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Meta-Analysis
. 2018 Feb 8;9(1):556.
doi: 10.1038/s41467-018-02942-5.

Genome-wide Meta-Analysis Identifies Five New Susceptibility Loci for Pancreatic Cancer

Alison P Klein  1   2 Brian M Wolpin  3 Harvey A Risch  4 Rachael Z Stolzenberg-Solomon  5 Evelina Mocci  6 Mingfeng Zhang  7 Federico Canzian  8 Erica J Childs  6 Jason W Hoskins  7 Ashley Jermusyk  7 Jun Zhong  7 Fei Chen  6 Demetrius Albanes  5 Gabriella Andreotti  5 Alan A Arslan  9   10   11 Ana Babic  3 William R Bamlet  12 Laura Beane-Freeman  5 Sonja I Berndt  5 Amanda Blackford  6 Michael Borges  13 Ayelet Borgida  14 Paige M Bracci  15 Lauren Brais  3 Paul Brennan  16 Hermann Brenner  17   18   19 Bas Bueno-de-Mesquita  20   21   22   23 Julie Buring  24   25 Daniele Campa  26 Gabriele Capurso  27 Giulia Martina Cavestro  28 Kari G Chaffee  12 Charles C Chung  5   29 Sean Cleary  14 Michelle Cotterchio  30   31 Frederike Dijk  32 Eric J Duell  33 Lenka Foretova  34 Charles Fuchs  35 Niccola Funel  36 Steven Gallinger  14 J Michael M Gaziano  37   38 Maria Gazouli  39 Graham G Giles  40   41   42 Edward Giovannucci  3 Michael Goggins  13 Gary E Goodman  43 Phyllis J Goodman  44 Thilo Hackert  45 Christopher Haiman  46 Patricia Hartge  5 Manal Hasan  47 Peter Hegyi  48 Kathy J Helzlsouer  49 Joseph Herman  50 Ivana Holcatova  51 Elizabeth A Holly  15 Robert Hoover  5 Rayjean J Hung  14 Eric J Jacobs  52 Krzysztof Jamroziak  53 Vladimir Janout  54   55 Rudolf Kaaks  56 Kay-Tee Khaw  57 Eric A Klein  58 Manolis Kogevinas  59   60   61   62 Charles Kooperberg  43 Matthew H Kulke  3 Juozas Kupcinskas  63 Robert J Kurtz  64 Daniel Laheru  6 Stefano Landi  26 Rita T Lawlor  65 I-Min Lee  24   66 Loic LeMarchand  67 Lingeng Lu  4 Núria Malats  68   69 Andrea Mambrini  70 Satu Mannisto  71 Roger L Milne  40   41 Beatrice Mohelníková-Duchoňová  72 Rachel E Neale  73 John P Neoptolemos  74 Ann L Oberg  12 Sara H Olson  75 Irene Orlow  75 Claudio Pasquali  76 Alpa V Patel  52 Ulrike Peters  43 Raffaele Pezzilli  77 Miquel Porta  60   61 Francisco X Real  69   78   79 Nathaniel Rothman  5 Ghislaine Scelo  16 Howard D Sesso  24   25 Gianluca Severi  40   41   80 Xiao-Ou Shu  81 Debra Silverman  5 Jill P Smith  82 Pavel Soucek  83 Malin Sund  84 Renata Talar-Wojnarowska  85 Francesca Tavano  86 Mark D Thornquist  43 Geoffrey S Tobias  5 Stephen K Van Den Eeden  87 Yogesh Vashist  88 Kala Visvanathan  89 Pavel Vodicka  90 Jean Wactawski-Wende  91 Zhaoming Wang  92 Nicolas Wentzensen  5 Emily White  43   93 Herbert Yu  67 Kai Yu  5 Anne Zeleniuch-Jacquotte  10   94 Wei Zheng  81 Peter Kraft  25   95 Donghui Li  96 Stephen Chanock  5 Ofure Obazee  8 Gloria M Petersen  12 Laufey T Amundadottir  97
Affiliations
Free PMC article
Meta-Analysis

Genome-wide Meta-Analysis Identifies Five New Susceptibility Loci for Pancreatic Cancer

Alison P Klein et al. Nat Commun. .
Free PMC article

Abstract

In 2020, 146,063 deaths due to pancreatic cancer are estimated to occur in Europe and the United States combined. To identify common susceptibility alleles, we performed the largest pancreatic cancer GWAS to date, including 9040 patients and 12,496 controls of European ancestry from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Here, we find significant evidence of a novel association at rs78417682 (7p12/TNS3, P = 4.35 × 10-8). Replication of 10 promising signals in up to 2737 patients and 4752 controls from the PANcreatic Disease ReseArch (PANDoRA) consortium yields new genome-wide significant loci: rs13303010 at 1p36.33 (NOC2L, P = 8.36 × 10-14), rs2941471 at 8q21.11 (HNF4G, P = 6.60 × 10-10), rs4795218 at 17q12 (HNF1B, P = 1.32 × 10-8), and rs1517037 at 18q21.32 (GRP, P = 3.28 × 10-8). rs78417682 is not statistically significantly associated with pancreatic cancer in PANDoRA. Expression quantitative trait locus analysis in three independent pancreatic data sets provides molecular support of NOC2L as a pancreatic cancer susceptibility gene.

Conflict of interest statement

The authors declare no competing financial interests.

Figures

Fig. 1
Fig. 1
Association results, recombination hotspots, and LD plots for new pancreatic cancer susceptibility regions. The top half of each panel shows the association results for the meta-analysis of PanScan I+II, PanScan III, and PanC4 (gray diamonds). The results for the replication of the marker SNP at each locus are shown for PANDoRA (light blue diamonds) and the combined meta-analysis results (red diamonds). Overlaid are likelihood ratio statistics estimating putative recombination hotspots across the region based on the inference using the CEU 1000 G Phase 3 data. Genomic coordinates are plotted on the x axis (Genome build hg19), P values for the association analysis are shown on the left y axis, and recombination hotspot likelihood ratio on the right y axis. The bottom half of each panel shows LD heat maps based on r2 values from the 1000 G Phase 3 CEU population for all variants included in the analysis. Shown are results for chromosomes 1p36.33 (a), 8q21.11 (b), 17q12 (c), 18q21.32 (d), and 7p12 (e)
Fig. 2
Fig. 2
Functional analysis of the 1p36.33 risk locus. a The set of most likely functional variants at 1p36.33 and their P value rank (1–10, in red) is shown as well as overlapping RefSeq genes on chr1: 885,555-904,522 (NCBI GRCh37/Hg19). ENCODE data for histone modification marks (H3K4me1, H3K4me3, H3K27Ac) are indicated by colored density plots. Open chromatin (DNase hypersensitivity regions, DNase clusters) and binding of transcription factors (TF ChIP) are indicated by horizontal bars. The numbers next to each bar indicate the number of cell lines with DNase clusters, or the number of different transcription factors bound across all tested cell lines. The panel is adapted from the UCSC Genome Browser. b Expression QTLs in histologically normal autopsy-derived pancreatic tissues (n = 149) from the GTEx consortium (GTEx), the Laboratory of Translational Genomics histologically normal adjacent-to-tumor pancreatic tissue set (LTG, n = 95), and the TCGA pancreatic cancer tissue set (TCGA/PAAD, n = 115). Normalized NOC2L expression is shown on the y axis and genotypes at the marker SNP at 1p36.33 on the x axis. Risk-increasing alleles are marked in red. Note that no samples in the LTG and TCGA/PAAD sets were of the minor homozygous risk genotype (GG). The box-and-whisker plots show the median (horizontal middle line within each box), interquartile range (top and bottom horizontal lines of each box), and 1.5 times the IQR (whiskers). c Analysis of the effects of 1p36.33 variants on transcription factor motifs for rs13303160 (r2 = 0.93 with rs13303010 in 1000 G EUR). The risk allele (C) at this marker alters predicted DNA-binding motifs for SMARCC1 and AP-1 proteins

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