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Multicenter Study
. 2014 Dec 15;23(24):6616-33.
doi: 10.1093/hmg/ddu363. Epub 2014 Jul 15.

Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33

Zhaoming Wang  1 , Bin Zhu  2 , Mingfeng Zhang  2 , Hemang Parikh  2 , Jinping Jia  2 , Charles C Chung  1 , Joshua N Sampson  2 , Jason W Hoskins  2 , Amy Hutchinson  1 , Laurie Burdette  1 , Abdisamad Ibrahim  2 , Christopher Hautman  1 , Preethi S Raj  2 , Christian C Abnet  2 , Andrew A Adjei  3 , Anders Ahlbom  4 , Demetrius Albanes  2 , Naomi E Allen  5 , Christine B Ambrosone  6 , Melinda Aldrich  7 , Pilar Amiano  8 , Christopher Amos  9 , Ulrika Andersson  10 , Gerald Andriole Jr  11 , Irene L Andrulis  12 , Cecilia Arici  13 , Alan A Arslan  14 , Melissa A Austin  15 , Dalsu Baris  2 , Donald A Barkauskas  16 , Bryan A Bassig  17 , Laura E Beane Freeman  2 , Christine D Berg  18 , Sonja I Berndt  2 , Pier Alberto Bertazzi  19 , Richard B Biritwum  3 , Amanda Black  2 , William Blot  20 , Heiner Boeing  21 , Paolo Boffetta  22 , Kelly Bolton  23 , Marie-Christine Boutron-Ruault  24 , Paige M Bracci  25 , Paul Brennan  26 , Louise A Brinton  2 , Michelle Brotzman  27 , H Bas Bueno-de-Mesquita  28 , Julie E Buring  29 , Mary Ann Butler  30 , Qiuyin Cai  7 , Geraldine Cancel-Tassin  31 , Federico Canzian  32 , Guangwen Cao  33 , Neil E Caporaso  2 , Alfredo Carrato  34 , Tania Carreon  30 , Angela Carta  12 , Gee-Chen Chang  35 , I-Shou Chang  36 , Jenny Chang-Claude  32 , Xu Che  37 , Chien-Jen Chen  38 , Chih-Yi Chen  39 , Chung-Hsing Chen  36 , Constance Chen  40 , Kuan-Yu Chen  41 , Yuh-Min Chen  42 , Anand P Chokkalingam  43 , Lisa W Chu  44 , Francoise Clavel-Chapelon  45 , Graham A Colditz  46 , Joanne S Colt  2 , David Conti  16 , Michael B Cook  2 , Victoria K Cortessis  16 , E David Crawford  47 , Olivier Cussenot  48 , Faith G Davis  49 , Immaculata De Vivo  50 , Xiang Deng  1 , Ti Ding  51 , Colin P Dinney  52 , Anna Luisa Di Stefano  53 , W Ryan Diver  54 , Eric J Duell  55 , Joanne W Elena  56 , Jin-Hu Fan  57 , Heather Spencer Feigelson  58 , Maria Feychting  4 , Jonine D Figueroa  2 , Adrienne M Flanagan  59 , Joseph F Fraumeni Jr  2 , Neal D Freedman  2 , Brooke L Fridley  60 , Charles S Fuchs  61 , Manuela Gago-Dominguez  62 , Steven Gallinger  63 , Yu-Tang Gao  64 , Susan M Gapstur  54 , Montserrat Garcia-Closas  65 , Reina Garcia-Closas  66 , Julie M Gastier-Foster  67 , J Michael Gaziano  68 , Daniela S Gerhard  69 , Carol A Giffen  70 , Graham G Giles  71 , Elizabeth M Gillanders  72 , Edward L Giovannucci  73 , Michael Goggins  74 , Nalan Gokgoz  75 , Alisa M Goldstein  2 , Carlos Gonzalez  76 , Richard Gorlick  77 , Mark H Greene  2 , Myron Gross  78 , H Barton Grossman  52 , Robert Grubb 3rd  79 , Jian Gu  80 , Peng Guan  81 , Christopher A Haiman  82 , Goran Hallmans  83 , Susan E Hankinson  84 , Curtis C Harris  85 , Patricia Hartge  2 , Claudia Hattinger  86 , Richard B Hayes  87 , Qincheng He  81 , Lee Helman  88 , Brian E Henderson  82 , Roger Henriksson  10 , Judith Hoffman-Bolton  89 , Chancellor Hohensee  90 , Elizabeth A Holly  25 , Yun-Chul Hong  91 , Robert N Hoover  2 , H Dean Hosgood 3rd  92 , Chin-Fu Hsiao  93 , Ann W Hsing  94 , Chao Agnes Hsiung  95 , Nan Hu  2 , Wei Hu  2 , Zhibin Hu  96 , Ming-Shyan Huang  41 , David J Hunter  97 , Peter D Inskip  2 , Hidemi Ito  98 , Eric J Jacobs  54 , Kevin B Jacobs  99 , Mazda Jenab  26 , Bu-Tian Ji  2 , Christoffer Johansen  100 , Mattias Johansson  101 , Alison Johnson  102 , Rudolf Kaaks  32 , Ashish M Kamat  52 , Aruna Kamineni  103 , Margaret Karagas  9 , Chand Khanna  88 , Kay-Tee Khaw  104 , Christopher Kim  2 , In-Sam Kim  105 , Jin Hee Kim  106 , Yeul Hong Kim  107 , Young-Chul Kim  108 , Young Tae Kim  109 , Chang Hyun Kang  109 , Yoo Jin Jung  109 , Cari M Kitahara  2 , Alison P Klein  110 , Robert Klein  111 , Manolis Kogevinas  112 , Woon-Puay Koh  113 , Takashi Kohno  114 , Laurence N Kolonel  115 , Charles Kooperberg  90 , Christian P Kratz  2 , Vittorio Krogh  116 , Hideo Kunitoh  117 , Robert C Kurtz  111 , Nilgun Kurucu  118 , Qing Lan  2 , Mark Lathrop  119 , Ching C Lau  120 , Fernando Lecanda  121 , Kyoung-Mu Lee  122 , Maxwell P Lee  88 , Loic Le Marchand  115 , Seth P Lerner  123 , Donghui Li  124 , Linda M Liao  2 , Wei-Yen Lim  125 , Dongxin Lin  126 , Jie Lin  80 , Sara Lindstrom  40 , Martha S Linet  2 , Jolanta Lissowska  127 , Jianjun Liu  128 , Börje Ljungberg  129 , Josep Lloreta  130 , Daru Lu  131 , Jing Ma  132 , Nuria Malats  133 , Satu Mannisto  134 , Neyssa Marina  135 , Giuseppe Mastrangelo  136 , Keitaro Matsuo  137 , Katherine A McGlynn  2 , Roberta McKean-Cowdin  80 , Lorna H McNeill  138 , Robert R McWilliams  139 , Beatrice S Melin  10 , Paul S Meltzer  88 , James E Mensah  3 , Xiaoping Miao  140 , Dominique S Michaud  141 , Alison M Mondul  2 , Lee E Moore  2 , Kenneth Muir  142 , Shelley Niwa  27 , Sara H Olson  143 , Nick Orr  144 , Salvatore Panico  145 , Jae Yong Park  146 , Alpa V Patel  54 , Ana Patino-Garcia  121 , Sofia Pavanello  136 , Petra H M Peeters  147 , Beata Peplonska  148 , Ulrike Peters  90 , Gloria M Petersen  139 , Piero Picci  86 , Malcolm C Pike  149 , Stefano Porru  13 , Jennifer Prescott  50 , Xia Pu  80 , Mark P Purdue  2 , You-Lin Qiao  150 , Preetha Rajaraman  2 , Elio Riboli  151 , Harvey A Risch  152 , Rebecca J Rodabough  90 , Nathaniel Rothman  2 , Avima M Ruder  30 , Jeong-Seon Ryu  153 , Marc Sanson  53 , Alan Schned  9 , Fredrick R Schumacher  82 , Ann G Schwartz  154 , Kendra L Schwartz  155 , Molly Schwenn  156 , Katia Scotlandi  86 , Adeline Seow  125 , Consol Serra  157 , Massimo Serra  86 , Howard D Sesso  29 , Gianluca Severi  71 , Hongbing Shen  96 , Min Shen  2 , Sanjay Shete  158 , Kouya Shiraishi  114 , Xiao-Ou Shu  7 , Afshan Siddiq  159 , Luis Sierrasesumaga  121 , Sabina Sierri  160 , Alan Dart Loon Sihoe  161 , Debra T Silverman  2 , Matthias Simon  162 , Melissa C Southey  163 , Logan Spector  164 , Margaret Spitz  165 , Meir Stampfer  132 , Par Stattin  129 , Mariana C Stern  82 , Victoria L Stevens  54 , Rachael Z Stolzenberg-Solomon  2 , Daniel O Stram  82 , Sara S Strom  166 , Wu-Chou Su  167 , Malin Sund  168 , Sook Whan Sung  169 , Anthony Swerdlow  170 , Wen Tan  126 , Hideo Tanaka  98 , Wei Tang  2 , Ze-Zhang Tang  51 , Adonina Tardon  171 , Evelyn Tay  3 , Philip R Taylor  2 , Yao Tettey  3 , David M Thomas  172 , Roberto Tirabosco  173 , Anne Tjonneland  174 , Geoffrey S Tobias  2 , Jorge R Toro  2 , Ruth C Travis  5 , Dimitrios Trichopoulos  175 , Rebecca Troisi  2 , Ann Truelove  27 , Ying-Huang Tsai  176 , Margaret A Tucker  2 , Rosario Tumino  177 , David Van Den Berg  82 , Stephen K Van Den Eeden  178 , Roel Vermeulen  179 , Paolo Vineis  180 , Kala Visvanathan  89 , Ulla Vogel  181 , Chaoyu Wang  2 , Chengfeng Wang  37 , Junwen Wang  182 , Sophia S Wang  183 , Elisabete Weiderpass  184 , Stephanie J Weinstein  2 , Nicolas Wentzensen  2 , William Wheeler  70 , Emily White  90 , John K Wiencke  185 , Alicja Wolk  186 , Brian M Wolpin  61 , Maria Pik Wong  187 , Margaret Wrensch  185 , Chen Wu  126 , Tangchun Wu  136 , Xifeng Wu  80 , Yi-Long Wu  188 , Jay S Wunder  11 , Yong-Bing Xiang  64 , Jun Xu  189 , Hannah P Yang  2 , Pan-Chyr Yang  41 , Yasushi Yatabe  190 , Yuanqing Ye  80 , Edward D Yeboah  3 , Zhihua Yin  81 , Chen Ying  125 , Chong-Jen Yu  167 , Kai Yu  2 , Jian-Min Yuan  191 , Krista A Zanetti  56 , Anne Zeleniuch-Jacquotte  192 , Wei Zheng  7 , Baosen Zhou  81 , Lisa Mirabello  2 , Sharon A Savage  2 , Peter Kraft  193 , Stephen J Chanock  1 , Meredith Yeager  1 , Maria Terese Landi  2 , Jianxin Shi  2 , Nilanjan Chatterjee  2 , Laufey T Amundadottir  194
Affiliations
Multicenter Study

Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33

Zhaoming Wang et al. Hum Mol Genet. .

Abstract

Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.

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Figures

Figure 1.
Figure 1.
Sequential conditional analyses and ASSET meta-analyses identified up to six independent signals for the TERT-CLPTM1L region on chromosome 5p15.33. SNPs marking each region are plotted in the upper panel with two P-values (solid diamonds correspond to an unconditional test and open diamonds correspond to a conditional test) on a negative log scale (left y-axis) against genomic coordinates (x-axis, hg19). Cancers from different GWAS scans (acronyms detailed in box in top panel) that are associated within each region in the subset meta-analysis are listed (red, positively associated; green, negatively associated) from the unconditional ASSET meta-analysis. Effect alleles are shown next to SNP identifiers. Recombination hotspots (curved lines, top panel) were inferred from three populations from the DCEG Imputation Reference Set version 1 (red, CEU; green, ASN; blue, YRI) as the likelihood ratio statistics (right y-axis). Also shown are the gene structures for TERT, MIR4457 and CLPTM1L (middle panel), and LD heat map based on r2 using the 1000 Genomes CEU population (lower panel). Results are shown for the ALL analysis except the region marked by rs10069690 (top panel) and labeled with a ‘*’ that was identified in the European ancestry-only analysis (EUR).
Figure 2.
Figure 2.
(A–F) Forest plots for individual risk loci on chr5p15.33 for the unconditional ASSET meta-analysis. For each cancer/GWAS scan, OR and 95% CI were listed and plotted along each line as per the unconditional association analysis. A vertical line of OR = 1 indicates the null. Two summary lines list ORs for the positively or negatively associated subsets as estimated by the ASSET program. (A) rs7726159, (B) rs451360, (C) rs2853677, (D) rs2736098, (E) rs13172201 and (F) rs10069690 in the analysis of European-ancestry studies only. Forest plots for the conditional analyses are shown in Supplementary Material, Figure S1A–E.
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