the 15q25 locus and lung cancer risk is indirect, deriving from association of the same locus with smoking habit. Since nicotine is not carcinogenic, available data do not provide plausibility of the association between the nicotinic 15q25 locus and lung cancer pathogenesis. Thus, a direct link between the 15q25 locus and lung cancer risk has yet to be established.
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http://dx.doi.org/10.1093/carcin/bgp282DOI Listing
March 2010

FGFR4 Gly388Arg polymorphism may affect the clinical stage of patients with lung cancer by modulating the transcriptional profile of normal lung.

Int J Cancer 2009 Jun;124(12):2880-5

Fondazione IRCCS, Istituto Nazionale Tumori, Milan, Italy.

The association of the fibroblast growth factor receptor 4 (FGFR4) Gly388Arg polymorphism with clinical stage and overall survival in a series of 541 Italian lung adenocarcinoma (ADCA) patients indicated a significantly decreased survival in patients carrying the rare Arg388 allele as compared to that in Gly/Gly homozygous patients [hazard ratio (HR) = 1.5; 95% confidence interval (CI) 1.1-1.9], with the decrease related to the association of the same polymorphism with clinical stage (HR = 1.8, 95% CI 1.3-2.6). By contrast, no significant association was detected in small series of either Norwegian lung ADCA patients or Italian lung squamous cell carcinoma (SQCC) patients. Single nucleotide polymorphisms of known FGFR4 ligands expressed in lung (FGF9, FGF18 and FGF19) were not associated with clinical stage or survival and showed no interaction with FGFR4. Analysis of gene expression profile in normal lungs according to FGFR4 genotype indicated a specific transcript pattern associated with the allele carrier status, suggesting a functional role for the FGFR4 polymorphism already detectable in normal lung. These findings confirm the significant association of the FGFR4 Gly388Arg polymorphism with clinical stage and overall survival in an Italian lung ADCA population and demonstrate a FGFR4 genotype-dependent transcriptional profile present in normal lung tissue.
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http://dx.doi.org/10.1002/ijc.24302DOI Listing
June 2009

Transcription deregulation at the 15q25 locus in association with lung adenocarcinoma risk.

Clin Cancer Res 2009 Mar 17;15(5):1837-42. Epub 2009 Feb 17.

Fondazione IRCCS, Istituto Nazionale Tumori, Milan, Italy.

Purpose: We characterized the candidacy of the six candidate genes mapping in the chromosome 15q25 locus, which was previously reported as associated with lung cancer risk, and confirmed the locus association with lung cancer risk in an Italian population of lung adenocarcinoma patients and controls.

Experimental Design: We did a quantitative analysis of mRNA levels of IREB2 (iron-responsive element-binding protein 2), LOC123688, PMSA4 [proteasome (prosome, macropain) subunit alpha type 4], CHRNB4 (cholinergic receptor nicotinic beta 4), CHRNA3 (cholinergic receptor nicotinic alpha 3), and CHRNA5 (cholinergic receptor nicotinic alpha 5) genes in paired normal lung and lung adenocarcinoma tissue, and an immunohistochemical localization of CHRNA3- and CHRNA5-encoded proteins. We also examined the association of CHRNA5 D398N polymorphism with lung cancer risk and with CHRNA5 mRNA levels in the normal lung.

Results: Expression analysis of the six candidate genes mapping in the lung cancer risk-associated chromosome 15q25 locus revealed a 30-fold up-regulation of the gene encoding the CHRNA5 subunit and a 2-fold down-regulation of the CHRNA3 subunit in lung adenocarcinoma as compared with the normal lung. The expression of the four other candidate genes resulted either unchanged or absent. The carrier status of the 398N allele at the D398N polymorphism of the CHRNA5 gene was associated with lung adenocarcinoma risk (odds ratio, 1.5; 95% confidence interval, 1.2-2.0) in a population-based series of lung adenocarcinoma patients (n=467) and healthy controls (n=739). Analysis of a family-based series of nonsmoker lung cancer cases (n=80) and healthy sib controls (n=80) indicated a similar trend. In addition, the same D398N variation correlated with CHRNA5 mRNA levels in normal lung of adenocarcinoma patients.

Conclusions: Our results point to the candidacy of the CHRNA5 gene for the 15q25 locus.
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http://dx.doi.org/10.1158/1078-0432.CCR-08-2107DOI Listing
March 2009

Mouse genome-wide association mapping needs linkage analysis to avoid false-positive Loci.

PLoS Genet 2009 Jan 9;5(1):e1000331. Epub 2009 Jan 9.

Department of Experimental Oncology and Laboratories, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.

We carried out genome-wide association (GWA) studies in inbred mouse strains characterized for their lung tumor susceptibility phenotypes (spontaneous or urethane-induced) with panels of 12,959 (13K) or 138,793 (140K) single-nucleotide polymorphisms (SNPs). Above the statistical thresholds, we detected only SNP rs3681853 on Chromosome 5, two SNPs in the pulmonary adenoma susceptibility 1 (Pas1) locus, and SNP rs4174648 on Chromosome 16 for spontaneous tumor incidence, urethane-induced tumor incidence, and urethane-induced tumor multiplicity, respectively, with the 13K SNP panel, but only the Pas1 locus with the 140K SNP panel. Haplotype analysis carried out in the latter panel detected four additional loci. Loci reported in previous GWA studies failed to replicate. Genome-wide genetic linkage analysis in urethane-treated (BALB/cxC3H/He)F2, (BALB/cxSWR/J)F2, and (A/JxC3H/He)F2 mice showed that Pas1, but none of the other loci detected previously or herein by GWA, had a significant effect. The Lasc1 gene, identified by GWA as a functional element (Nat. Genet., 38:888-95, 2006), showed no genetic effects in the two independent intercross mouse populations containing both alleles, nor was it expressed in mouse normal lung or lung tumors. Our results indicate that GWA studies in mouse inbred strains can suffer a high rate of false-positive results and that such an approach should be used in conjunction with classical linkage mapping in genetic crosses.
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http://dx.doi.org/10.1371/journal.pgen.1000331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2614123PMC
January 2009

Aryl hydrocarbon receptor polymorphism modulates DMBA-induced inflammation and carcinogenesis in phenotypically selected mice.

Int J Cancer 2009 Mar;124(6):1478-82

Laboratório de Imunogenética, Instituto Butantan, São Paulo, Brazil.

We tested the role of aryl hydrocarbon receptor (Ahr) gene polymorphism in the inflammatory response and in skin and lung tumorigenesis in 2 lines of mice phenotypically selected for maximum or minimum acute inflammatory reaction (AIRmax and AIRmin, respectively). Following 7,12-dimethylbenz[a]anthracene (DMBA) treatment, AIRmin but not AIRmax mice showed early skin reactions and eventually developed malignant skin tumors and lung adenocarcinomas. In skin tissue, transcript levels of IL1beta, Tnf, Il6, Tgfbeta1 and Cyp1b1 genes were upregulated in AIRmin but not AIRmax mice, consistent with the inflammatory responses to the carcinogen. These findings appeared to be related to the homozygosity status of the Ahr functional A375V polymorphism, which influences the binding capability of the receptor for DMBA: the 375A allele, encoding the high-affinity ligand-binding receptor (Ahr(b1)), segregated in AIRmin mice, whereas AIRmax mice carried the 375V, corresponding to the low-affinity binding receptor (Ahr(d)), to DMBA. The differential segregation of Ahr functional Ahr(d)versus Ahr(b1) alleles in AIRmax and AIRmin suggests a role for the Ahr gene in the control of inflammatory responsiveness and tumor development of these mouse lines.
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http://dx.doi.org/10.1002/ijc.24066DOI Listing
March 2009

Genetic background modulates gene expression profile induced by skin irradiation in ptch1 mice.

Int J Radiat Oncol Biol Phys 2008 Dec;72(5):1582-6

Department of Experimental Oncology and Laboratories, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.

Purpose: Ptch1 germ-line mutations in mice predispose to radiation-induced basal cell carcinoma of the skin, with tumor incidence modulated by the genetic background. Here, we examined the possible mechanisms underlying skin response to radiation in F1 progeny of Ptch1(neo67/+) mice crossed with either skin tumor-susceptible (Car-S) or -resistant (Car-R) mice and X-irradiated (3 Gy) at 2 days of age or left untreated.

Methods And Materials: We conducted a gene expression profile analysis in mRNA samples extracted from the skin of irradiated or control mice, using Affymetrix whole mouse genome expression array. Confirmation of the results was done using real-time reverse-transcriptase polymerase chain reaction.

Results: Analysis of the gene expression profile of normal skin of F1 mice at 4 weeks of age revealed a similar basal profile in the nonirradiated mice, but alterations in levels of 71 transcripts in irradiated Ptch1(neo67/+) mice of the Car-R cross and modulation of only eight genes in irradiated Ptch1(neo67/+) mice of the Car-S cross.

Conclusions: These results indicate that neonatal irradiation causes a persistent change in the gene expression profile of the skin. The tendency of mice genetically resistant to skin tumorigenesis to show a more complex pattern of transcriptional response to radiation than do genetically susceptible mice suggests a role for this response in genetic resistance to basal cell tumorigenesis.
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http://dx.doi.org/10.1016/j.ijrobp.2008.08.008DOI Listing
December 2008

A polygenic model with common variants may predict lung adenocarcinoma risk in humans.

Int J Cancer 2008 Nov;123(10):2327-30

Fondazione IRCCS, Istituto Nazionale Tumori, Milan, Italy.

Genome-wide screening for genetic loci associated with risk of lung adenocarcinoma (ADCA) was carried out in pooled DNA using the Illumina 300K single-nucleotide polymorphism (SNP) array, in a joint analysis of 2 Italian case-control series matched by age, gender and smoking habit. The rare allele carrier status of 8 SNPs was associated with a decreased lung ADCA risk [odds ratios (OR): 0.6-0.8]. In a polygenic model characterized by additive and interchangeable effects, individuals carrying 2 to 6 rare alleles at these 8 SNPs showed a significant trend toward a decreased risk of lung ADCA (up to OR of 0.3). These results suggest the relevance of a polygenic model in the modulation of individual risk of lung ADCA in the general population.
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http://dx.doi.org/10.1002/ijc.23789DOI Listing
November 2008