Abstract
Recent studies have found that cancer–testis (CT) genes, which are expressed predominantly in germ and cancer cells, may be candidate cancer drivers. Because of their crucial roles, genetic variants in these genes may contribute to the development of cancer. Here, we systematically evaluated associations of common variants in CT genes and their promoters for the risk of lung cancer in our initial GWAS (2331 cases and 3077 controls), followed by in silico replication using additional 10,512 lung cancer cases and 9562 controls. We found a significant association between rs3747093 located in the CCDC116 promoter and lung cancer risk (OR = 0.91, P meta = 7.81 × 10−6). Although CCDC116 was expressed at lower levels in somatic tissues compared to the testis, the protective allele A of rs3747093 was associated with decreased CCDC116 expression in many normal tissues, including the lung (P = 8.1 × 10−13). We subsequently genotyped this variant in another four commonly diagnosed cancers (gastric, esophageal, colorectal, and breast cancers), as we found expression quantitative trait locus (eQTL) signals for rs3747093 and CCDC116 in their corresponding normal tissues. Interestingly, we observed consistent associations between rs3747093 and multiple cancers (gastric cancer: OR = 0.85, P = 2.21 × 10−4; esophageal cancer: OR = 0.91, P = 2.57 × 10−2; colorectal cancer: OR = 0.80, P = 1.85 × 10−6; and breast cancer: OR = 0.87, P = 1.55 × 10−3). Taken together, the A allele of rs3747093 showed significant protective effects on cancer risk (OR = 0.88, P pool = 6.52 × 10−13) in an Asian population. Moreover, our findings suggest that low abundance expression of CT genes in normal tissues may also contribute to tumorigenesis, providing a new mechanism of CT genes in the development of cancer.
Abbreviations
- CT:
-
Cancer–testis
- GWAS:
-
Genome-wide association study
- eQTL:
-
Expression quantitative trait locus
- SNP:
-
Single nucleotide polymorphism
- QC:
-
Quality control
- FDR:
-
False discovery rate
- ENCODE:
-
Encyclopedia of DNA elements
- GTEx:
-
The genotype-tissue expression
- LD:
-
Linkage disequilibrium
- HWE:
-
Hardy–Weinberg equilibrium
- AICNA:
-
Allele-imbalanced copy number aberrations
- TSS:
-
Transcription start site
- FLCCA:
-
Female Lung Cancer Consortium in Asia
- NCI:
-
National Cancer Institute
- EAGLE:
-
Environment and genetics in lung cancer etiology
- ATBC:
-
Alpha-tocopherol, beta-carotene cancer prevention study
- PLCO:
-
Prostate, lung, colon, ovary screening trial
- CPS-II:
-
Cancer Prevention Study II Nutrition Cohort
- MAF:
-
Minor allele frequency
- PCA:
-
Principal-component analysis
- LUAD:
-
Lung adenocarcinoma
- LUSC:
-
Lung squamous cell carcinoma
- ORs:
-
Odds ratios
- CIs:
-
Confidence intervals
References
(1994) The alpha-tocopherol, beta-carotene lung cancer prevention study: design, methods, participant characteristics, and compliance. The ATBC Cancer Prevention Study Group. Ann Epidemiol 4:1–10
Bentham J, Morris DL, Cunninghame Graham DS, Pinder CL, Tombleson P, Behrens TW, Martin J, Fairfax BP, Knight JC, Chen L, Replogle J, Syvanen AC, Ronnblom L, Graham RR, Wither JE, Rioux JD, Alarcon-Riquelme ME, Vyse TJ (2015) Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus. Nat Genet 47:1457–1464. doi:10.1038/ng.3434
Boon T, Cerottini JC, Van den Eynde B, van der Bruggen P, Van Pel A (1994) Tumor antigens recognized by T lymphocytes. Annu Rev Immunol 12:337–365. doi:10.1146/annurev.iy.12.040194.002005
Calle EE, Rodriguez C, Jacobs EJ, Almon ML, Chao A, McCullough ML, Feigelson HS, Thun MJ (2002) The American Cancer Society Cancer Prevention Study II Nutrition Cohort: rationale, study design, and baseline characteristics. Cancer 94:2490–2501. doi:10.1002/cncr.101970
Cantor RM, Lange K, Sinsheimer JS (2010) Prioritizing GWAS results: a review of statistical methods and recommendations for their application. Am J Hum Genet 86:6–22. doi:10.1016/j.ajhg.2009.11.017
Chen M, Ni J, Chang HC, Lin CY, Muyan M, Yeh S (2009) CCDC62/ERAP75 functions as a coactivator to enhance estrogen receptor beta-mediated transactivation and target gene expression in prostate cancer cells. Carcinogenesis 30:841–850. doi:10.1093/carcin/bgn288
Chung SA, Taylor KE, Graham RR, Nititham J, Lee AT, Ortmann WA, Jacob CO, Alarcon-Riquelme ME, Tsao BP, Harley JB, Gaffney PM, Moser KL, Slegen Petri M, Demirci FY, Kamboh MI, Manzi S, Gregersen PK, Langefeld CD, Behrens TW, Criswell LA (2011) Differential genetic associations for systemic lupus erythematosus based on anti-dsDNA autoantibody production. PLoS Genet 7:e1001323. doi:10.1371/journal.pgen.1001323
Dubois PC, Trynka G, Franke L, Hunt KA, Romanos J, Curtotti A, Zhernakova A, Heap GA, Adany R, Aromaa A, Bardella MT, van den Berg LH, Bockett NA, de la Concha EG, Dema B, Fehrmann RS, Fernandez-Arquero M, Fiatal S, Grandone E, Green PM, Groen HJ, Gwilliam R, Houwen RH, Hunt SE, Kaukinen K, Kelleher D, Korponay-Szabo I, Kurppa K, MacMathuna P, Maki M, Mazzilli MC, McCann OT, Mearin ML, Mein CA, Mirza MM, Mistry V, Mora B, Morley KI, Mulder CJ, Murray JA, Nunez C, Oosterom E, Ophoff RA, Polanco I, Peltonen L, Platteel M, Rybak A, Salomaa V, Schweizer JJ, Sperandeo MP, Tack GJ, Turner G, Veldink JH, Verbeek WH, Weersma RK, Wolters VM, Urcelay E, Cukrowska B, Greco L, Neuhausen SL, McManus R, Barisani D, Deloukas P, Barrett JC, Saavalainen P, Wijmenga C, van Heel DA (2010) Multiple common variants for celiac disease influencing immune gene expression. Nat Genet 42:295–302. doi:10.1038/ng.543
Figueiredo JC, Hsu L, Hutter CM, Lin Y, Campbell PT, Baron JA, Berndt SI, Jiao S, Casey G, Fortini B, Chan AT, Cotterchio M, Lemire M, Gallinger S, Harrison TA, Le Marchand L, Newcomb PA, Slattery ML, Caan BJ, Carlson CS, Zanke BW, Rosse SA, Brenner H, Giovannucci EL, Wu K, Chang-Claude J, Chanock SJ, Curtis KR, Duggan D, Gong J, Haile RW, Hayes RB, Hoffmeister M, Hopper JL, Jenkins MA, Kolonel LN, Qu C, Rudolph A, Schoen RE, Schumacher FR, Seminara D, Stelling DL, Thibodeau SN, Thornquist M, Warnick GS, Henderson BE, Ulrich CM, Gauderman WJ, Potter JD, White E, Peters U, Ccfr Gecco (2014) Genome-wide diet-gene interaction analyses for risk of colorectal cancer. PLoS Genet 10:e1004228. doi:10.1371/journal.pgen.1004228
Firat-Karalar EN, Sante J, Elliott S, Stearns T (2014) Proteomic analysis of mammalian sperm cells identifies new components of the centrosome. J Cell Sci 127:4128–4133. doi:10.1242/jcs.157008
Franke A, McGovern DP, Barrett JC, Wang K, Radford-Smith GL, Ahmad T, Lees CW, Balschun T, Lee J, Roberts R, Anderson CA, Bis JC, Bumpstead S, Ellinghaus D, Festen EM, Georges M, Green T, Haritunians T, Jostins L, Latiano A, Mathew CG, Montgomery GW, Prescott NJ, Raychaudhuri S, Rotter JI, Schumm P, Sharma Y, Simms LA, Taylor KD, Whiteman D, Wijmenga C, Baldassano RN, Barclay M, Bayless TM, Brand S, Buning C, Cohen A, Colombel JF, Cottone M, Stronati L, Denson T, De Vos M, D’Inca R, Dubinsky M, Edwards C, Florin T, Franchimont D, Gearry R, Glas J, Van Gossum A, Guthery SL, Halfvarson J, Verspaget HW, Hugot JP, Karban A, Laukens D, Lawrance I, Lemann M, Levine A, Libioulle C, Louis E, Mowat C, Newman W, Panes J, Phillips A, Proctor DD, Regueiro M, Russell R, Rutgeerts P, Sanderson J, Sans M, Seibold F, Steinhart AH, Stokkers PC, Torkvist L, Kullak-Ublick G, Wilson D, Walters T, Targan SR, Brant SR, Rioux JD, D’Amato M, Weersma RK, Kugathasan S, Griffiths AM, Mansfield JC, Vermeire S, Duerr RH, Silverberg MS, Satsangi J, Schreiber S, Cho JH, Annese V, Hakonarson H, Daly MJ, Parkes M (2010) Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci. Nat Genet 42:1118–1125. doi:10.1038/ng.717
Geng Q, Ni L, Ouyang B, Hu Y, Zhao Y, Guo J (2016) A novel testis-specific gene, Ccdc136, is required for acrosome formation and fertilization in mice. Reprod Sci. doi:10.1177/1933719116641762
Gonczy P (2015) Centrosomes and cancer: revisiting a long-standing relationship. Nat Rev Cancer 15:639–652. doi:10.1038/nrc3995
Grivennikov SI, Greten FR, Karin M (2010) Immunity, inflammation, and cancer. Cell 140:883–899. doi:10.1016/j.cell.2010.01.025
Han JW, Zheng HF, Cui Y, Sun LD, Ye DQ, Hu Z, Xu JH, Cai ZM, Huang W, Zhao GP, Xie HF, Fang H, Lu QJ, Xu JH, Li XP, Pan YF, Deng DQ, Zeng FQ, Ye ZZ, Zhang XY, Wang QW, Hao F, Ma L, Zuo XB, Zhou FS, Du WH, Cheng YL, Yang JQ, Shen SK, Li J, Sheng YJ, Zuo XX, Zhu WF, Gao F, Zhang PL, Guo Q, Li B, Gao M, Xiao FL, Quan C, Zhang C, Zhang Z, Zhu KJ, Li Y, Hu DY, Lu WS, Huang JL, Liu SX, Li H, Ren YQ, Wang ZX, Yang CJ, Wang PG, Zhou WM, Lv YM, Zhang AP, Zhang SQ, Lin D, Li Y, Low HQ, Shen M, Zhai ZF, Wang Y, Zhang FY, Yang S, Liu JJ, Zhang XJ (2009) Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus. Nat Genet 41:1234–1237. doi:10.1038/ng.472
Hayes RB, Sigurdson A, Moore L, Peters U, Huang WY, Pinsky P, Reding D, Gelmann EP, Rothman N, Pfeiffer RM, Hoover RN, Berg CD, Team PT (2005) Methods for etiologic and early marker investigations in the PLCO trial. Mutat Res 592:147–154. doi:10.1016/j.mrfmmm.2005.06.013
Her J, Soo Lee N, Kim Y, Kim H (2016) Factors forming the BRCA1-A complex orchestrate BRCA1 recruitment to the sites of DNA damage. Acta Biochim Biophys Sin (Shanghai) 48:658–664. doi:10.1093/abbs/gmw047
Hindorff LA, Sethupathy P, Junkins HA, Ramos EM, Mehta JP, Collins FS, Manolio TA (2009) Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc Natl Acad Sci USA 106:9362–9367. doi:10.1073/pnas.0903103106
Hofmann O, Caballero OL, Stevenson BJ, Chen YT, Cohen T, Chua R, Maher CA, Panji S, Schaefer U, Kruger A, Lehvaslaiho M, Carninci P, Hayashizaki Y, Jongeneel CV, Simpson AJ, Old LJ, Hide W (2008) Genome-wide analysis of cancer/testis gene expression. Proc Natl Acad Sci USA 105:20422–20427. doi:10.1073/pnas.0810777105
Hu Z, Wu C, Shi Y, Guo H, Zhao X, Yin Z, Yang L, Dai J, Hu L, Tan W, Li Z, Deng Q, Wang J, Wu W, Jin G, Jiang Y, Yu D, Zhou G, Chen H, Guan P, Chen Y, Shu Y, Xu L, Liu X, Liu L, Xu P, Han B, Bai C, Zhao Y, Zhang H, Yan Y, Ma H, Chen J, Chu M, Lu F, Zhang Z, Chen F, Wang X, Jin L, Lu J, Zhou B, Lu D, Wu T, Lin D, Shen H (2011) A genome-wide association study identifies two new lung cancer susceptibility loci at 13q12.12 and 22q12.2 in Han Chinese. Nat Genet 43:792–796. doi:10.1038/ng.875
Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP, Hui KY, Lee JC, Schumm LP, Sharma Y, Anderson CA, Essers J, Mitrovic M, Ning K, Cleynen I, Theatre E, Spain SL, Raychaudhuri S, Goyette P, Wei Z, Abraham C, Achkar JP, Ahmad T, Amininejad L, Ananthakrishnan AN, Andersen V, Andrews JM, Baidoo L, Balschun T, Bampton PA, Bitton A, Boucher G, Brand S, Buning C, Cohain A, Cichon S, D’Amato M, De Jong D, Devaney KL, Dubinsky M, Edwards C, Ellinghaus D, Ferguson LR, Franchimont D, Fransen K, Gearry R, Georges M, Gieger C, Glas J, Haritunians T, Hart A, Hawkey C, Hedl M, Hu X, Karlsen TH, Kupcinskas L, Kugathasan S, Latiano A, Laukens D, Lawrance IC, Lees CW, Louis E, Mahy G, Mansfield J, Morgan AR, Mowat C, Newman W, Palmieri O, Ponsioen CY, Potocnik U, Prescott NJ, Regueiro M, Rotter JI, Russell RK, Sanderson JD, Sans M, Satsangi J, Schreiber S, Simms LA, Sventoraityte J, Targan SR, Taylor KD, Tremelling M, Verspaget HW, De Vos M, Wijmenga C, Wilson DC, Winkelmann J, Xavier RJ, Zeissig S, Zhang B, Zhang CK, Zhao H, International IBDGC, Silverberg MS, Annese V, Hakonarson H, Brant SR, Radford-Smith G, Mathew CG, Rioux JD et al (2012) Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491:119–124. doi:10.1038/nature11582
Lan Q, Hsiung CA, Matsuo K, Hong YC, Seow A, Wang Z, Hosgood HD 3rd, Chen K, Wang JC, Chatterjee N, Hu W, Wong MP, Zheng W, Caporaso N, Park JY, Chen CJ, Kim YH, Kim YT, Landi MT, Shen H, Lawrence C, Burdett L, Yeager M, Yuenger J, Jacobs KB, Chang IS, Mitsudomi T, Kim HN, Chang GC, Bassig BA, Tucker M, Wei F, Yin Z, Wu C, An SJ, Qian B, Lee VH, Lu D, Liu J, Jeon HS, Hsiao CF, Sung JS, Kim JH, Gao YT, Tsai YH, Jung YJ, Guo H, Hu Z, Hutchinson A, Wang WC, Klein R, Chung CC, Oh IJ, Chen KY, Berndt SI, He X, Wu W, Chang J, Zhang XC, Huang MS, Zheng H, Wang J, Zhao X, Li Y, Choi JE, Su WC, Park KH, Sung SW, Shu XO, Chen YM, Liu L, Kang CH, Hu L, Chen CH, Pao W, Kim YC, Yang TY, Xu J, Guan P, Tan W, Su J, Wang CL, Li H, Sihoe AD, Zhao Z, Chen Y, Choi YY, Hung JY, Kim JS, Yoon HI, Cai Q, Lin CC, Park IK, Xu P, Dong J, Kim C, He Q, Perng RP, Kohno T, Kweon SS et al (2012) Genome-wide association analysis identifies new lung cancer susceptibility loci in never-smoking women in Asia. Nat Genet 44:1330–1335. doi:10.1038/ng.2456
Landi MT, Consonni D, Rotunno M, Bergen AW, Goldstein AM, Lubin JH, Goldin L, Alavanja M, Morgan G, Subar AF, Linnoila I, Previdi F, Corno M, Rubagotti M, Marinelli B, Albetti B, Colombi A, Tucker M, Wacholder S, Pesatori AC, Caporaso NE, Bertazzi PA (2008) Environment and genetics in lung cancer etiology (EAGLE) study: an integrative population-based case-control study of lung cancer. BMC Public Health 8:203. doi:10.1186/1471-2458-8-203
Landi MT, Chatterjee N, Yu K, Goldin LR, Goldstein AM, Rotunno M, Mirabello L, Jacobs K, Wheeler W, Yeager M, Bergen AW, Li Q, Consonni D, Pesatori AC, Wacholder S, Thun M, Diver R, Oken M, Virtamo J, Albanes D, Wang Z, Burdette L, Doheny KF, Pugh EW, Laurie C, Brennan P, Hung R, Gaborieau V, McKay JD, Lathrop M, McLaughlin J, Wang Y, Tsao MS, Spitz MR, Wang Y, Krokan H, Vatten L, Skorpen F, Arnesen E, Benhamou S, Bouchard C, Metspalu A, Vooder T, Nelis M, Valk K, Field JK, Chen C, Goodman G, Sulem P, Thorleifsson G, Rafnar T, Eisen T, Sauter W, Rosenberger A, Bickeboller H, Risch A, Chang-Claude J, Wichmann HE, Stefansson K, Houlston R, Amos CI, Fraumeni JF Jr, Savage SA, Bertazzi PA, Tucker MA, Chanock S, Caporaso NE (2009) A genome-wide association study of lung cancer identifies a region of chromosome 5p15 associated with risk for adenocarcinoma. Am J Hum Genet 85:679–691. doi:10.1016/j.ajhg.2009.09.012
Lewis MJ, Vyse S, Shields AM, Boeltz S, Gordon PA, Spector TD, Lehner PJ, Walczak H, Vyse TJ (2015) UBE2L3 polymorphism amplifies NF-kappaB activation and promotes plasma cell development, linking linear ubiquitination to multiple autoimmune diseases. Am J Hum Genet 96:221–234. doi:10.1016/j.ajhg.2014.12.024
Miftakhova R, Hedblom A, Semenas J, Robinson B, Simoulis A, Malm J, Rizvanov A, Heery DM, Mongan NP, Maitland NJ, Allegrucci C, Persson JL (2016) Cyclin A1 and P450 aromatase promote metastatic homing and growth of stem-like prostate cancer cells in the bone marrow. Cancer Res 76:2453–2464. doi:10.1158/0008-5472.CAN-15-2340
Molenaar JJ, Domingo-Fernandez R, Ebus ME, Lindner S, Koster J, Drabek K, Mestdagh P, van Sluis P, Valentijn LJ, van Nes J, Broekmans M, Haneveld F, Volckmann R, Bray I, Heukamp L, Sprussel A, Thor T, Kieckbusch K, Klein-Hitpass L, Fischer M, Vandesompele J, Schramm A, van Noesel MM, Varesio L, Speleman F, Eggert A, Stallings RL, Caron HN, Versteeg R, Schulte JH (2012) LIN28B induces neuroblastoma and enhances MYCN levels via let-7 suppression. Nat Genet 44:1199–1206. doi:10.1038/ng.2436
Nguyen LH, Robinton DA, Seligson MT, Wu L, Li L, Rakheja D, Comerford SA, Ramezani S, Sun X, Parikh MS, Yang EH, Powers JT, Shinoda G, Shah SP, Hammer RE, Daley GQ, Zhu H (2014) Lin28b is sufficient to drive liver cancer and necessary for its maintenance in murine models. Cancer Cell 26:248–261. doi:10.1016/j.ccr.2014.06.018
Okada Y, Wu D, Trynka G, Raj T, Terao C, Ikari K, Kochi Y, Ohmura K, Suzuki A, Yoshida S, Graham RR, Manoharan A, Ortmann W, Bhangale T, Denny JC, Carroll RJ, Eyler AE, Greenberg JD, Kremer JM, Pappas DA, Jiang L, Yin J, Ye L, Su DF, Yang J, Xie G, Keystone E, Westra HJ, Esko T, Metspalu A, Zhou X, Gupta N, Mirel D, Stahl EA, Diogo D, Cui J, Liao K, Guo MH, Myouzen K, Kawaguchi T, Coenen MJ, van Riel PL, van de Laar MA, Guchelaar HJ, Huizinga TW, Dieude P, Mariette X, Bridges SL Jr, Zhernakova A, Toes RE, Tak PP, Miceli-Richard C, Bang SY, Lee HS, Martin J, Gonzalez-Gay MA, Rodriguez-Rodriguez L, Rantapaa-Dahlqvist S, Arlestig L, Choi HK, Kamatani Y, Galan P, Lathrop M, Eyre S, Bowes J, Barton A, de Vries N, Moreland LW, Criswell LA, Karlson EW, Taniguchi A, Yamada R, Kubo M, Liu JS, Bae SC, Worthington J, Padyukov L, Klareskog L, Gregersen PK, Raychaudhuri S, Stranger BE, De Jager PL, Franke L, Visscher PM, Brown MA, Yamanaka H, Mimori T, Takahashi A, Xu H, Behrens TW, Siminovitch KA, Momohara S, Matsuda F, Yamamoto K, Plenge RM, Consortium R, Consortium G (2014) Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature 506:376–381. doi:10.1038/nature12873
Pasek RC, Malarkey E, Berbari NF, Sharma N, Kesterson RA, Tres LL, Kierszenbaum AL, Yoder BK (2016) Coiled-coil domain containing 42 (Ccdc42) is necessary for proper sperm development and male fertility in the mouse. Dev Biol 412:208–218. doi:10.1016/j.ydbio.2016.01.042
Pettersson T, Pukkala E, Teppo L, Friman C (1992) Increased risk of cancer in patients with systemic lupus erythematosus. Ann Rheum Dis 51:437–439
Pickrell JK (2014) Joint analysis of functional genomic data and genome-wide association studies of 18 human traits. Am J Hum Genet 94:559–573. doi:10.1016/j.ajhg.2014.03.004
Postow MA, Callahan MK, Barker CA, Yamada Y, Yuan J, Kitano S, Mu Z, Rasalan T, Adamow M, Ritter E, Sedrak C, Jungbluth AA, Chua R, Yang AS, Roman RA, Rosner S, Benson B, Allison JP, Lesokhin AM, Gnjatic S, Wolchok JD (2012) Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med 366:925–931. doi:10.1056/NEJMoa1112824
Powers JT, Tsanov KM, Pearson DS, Roels F, Spina CS, Ebright R, Seligson M, de Soysa Y, Cahan P, Theissen J, Tu HC, Han A, Kurek KC, LaPier GS, Osborne JK, Ross SJ, Cesana M, Collins JJ, Berthold F, Daley GQ (2016) Multiple mechanisms disrupt the let-7 microRNA family in neuroblastoma. Nature 535:246–251. doi:10.1038/nature18632
Renaud S, Loukinov D, Alberti L, Vostrov A, Kwon YW, Bosman FT, Lobanenkov V, Benhattar J (2011) BORIS/CTCFL-mediated transcriptional regulation of the hTERT telomerase gene in testicular and ovarian tumor cells. Nucl Acids Res 39:862–873. doi:10.1093/nar/gkq827
Simpson AJ, Caballero OL, Jungbluth A, Chen YT, Old LJ (2005) Cancer/testis antigens, gametogenesis and cancer. Nat Rev Cancer 5:615–625. doi:10.1038/nrc1669
Tao S, Wang Z, Feng J, Hsu FC, Jin G, Kim ST, Zhang Z, Gronberg H, Zheng LS, Isaacs WB, Xu J, Sun J (2012) A genome-wide search for loci interacting with known prostate cancer risk-associated genetic variants. Carcinogenesis 33:598–603. doi:10.1093/carcin/bgr316
Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A (2015) Global cancer statistics, 2012. CA Cancer J Clin 65:87–108. doi:10.3322/caac.21262
van der Bruggen P, Traversari C, Chomez P, Lurquin C, De Plaen E, Van den Eynde B, Knuth A, Boon T (1991) A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science 254:1643–1647
Viswanathan SR, Powers JT, Einhorn W, Hoshida Y, Ng TL, Toffanin S, O’Sullivan M, Lu J, Phillips LA, Lockhart VL, Shah SP, Tanwar PS, Mermel CH, Beroukhim R, Azam M, Teixeira J, Meyerson M, Hughes TP, Llovet JM, Radich J, Mullighan CG, Golub TR, Sorensen PH, Daley GQ (2009) Lin28 promotes transformation and is associated with advanced human malignancies. Nat Genet 41:843–848. doi:10.1038/ng.392
Wang WY, Barratt BJ, Clayton DG, Todd JA (2005) Genome-wide association studies: theoretical and practical concerns. Nat Rev Genet 6:109–118. doi:10.1038/nrg1522
Wang S, Adrianto I, Wiley GB, Lessard CJ, Kelly JA, Adler AJ, Glenn SB, Williams AH, Ziegler JT, Comeau ME, Marion MC, Wakeland BE, Liang C, Kaufman KM, Guthridge JM, Alarcon-Riquelme ME, Biolupus Networks G, Alarcon GS, Anaya JM, Bae SC, Kim JH, Joo YB, Boackle SA, Brown EE, Petri MA, Ramsey-Goldman R, Reveille JD, Vila LM, Criswell LA, Edberg JC, Freedman BI, Gilkeson GS, Jacob CO, James JA, Kamen DL, Kimberly RP, Martin J, Merrill JT, Niewold TB, Pons-Estel BA, Scofield RH, Stevens AM, Tsao BP, Vyse TJ, Langefeld CD, Harley JB, Wakeland EK, Moser KL, Montgomery CG, Gaffney PM (2012) A functional haplotype of UBE2L3 confers risk for systemic lupus erythematosus. Genes Immun 13:380–387. doi:10.1038/gene.2012.6
Wang C, Gu Y, Zhang K, Xie K, Zhu M, Dai N, Jiang Y, Guo X, Liu M, Dai J, Wu L, Jin G, Ma H, Jiang T, Yin R, Xia Y, Liu L, Wang S, Shen B, Huo R, Wang Q, Xu L, Yang L, Huang X, Shen H, Sha J, Hu Z (2016) Systematic identification of genes with a cancer-testis expression pattern in 19 cancer types. Nat Commun 7:10499. doi:10.1038/ncomms10499
Watkins J, Weekes D, Shah V, Gazinska P, Joshi S, Sidhu B, Gillett C, Pinder S, Vanoli F, Jasin M, Mayrhofer M, Isaksson A, Cheang MC, Mirza H, Frankum J, Lord CJ, Ashworth A, Vinayak S, Ford JM, Telli ML, Grigoriadis A, Tutt AN (2015) Genomic complexity profiling reveals that HORMAD1 overexpression contributes to homologous recombination deficiency in triple-negative breast cancers. Cancer Discov 5:488–505. doi:10.1158/2159-8290.CD-14-1092
Yang W, Tang H, Zhang Y, Tang X, Zhang J, Sun L, Yang J, Cui Y, Zhang L, Hirankarn N, Cheng H, Pan HF, Gao J, Lee TL, Sheng Y, Lau CS, Li Y, Chan TM, Yin X, Ying D, Lu Q, Leung AM, Zuo X, Chen X, Tong KL, Zhou F, Diao Q, Tse NK, Xie H, Mok CC, Hao F, Wong SN, Shi B, Lee KW, Hui Y, Ho MH, Liang B, Lee PP, Cui H, Guo Q, Chung BH, Pu X, Liu Q, Zhang X, Zhang C, Chong CY, Fang H, Wong RW, Sun Y, Mok MY, Li XP, Avihingsanon Y, Zhai Z, Rianthavorn P, Deekajorndej T, Suphapeetiporn K, Gao F, Shotelersuk V, Kang X, Ying SK, Zhang L, Wong WH, Zhu D, Fung SK, Zeng F, Lai WM, Wong CM, Ng IO, Garcia-Barcelo MM, Cherny SS, Shen N, Tam PK, Sham PC, Ye DQ, Yang S, Zhang X, Lau YL (2013) Meta-analysis followed by replication identifies loci in or near CDKN1B, TET3, CD80, DRAM1, and ARID5B as associated with systemic lupus erythematosus in Asians. Am J Hum Genet 92:41–51. doi:10.1016/j.ajhg.2012.11.018
Zhernakova A, Stahl EA, Trynka G, Raychaudhuri S, Festen EA, Franke L, Westra HJ, Fehrmann RS, Kurreeman FA, Thomson B, Gupta N, Romanos J, McManus R, Ryan AW, Turner G, Brouwer E, Posthumus MD, Remmers EF, Tucci F, Toes R, Grandone E, Mazzilli MC, Rybak A, Cukrowska B, Coenen MJ, Radstake TR, van Riel PL, Li Y, de Bakker PI, Gregersen PK, Worthington J, Siminovitch KA, Klareskog L, Huizinga TW, Wijmenga C, Plenge RM (2011) Meta-analysis of genome-wide association studies in celiac disease and rheumatoid arthritis identifies fourteen non-HLA shared loci. PLoS Genet 7:e1002004. doi:10.1371/journal.pgen.1002004
Zhu Z, Zhang F, Hu H, Bakshi A, Robinson MR, Powell JE, Montgomery GW, Goddard ME, Wray NR, Visscher PM, Yang J (2016) Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets. Nat Genet 48:481–487. doi:10.1038/ng.3538
Acknowledgements
We would like to thank the GTEx project for the use of individual genotype data and expression data. The Genotype-Tissue Expression (GTEx) Project was supported by the Office of the Director of the National Institutes of Health and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from dbGaP accession number phs000424.v6.p1. We would like to thank all participants who contributed to this work. Z.H. initiated, conceived, and supervised the study. N.Q. performed bioinformatic and statistical analyses with C.W., M.Z., and J.D., and drafted the manuscript with Z.H., C.W., G.J., H.M., H.S., and D.L. and N.Q. performed the genotyping with Q.L., T.H., L.W., F.Y., and M.H., and Y.J. and C.W. collected the samples. This work was supported by the National Key Basic Research Program Grant (2013CB911400), the National Natural Science Foundation of China (81521004, 81230067), the Cheung Kong Scholars Program of China, National Program for Support of Top-notch Young Professionals from the Organization Department of the CPC Central Committee, Jiangsu Specially-Appointed Professor project, Top-notch Academic Programs Project of Jiangsu Higher Education Institutions (PPZY2015A067), the Science and Technology Development Fund of Nanjing Medical University (2016NJMUZD004), and the Priority Academic Program for the Development of Jiangsu Higher Education Institutions (Public Health and Preventive Medicine). The funder agencies had no role in the study design, data collection and analysis, decision to publish, or the preparation of the manuscript.
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Qin, N., Wang, C., Lu, Q. et al. A cis-eQTL genetic variant of the cancer–testis gene CCDC116 is associated with risk of multiple cancers. Hum Genet 136, 987–997 (2017). https://doi.org/10.1007/s00439-017-1827-2
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DOI: https://doi.org/10.1007/s00439-017-1827-2