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1.  Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer 
Wang, Yufei | McKay, James D. | Rafnar, Thorunn | Wang, Zhaoming | Timofeeva, Maria | Broderick, Peter | Zong, Xuchen | Laplana, Marina | Wei, Yongyue | Han, Younghun | Lloyd, Amy | Delahaye-Sourdeix, Manon | Chubb, Daniel | Gaborieau, Valerie | Wheeler, William | Chatterjee, Nilanjan | Thorleifsson, Gudmar | Sulem, Patrick | Liu, Geoffrey | Kaaks, Rudolf | Henrion, Marc | Kinnersley, Ben | Vallée, Maxime | LeCalvez-Kelm, Florence | Stevens, Victoria L. | Gapstur, Susan M. | Chen, Wei V. | Zaridze, David | Szeszenia-Dabrowska, Neonilia | Lissowska, Jolanta | Rudnai, Peter | Fabianova, Eleonora | Mates, Dana | Bencko, Vladimir | Foretova, Lenka | Janout, Vladimir | Krokan, Hans E. | Gabrielsen, Maiken Elvestad | Skorpen, Frank | Vatten, Lars | Njølstad, Inger | Chen, Chu | Goodman, Gary | Benhamou, Simone | Vooder, Tonu | Valk, Kristjan | Nelis, Mari | Metspalu, Andres | Lener, Marcin | Lubiński, Jan | Johansson, Mattias | Vineis, Paolo | Agudo, Antonio | Clavel-Chapelon, Francoise | Bueno-de-Mesquita, H.Bas | Trichopoulos, Dimitrios | Khaw, Kay-Tee | Johansson, Mikael | Weiderpass, Elisabete | Tjønneland, Anne | Riboli, Elio | Lathrop, Mark | Scelo, Ghislaine | Albanes, Demetrius | Caporaso, Neil E. | Ye, Yuanqing | Gu, Jian | Wu, Xifeng | Spitz, Margaret R. | Dienemann, Hendrik | Rosenberger, Albert | Su, Li | Matakidou, Athena | Eisen, Timothy | Stefansson, Kari | Risch, Angela | Chanock, Stephen J. | Christiani, David C. | Hung, Rayjean J. | Brennan, Paul | Landi, Maria Teresa | Houlston, Richard S. | Amos, Christopher I.
Nature genetics  2014;46(7):736-741.
We conducted imputation to the 1000 Genomes Project of four genome-wide association studies of lung cancer in populations of European ancestry (11,348 cases and 15,861 controls) and genotyped an additional 10,246 cases and 38,295 controls for follow-up. We identified large-effect genome-wide associations for squamous lung cancer with the rare variants of BRCA2-K3326X (rs11571833; odds ratio [OR]=2.47, P=4.74×10−20) and of CHEK2-I157T (rs17879961; OR=0.38 P=1.27×10−13). We also showed an association between common variation at 3q28 (TP63; rs13314271; OR=1.13, P=7.22×10−10) and lung adenocarcinoma previously only reported in Asians. These findings provide further evidence for inherited genetic susceptibility to lung cancer and its biological basis. Additionally, our analysis demonstrates that imputation can identify rare disease-causing variants having substantive effects on cancer risk from pre-existing GWAS data.
doi:10.1038/ng.3002
PMCID: PMC4074058  PMID: 24880342
3.  Multistage analysis of variants in the Inflammation pathway and lung cancer risk in smokers 
BACKGROUND
Tobacco-induced lung cancer is characterized by a deregulated inflammatory microenvironment. Variants in multiple genes in inflammation pathways may contribute to risk of lung cancer.
METHODS
We therefore conducted a three-stage comprehensive pathway analysis (discovery, replication and meta-analysis) of inflammation gene variants in ever smoking lung cancer cases and controls. A discovery set (1096 cases; 727 controls) and an independent and non-overlapping internal replication set (1154 cases; 1137 controls) were derived from an ongoing case-control study. For discovery, we used an iSelect BeadChip to interrogate a comprehensive panel of 11737 inflammation pathway SNPs and selected nominally significant (p<0.05) SNPs for internal replication.
RESULTS
There were 6 SNPs that achieved statistical significance (p<0.05) in the internal replication dataset with concordant risk estimates for former smokers and 5 concordant and replicated SNPs in current smokers. Replicated hits were further tested in a subsequent meta-analysis using external data derived from two published GWAS and a case-control study. Two of these variants (a BCL2L14 SNP in former smokers and a SNP in IL2RB in current smokers) were further validated. In risk score analyses, there was a 26% increase in risk with each additional adverse allele when we combined the genotyped SNP and the most significant imputed SNP in IL2RB in current smokers and a 36% similar increase in risk for former smokers associated with genotyped and imputed BCL2L14 SNPs.
CONCLUSIONS/IMPACT
Before they can be applied for risk prediction efforts, these SNPs should be subject to further external replication and more extensive fine mapping studies.
doi:10.1158/1055-9965.EPI-12-0352-T
PMCID: PMC3487592  PMID: 22573796
Inflammation SNPS; lung cancer; smokers
4.  Detectable clonal mosaicism and its relationship to aging and cancer 
Jacobs, Kevin B | Yeager, Meredith | Zhou, Weiyin | Wacholder, Sholom | Wang, Zhaoming | Rodriguez-Santiago, Benjamin | Hutchinson, Amy | Deng, Xiang | Liu, Chenwei | Horner, Marie-Josephe | Cullen, Michael | Epstein, Caroline G | Burdett, Laurie | Dean, Michael C | Chatterjee, Nilanjan | Sampson, Joshua | Chung, Charles C | Kovaks, Joseph | Gapstur, Susan M | Stevens, Victoria L | Teras, Lauren T | Gaudet, Mia M | Albanes, Demetrius | Weinstein, Stephanie J | Virtamo, Jarmo | Taylor, Philip R | Freedman, Neal D | Abnet, Christian C | Goldstein, Alisa M | Hu, Nan | Yu, Kai | Yuan, Jian-Min | Liao, Linda | Ding, Ti | Qiao, You-Lin | Gao, Yu-Tang | Koh, Woon-Puay | Xiang, Yong-Bing | Tang, Ze-Zhong | Fan, Jin-Hu | Aldrich, Melinda C | Amos, Christopher | Blot, William J | Bock, Cathryn H | Gillanders, Elizabeth M | Harris, Curtis C | Haiman, Christopher A | Henderson, Brian E | Kolonel, Laurence N | Le Marchand, Loic | McNeill, Lorna H | Rybicki, Benjamin A | Schwartz, Ann G | Signorello, Lisa B | Spitz, Margaret R | Wiencke, John K | Wrensch, Margaret | Wu, Xifeng | Zanetti, Krista A | Ziegler, Regina G | Figueroa, Jonine D | Garcia-Closas, Montserrat | Malats, Nuria | Marenne, Gaelle | Prokunina-Olsson, Ludmila | Baris, Dalsu | Schwenn, Molly | Johnson, Alison | Landi, Maria Teresa | Goldin, Lynn | Consonni, Dario | Bertazzi, Pier Alberto | Rotunno, Melissa | Rajaraman, Preetha | Andersson, Ulrika | Freeman, Laura E Beane | Berg, Christine D | Buring, Julie E | Butler, Mary A | Carreon, Tania | Feychting, Maria | Ahlbom, Anders | Gaziano, J Michael | Giles, Graham G | Hallmans, Goran | Hankinson, Susan E | Hartge, Patricia | Henriksson, Roger | Inskip, Peter D | Johansen, Christoffer | Landgren, Annelie | McKean-Cowdin, Roberta | Michaud, Dominique S | Melin, Beatrice S | Peters, Ulrike | Ruder, Avima M | Sesso, Howard D | Severi, Gianluca | Shu, Xiao-Ou | Visvanathan, Kala | White, Emily | Wolk, Alicja | Zeleniuch-Jacquotte, Anne | Zheng, Wei | Silverman, Debra T | Kogevinas, Manolis | Gonzalez, Juan R | Villa, Olaya | Li, Donghui | Duell, Eric J | Risch, Harvey A | Olson, Sara H | Kooperberg, Charles | Wolpin, Brian M | Jiao, Li | Hassan, Manal | Wheeler, William | Arslan, Alan A | Bas Bueno-de-Mesquita, H | Fuchs, Charles S | Gallinger, Steven | Gross, Myron D | Holly, Elizabeth A | Klein, Alison P | LaCroix, Andrea | Mandelson, Margaret T | Petersen, Gloria | Boutron-Ruault, Marie-Christine | Bracci, Paige M | Canzian, Federico | Chang, Kenneth | Cotterchio, Michelle | Giovannucci, Edward L | Goggins, Michael | Bolton, Judith A Hoffman | Jenab, Mazda | Khaw, Kay-Tee | Krogh, Vittorio | Kurtz, Robert C | McWilliams, Robert R | Mendelsohn, Julie B | Rabe, Kari G | Riboli, Elio | Tjønneland, Anne | Tobias, Geoffrey S | Trichopoulos, Dimitrios | Elena, Joanne W | Yu, Herbert | Amundadottir, Laufey | Stolzenberg-Solomon, Rachael Z | Kraft, Peter | Schumacher, Fredrick | Stram, Daniel | Savage, Sharon A | Mirabello, Lisa | Andrulis, Irene L | Wunder, Jay S | García, Ana Patiño | Sierrasesúmaga, Luis | Barkauskas, Donald A | Gorlick, Richard G | Purdue, Mark | Chow, Wong-Ho | Moore, Lee E | Schwartz, Kendra L | Davis, Faith G | Hsing, Ann W | Berndt, Sonja I | Black, Amanda | Wentzensen, Nicolas | Brinton, Louise A | Lissowska, Jolanta | Peplonska, Beata | McGlynn, Katherine A | Cook, Michael B | Graubard, Barry I | Kratz, Christian P | Greene, Mark H | Erickson, Ralph L | Hunter, David J | Thomas, Gilles | Hoover, Robert N | Real, Francisco X | Fraumeni, Joseph F | Caporaso, Neil E | Tucker, Margaret | Rothman, Nathaniel | Pérez-Jurado, Luis A | Chanock, Stephen J
Nature genetics  2012;44(6):651-658.
In an analysis of 31,717 cancer cases and 26,136 cancer-free controls drawn from 13 genome-wide association studies (GWAS), we observed large chromosomal abnormalities in a subset of clones from DNA obtained from blood or buccal samples. Mosaic chromosomal abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of size >2 Mb were observed in autosomes of 517 individuals (0.89%) with abnormal cell proportions between 7% and 95%. In cancer-free individuals, the frequency increased with age; 0.23% under 50 and 1.91% between 75 and 79 (p=4.8×10−8). Mosaic abnormalities were more frequent in individuals with solid-tumors (0.97% versus 0.74% in cancer-free individuals, OR=1.25, p=0.016), with a stronger association for cases who had DNA collected prior to diagnosis or treatment (OR=1.45, p=0.0005). Detectable clonal mosaicism was common in individuals for whom DNA was collected at least one year prior to diagnosis of leukemia compared to cancer-free individuals (OR=35.4, p=3.8×10−11). These findings underscore the importance of the role and time-dependent nature of somatic events in the etiology of cancer and other late-onset diseases.
doi:10.1038/ng.2270
PMCID: PMC3372921  PMID: 22561519
5.  Inherited variation at chromosome 12p13.33 including RAD52 influences squamous cell lung carcinoma risk 
Cancer Discovery  2011;2(2):131-139.
While lung cancer is largely caused by tobacco smoking, inherited genetic factors play a role in its etiology. Genome-wide association studies (GWAS) in Europeans have robustly demonstrated only three polymorphic variations influencing lung cancer risk. Tumor heterogeneity may have hampered the detection of association signal when all lung cancer subtypes were analyzed together. In a GWAS of 5,355 European smoking lung cancer cases and 4,344 smoking controls, we conducted a pathway-based analysis in lung cancer histologic subtypes with 19,082 SNPs mapping to 917 genes in the HuGE-defined “inflammation” pathway. We identified a susceptibility locus for squamous cell lung carcinoma (SQ) at 12p13.33 (RAD52, rs6489769), and replicated the association in three independent samples totaling 3,359 SQ cases and 9,100 controls (odds ratio=1.20, Pcombined=2.3×10−8).
Significance
The combination of pathway-based approaches and information on disease specific subtypes can improve the identification of cancer susceptibility loci in heterogeneous diseases.
doi:10.1158/2159-8290.CD-11-0246
PMCID: PMC3354721  PMID: 22585858
Lung cancer; histology; squamous cell carcinoma; pathway analysis; RAD52
6.  An analysis of single nucleotide polymorphisms of 125 DNA repair genes in the Texas genome-wide association study of lung cancer with a replication for the XRCC4 SNPs 
DNA repair  2011;10(4):398-407.
DNA repair genes are important for maintaining genomic stability and limiting carcinogenesis. We analyzed all single nucleotide polymorphisms (SNPs) of 125 DNA repair genes covered by the Illumina HumanHap300 (v1.1) BeadChips in a previously conducted genome-wide association study (GWAS) of 1,154 lung cancer cases and 1,137 controls and replicated the top-hits of XRCC4 SNPs in an independent set of 597 cases and 611 controls in Texas populations. We found that six of 20 XRCC4 SNPs were associated with a decreased risk of lung cancer with a P value of 0.01 or lower in the discovery dataset, of which the most significant SNP was rs10040363 (P for allelic test = 4.89 ×10−4). Moreover, the data in this region allowed us to impute a potentially functional SNP rs2075685 (imputed P for allelic test = 1.3 ×10−3). A luciferase reporter assay demonstrated that the rs2075685G>T change in the XRCC4 promoter increased expression of the gene. In the replication study of rs10040363, rs1478486, rs9293329, and rs2075685, however, only rs10040363 achieved a borderline association with a decreased risk of lung cancer in a dominant model (adjusted OR = 0.80, 95% CI = 0.62–1.03, P = 0.079). In the final combined analysis of both the Texas GWAS discovery and replication datasets, the strength of the association was increased for rs10040363 (adjusted OR = 0.77, 95% CI = 0.66–0.89, Pdominant = 5×10−4 and P for trend = 5×10−4) and rs1478486 (adjusted OR = 0.82, 95% CI = 0.71 −0.94, Pdominant = 6×10−3 and P for trend = 3.5×10−3). Finally, we conducted a meta-analysis of these XRCC4 SNPs with available data from published GWA studies of lung cancer with a total of 12,312 cases and 47,921 controls, in which none of these XRCC4 SNPs was associated with lung cancer risk. It appeared that rs2075685, although associated with increased expression of a reporter gene and lung cancer risk in the Texas populations, did not have an effect on lung cancer risk in other populations. This study underscores the importance of replication using published data in larger populations.
doi:10.1016/j.dnarep.2011.01.005
PMCID: PMC3062723  PMID: 21296624
XRCC4; variant; Genetic susceptibility; genome-wide association study; replication study
8.  Multiple Independent Loci at Chromosome 15q25.1 Affect Smoking Quantity: a Meta-Analysis and Comparison with Lung Cancer and COPD 
PLoS Genetics  2010;6(8):e1001053.
Recently, genetic association findings for nicotine dependence, smoking behavior, and smoking-related diseases converged to implicate the chromosome 15q25.1 region, which includes the CHRNA5-CHRNA3-CHRNB4 cholinergic nicotinic receptor subunit genes. In particular, association with the nonsynonymous CHRNA5 SNP rs16969968 and correlates has been replicated in several independent studies. Extensive genotyping of this region has suggested additional statistically distinct signals for nicotine dependence, tagged by rs578776 and rs588765. One goal of the Consortium for the Genetic Analysis of Smoking Phenotypes (CGASP) is to elucidate the associations among these markers and dichotomous smoking quantity (heavy versus light smoking), lung cancer, and chronic obstructive pulmonary disease (COPD). We performed a meta-analysis across 34 datasets of European-ancestry subjects, including 38,617 smokers who were assessed for cigarettes-per-day, 7,700 lung cancer cases and 5,914 lung-cancer-free controls (all smokers), and 2,614 COPD cases and 3,568 COPD-free controls (all smokers). We demonstrate statistically independent associations of rs16969968 and rs588765 with smoking (mutually adjusted p-values<10−35 and <10−8 respectively). Because the risk alleles at these loci are negatively correlated, their association with smoking is stronger in the joint model than when each SNP is analyzed alone. Rs578776 also demonstrates association with smoking after adjustment for rs16969968 (p<10−6). In models adjusting for cigarettes-per-day, we confirm the association between rs16969968 and lung cancer (p<10−20) and observe a nominally significant association with COPD (p = 0.01); the other loci are not significantly associated with either lung cancer or COPD after adjusting for rs16969968. This study provides strong evidence that multiple statistically distinct loci in this region affect smoking behavior. This study is also the first report of association between rs588765 (and correlates) and smoking that achieves genome-wide significance; these SNPs have previously been associated with mRNA levels of CHRNA5 in brain and lung tissue.
Author Summary
Nicotine binds to cholinergic nicotinic receptors, which are composed of a variety of subunits. Genetic studies for smoking behavior and smoking-related diseases have implicated a genomic region that encodes the alpha5, alpha3, and beta4 subunits. We examined genetic data across this region for over 38,000 smokers, a subset of which had been assessed for lung cancer or chronic obstructive pulmonary disease. We demonstrate strong evidence that there are at least two statistically independent loci in this region that affect risk for heavy smoking. One of these loci represents a change in the protein structure of the alpha5 subunit. This work is also the first to report strong evidence of association between smoking and a group of genetic variants that are of biological interest because of their links to expression of the alpha5 cholinergic nicotinic receptor subunit gene. These advances in understanding the genetic influences on smoking behavior are important because of the profound public health burdens caused by smoking and nicotine addiction.
doi:10.1371/journal.pgen.1001053
PMCID: PMC2916847  PMID: 20700436
9.  International Lung Cancer Consortium: Pooled Analysis of Sequence Variants in DNA Repair and Cell Cycle Pathways 
Background
The International Lung Cancer Consortium was established in 2004. To clarify the role of DNA repair genes in lung cancer susceptibility, we conducted a pooled analysis of genetic variants in DNA repair pathways, whose associations have been investigated by at least 3 individual studies.
Methods
Data from 14 studies were pooled for 18 sequence variants in 12 DNA repair genes, including APEX1, OGG1, XRCC1, XRCC2, XRCC3, ERCC1, XPD, XPF, XPG, XPA, MGMT, and TP53. The total number of subjects included in the analysis for each variant ranged from 2,073 to 13,955 subjects.
Results
Four of the variants were found to be weakly associated with lung cancer risk with borderline significance: these were XRCC3 T241M [heterozygote odds ratio (OR), 0.89; 95% confidence interval (95% CI), 0.79–0.99 and homozygote OR, 0.84; 95% CI, 0.71–1.00] based on 3,467 cases and 5,021 controls from 8 studies, XPD K751Q (heterozygote OR, 0.99; 95% CI, 0.89–1.10 and homozygote OR, 1.19; 95% CI, 1.02–1.39) based on 6,463 cases and 6,603 controls from 9 studies, and TP53 R72P (heterozygote OR, 1.14; 95% CI, 1.00–1.29 and homozygote OR, 1.20; 95% CI, 1.02–1.42) based on 3,610 cases and 5,293 controls from 6 studies. OGG1 S326C homozygote was suggested to be associated with lung cancer risk in Caucasians (homozygote OR, 1.34; 95% CI, 1.01–1.79) based on 2,569 cases and 4,178 controls from 4 studies but not in Asians. The other 14 variants did not exhibit main effects on lung cancer risk.
Discussion
In addition to data pooling, future priorities of International Lung Cancer Consortium include coordinated genotyping and multistage validation for ongoing genome-wide association studies.
doi:10.1158/1055-9965.EPI-08-0411
PMCID: PMC2756735  PMID: 18990748

Results 1-9 (9)