Genetic polymorphism of the OPG gene associated with breast cancer

BMC Cancer

Jasmin Teresa Ney⁵  Ingolf Juhasz-Boess⁴  Frank Gruenhage⁶  Stefan Graeber¹  Rainer Maria Bohle³  Michael Pfreundschuh²  Erich Franz Solomayer⁴  Gunter Assmann² 

[1] Institute of Medical Biometry, Epidemiology and Medical Informatics, Saarland University, 66421, Homburg/Saar, Saarland, Germany

[2] Internal Medicine I, José-Carreras-Center for Immuno- and Gene Therapy, University Medical School of Saarland, 66421, Homburg/Saar, Saarland, Germany

[3] General and Surgical Pathology, University Medical School of Saarland, 66421, Homburg/Saar, Saarland, Germany

[4] Gynecology, Obstetrics and Reproductive Medicine, University Medical School of Saarland, 66421, Homburg/Saar, Saarland, Germany

[5] Universitätsklinikum des Saarlandes, Klinik für Frauenheilkunde, Geburtshilfe und Reproduktionsmedizin, Kirrbergerstr, 66421, Homburg/Saar, Germany

[6] Internal Medicine II, University Medical School of Saarland, 66421, Homburg/Saar, Saarland, Germany

关键词: rs3102735;    RANKL;    RANK;    Polymorphism;    OPG;    Case control study;    Breast cancer;   

Others  :  1079950
DOI  :  10.1186/1471-2407-13-40

 received in 2012-11-01, accepted in 2013-01-22,  发布年份 2013

【 摘 要 】

Background

The receptor activator of NF-κB (RANK), its ligand (RANKL) and osteoprotegerin (OPG) have been reported to play a role in the pathophysiological bone turnover and in the pathogenesis of breast cancer. Based on this we investigated the role of single nucleotide polymorphisms (SNPs) within RANK, RANKL and OPG and their possible association to breast cancer risk.

Methods

Genomic DNA was obtained from Caucasian participants consisting of 307 female breast cancer patients and 396 gender-matched healthy controls. We studied seven SNPs in the genes of OPG (rs3102735, rs2073618), RANK (rs1805034, rs35211496) and RANKL (rs9533156, rs2277438, rs1054016) using TaqMan genotyping assays. Statistical analyses were performed using the χ²-tests for 2 x 2 and 2 x 3 tables.

Results

The allelic frequencies (OR: 1.508 CI: 1.127-2.018, p=0.006) and the genotype distribution (p=0.019) of the OPG SNP rs3102735 differed significantly between breast cancer patients and healthy controls. The minor allele C and the corresponding homo- and heterozygous genotypes are more common in breast cancer patients (minor allele C: 18.4% vs. 13.0%; genotype CC: 3.3% vs. 1.3%; genotype CT: 30.3% vs. 23.5%). No significantly changed risk was detected in the other investigated SNPs. Additional analysis showed significant differences when comparing patients with invasive vs. non-invasive tumors (OPG rs2073618) as well as in terms of tumor localization (RANK rs35211496) and body mass index (RANKL rs9533156 and rs1054016).

Conclusions

This is the first study reporting a significant association of the SNP rs3102735 (OPG) with the susceptibility to develop breast cancer in the Caucasian population.

【 授权许可】

   
2013 Ney et al.; licensee BioMed Central Ltd.

【 参考文献 】

• [1]Coleman RE: Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin Cancer Res 2006, 12:6243s-6249s.
• [2]Wittrant Y, Theoleyre S, Chipoy C, Padrines M, Blanchard F, Heymann D, Redini F: RANKL/RANK/OPG: new therapeutic targets in bone tumours and associated osteolysis. Biochim Biophys Acta 2004, 1704:49-57.
• [3]Bhatia P, Sanders MM, Hansen MF: Expression of receptor activator of nuclear factor-kappaB is inversely correlated with metastatic phenotype in breast carcinoma. Clin Cancer Res 2005, 11:162-165.
• [4]Heider U, Langelotz C, Jakob C, Zavrski I, Fleissner C, Eucker J, Possinger K, Hofbauer LC, Sezer O: Expression of receptor activator of nuclear factor kappaB ligand on bone marrow plasma cells correlates with osteolytic bone disease in patients with multiple myeloma. Clin Cancer Res 2003, 9:1436-1440.
• [5]Kong YY, Feige U, Sarosi I, Bolon B, Tafuri A, Morony S, Capparelli C, Li J, Elliott R, McCabe S, Wong T, Campagnuolo G, Moran E, Bogoch ER, Van G, Nguyen LT, Ohashi PS, Lacey DL, Fish E, Boyle WJ, Penninger JM: Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature 1999, 402:304-309.
• [6]Lacey DL, Timms E, Tan HL, Kelley MJ, Dunstan CR, Burgess T, Elliott R, Colombero A, Elliott G, Scully S, Hsu H, Sullivan J, Hawkins N, Davy E, Capparelli C, Eli A, Qian YX, Kaufman S, Sarosi I, Shalhoub V, Senaldi G, Guo J, Delaney J, Boyle WJ: Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 1998, 93:165-176.
• [7]Anderson DM, Maraskovsky E, Billingsley WL, Dougall WC, Tometsko ME, Roux ER, Teepe MC, DuBose RF, Cosman D, Galibert L: A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature 1997, 390:175-179.
• [8]Fata JE, Kong YY, Li J, Sasaki T, Irie-Sasaki J, Moorehead RA, Elliott R, Scully S, Voura EB, Lacey DL, Boyle WJ, Khokha R, Penninger JM: The osteoclast differentiation factor osteoprotegerin-ligand is essential for mammary gland development. Cell 2000, 103:41-50.
• [9]Hsu H, Lacey DL, Dunstan CR, Solovyev I, Colombero A, Timms E, Tan HL, Elliott G, Kelley MJ, Sarosi I, Wang L, Xia XZ, Elliott R, Chiu L, Black T, Scully S, Capparelli C, Morony S, Shimamoto G, Bass MB, Boyle WJ: Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand. Proc Natl Acad Sci U S A 1999, 96:3540-3545.
• [10]Min JK, Kim YM, Kim YM, Kim EC, Gho YS, Kang IJ, Lee SY, Kong YY, Kwon YG: Vascular endothelial growth factor up-regulates expression of receptor activator of NF-kappa B (RANK) in endothelial cells. Concomitant increase of angiogenic responses to RANK ligand. J Biol Chem 2003, 278:39548-39557.
• [11]Santini D, Perrone G, Roato I, Godio L, Pantano F, Grasso D, Russo A, Vincenzi B, Fratto ME, Sabbatini R, Della Pepa C, Porta C, Del Conte A, Schiavon G, Berruti A, Tomasino RM, Papotti M, Papapietro N, Onetti Muda A, Denaro V, Tonini G: Expression pattern of receptor activator of NFkappaB (RANK) in a series of primary solid tumors and related bone metastases. J Cell Physiol 2011, 226:780-784.
• [12]Dougall WC, Glaccum M, Charrier K, Rohrbach K, Brasel K, De Smedt T, Daro E, Smith J, Tometsko ME, Maliszewski CR, Armstrong A, Shen V, Bain S, Cosman D, Anderson D, Morrissey PJ, Peschon JJ, Schuh J: RANK is essential for osteoclast and lymph node development. Genes Dev 1999, 13:2412-2424.
• [13]Kong YY, Yoshida H, Sarosi I, Tan HL, Timms E, Capparelli C, Morony S, Oliveira-dos-Santos AJ, Van G, Itie A, Khoo W, Wakeham A, Dunstan CR, Lacey DL, Mak TW, Boyle WJ, Penninger JM: OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 1999, 397:315-323.
• [14]Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Luthy R, Nguyen HQ, Wooden S, Bennett L, Boone T, Shimamoto G, DeRose M, Elliott R, Colombero A, Tan HL, Trail G, Sullivan J, Davy E, Bucay N, Renshaw-Gegg L, Hughes TM, Hill D, Pattison W, Campbell P, Sander S, Van G, Tarpley J, Derby P, Lee R, Boyle WJ: Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 1997, 89:309-319.
• [15]Yasuda H, Shima N, Nakagawa N, Yamaguchi K, Kinosaki M, Mochizuki S, Tomoyasu A, Yano K, Goto M, Murakami A, Tsuda E, Morinaga T, Higashio K, Udagawa N, Takahashi N, Suda T: Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci U S A 1998, 95:3597-3602.
• [16]Bucay N, Sarosi I, Dunstan CR, Morony S, Tarpley J, Capparelli C, Scully S, Tan HL, Xu W, Lacey DL, Boyle WJ, Simonet WS: Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev 1998, 12:1260-1268.
• [17]McGonigle JS, Giachelli CM, Scatena M: Osteoprotegerin and RANKL differentially regulate angiogenesis and endothelial cell function. Angiogenesis 2009, 12:35-46.
• [18]Fisher JL, Thomas-Mudge RJ, Elliott J, Hards DK, Sims NA, Slavin J, Martin TJ, Gillespie MT: Osteoprotegerin overexpression by breast cancer cells enhances orthotopic and osseous tumor growth and contrasts with that delivered therapeutically. Cancer Res 2006, 66:3620-3628.
• [19]Gonzalez-Suarez E, Jacob AP, Jones J, Miller R, Roudier-Meyer MP, Erwert R, Pinkas J, Branstetter D, Dougall WC: RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis. Nature 2010, 468:103-107.
• [20]Schramek D, Leibbrandt A, Sigl V, Kenner L, Pospisilik JA, Lee HJ, Hanada R, Joshi PA, Aliprantis A, Glimcher L, Pasparakis M, Khokha R, Ormandy CJ, Widschwendter M, Schett G, Penninger JM: Osteoclast differentiation factor RANKL controls development of progestin-driven mammary cancer. Nature 2010, 468:98-102.
• [21]Jones DH, Nakashima T, Sanchez OH, Kozieradzki I, Komarova SV, Sarosi I, Morony S, Rubin E, Sarao R, Hojilla CV, Komnenovic V, Kong YY, Schreiber M, Dixon SJ, Sims SM, Khokha R, Wada T, Penninger JM: Regulation of cancer cell migration and bone metastasis by RANKL. Nature 2006, 440:692-696.
• [22]Eastell R, Christiansen C, Grauer A, Kutilek S, Libanati C, McClung MR, Reid IR, Resch H, Siris E, Uebelhart D, Wang A, Weryha G, Cummings SR: Effects of denosumab on bone turnover markers in postmenopausal osteoporosis. J Bone Miner Res 2011, 26:530-537.
• [23]Stopeck AT, Lipton A, Body JJ, Steger GG, Tonkin K, de Boer RH, Lichinitser M, Fujiwara Y, Yardley DA, Viniegra M, Fan M, Jiang Q, Dansey R, Jun S, Braun A: Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol 2010, 28:5132-5139.
• [24]Choi JY, Shin A, Park SK, Chung HW, Cho SI, Shin CS, Kim H, Lee KM, Lee KH, Kang C, Cho DY, Kang D: Genetic polymorphisms of OPG, RANK, and ESR1 and bone mineral density in Korean postmenopausal women. Calcif Tissue Int 2005, 77:152-159.
• [25]Eun IS, Park WW, Suh KT, Kim JI, Lee JS: Association between osteoprotegerin gene polymorphism and bone mineral density in patients with adolescent idiopathic scoliosis. Eur Spine J 2009, 18:1936-1940.
• [26]Hsu YH, Niu T, Terwedow HA, Xu X, Feng Y, Li Z, Brain JD, Rosen CJ, Laird N, Xu X: Variation in genes involved in the RANKL/RANK/OPG bone remodeling pathway are associated with bone mineral density at different skeletal sites in men. Hum Genet 2006, 118:568-577.
• [27]Kim JG, Kim JH, Kim JY, Ku SY, Jee BC, Suh CS, Kim SH, Choi YM: Association between osteoprotegerin (OPG), receptor activator of nuclear factor-kappaB (RANK), and RANK ligand (RANKL) gene polymorphisms and circulating OPG, soluble RANKL levels, and bone mineral density in Korean postmenopausal women. Menopause 2007, 14:913-918.
• [28]Langdahl BL, Carstens M, Stenkjaer L, Eriksen EF: Polymorphisms in the osteoprotegerin gene are associated with osteoporotic fractures. J Bone Miner Res 2002, 17:1245-1255.
• [29]Mencej-Bedrac S, Prezelj J, Marc J: TNFRSF11B gene polymorphisms 1181 G > C and 245 T > G as well as haplotype CT influence bone mineral density in postmenopausal women. Maturitas 2011, 69:263-267.
• [30]Piedra M, Garcia-Unzueta MT, Berja A, Paule B, Lavin BA, Valero C, Riancho JA, Amado JA: Single nucleotide polymorphisms of the OPG/RANKL system genes in primary hyperparathyroidism and their relationship with bone mineral density. BMC Med Genet 2011, 12:168. BioMed Central Full Text
• [31]Roshandel D, Holliday KL, Pye SR, Boonen S, Borghs H, Vanderschueren D, Huhtaniemi IT, Adams JE, Ward KA, Bartfai G, Casanueva F, Finn JD, Forti G, Giwercman A, Han TS, Kula K, Lean ME, Pendleton N, Punab M, Silman AJ, Wu FC, Thomson W, O'Neill TW: Genetic variation in the RANKL/RANK/OPG signaling pathway is associated with bone turnover and bone mineral density in men. J Bone Miner Res 2010, 25:1830-1838.
• [32]Roshandel D, Holliday KL, Pye SR, Ward KA, Boonen S, Vanderschueren D, Borghs H, Huhtaniemi IT, Adams JE, Bartfai G, Casanueva FF, Finn JD, Forti G, Giwercman A, Han TS, Kula K, Lean ME, Pendleton N, Punab M, Silman AJ, Wu FC, Thomson W: TW ON: Influence of polymorphisms in the RANKL/RANK/OPG signaling pathway on volumetric bone mineral density and bone geometry at the forearm in men. Calcif Tissue Int 2011, 89:446-455.
• [33]Zhao HY, Liu JM, Ning G, Zhao YJ, Zhang LZ, Sun LH, Xu MY, Uitterlinden AG, Chen JL: The influence of Lys3Asn polymorphism in the osteoprotegerin gene on bone mineral density in Chinese postmenopausal women. Osteoporos Int 2005, 16:1519-1524.
• [34]Jorgensen HL, Kusk P, Madsen B, Fenger M, Lauritzen JB: Serum osteoprotegerin (OPG) and the A163G polymorphism in the OPG promoter region are related to peripheral measures of bone mass and fracture odds ratios. J Bone Miner Metab 2004, 22:132-138.
• [35]Katz J, Gong Y, Salmasinia D, Hou W, Burkley B, Ferreira P, Casanova O, Langaee TY, Moreb JS: Genetic polymorphisms and other risk factors associated with bisphosphonate induced osteonecrosis of the jaw. Int J Oral Maxillofac Surg 2011, 40:605-611.
• [36]Zajickova K, Zemanova A, Hill M, Zofkova I: Is A163G polymorphism in the osteoprotegerin gene associated with heel velocity of sound in postmenopausal women? Physiol Res 2008, 57(Suppl 1):S153-157.
• [37]Huang CH, Wei JC, Hung PS, Shiu LJ, Tsay MD, Wong RH, Lee HS: Osteoprotegerin genetic polymorphisms and age of symptom onset in ankylosing spondylitis. Rheumatology (Oxford) 2011, 50:359-365.
• [38]Pitocco D, Zelano G, Gioffre G, Di Stasio E, Zaccardi F, Martini F, Musella T, Scavone G, Galli M, Caputo S, Mancini L, Ghirlanda G: Association between osteoprotegerin G1181C and T245G polymorphisms and diabetic charcot neuroarthropathy: a case-control study. Diabetes Care 2009, 32:1694-1697.
• [39]Assmann G, Pfoehler C, Simon P, Pfreundschuh M, Tilgen W, Wieczorek S: Genetic variations in the genes encoding receptor activator nuclear factor kappa B (RANK), receptor activator nuclear factor kappa B ligand (RANKL) and osteoprotegerin (OPG) in patients with psoriasis and psoriatic arthritis: a case-control study. J Dermatol 2011, 38:519-523.
• [40]Campa D, Kaaks R, Le Marchand L, Haiman CA, Travis RC, Berg CD, Buring JE, Chanock SJ, Diver WR, Dostal L, Fournier A, Hankinson SE, Henderson BE, Hoover RN, Isaacs C, Johansson M, Kolonel LN, Kraft P, Lee IM, McCarty CA, Overvad K, Panico S, Peeters PH, Riboli E, Sanchez MJ, Schumacher FR, Skeie G, Stram DO, Thun MJ, Trichopoulos D, et al.: Interactions between genetic variants and breast cancer risk factors in the breast and prostate cancer cohort consortium. J Natl Cancer Inst 2011, 103:1252-1263.
• [41]Easton DF, Pooley KA, Dunning AM, Pharoah PD, Thompson D, Ballinger DG, Struewing JP, Morrison J, Field H, Luben R, Wareham N, Ahmed S, Healey CS, Bowman R, Meyer KB, Haiman CA, Kolonel LK, Henderson BE, Le Marchand L, Brennan P, Sangrajrang S, Gaborieau V, Odefrey F, Shen CY, Wu PE, Wang HC, Eccles D, Evans DG, Peto J, Fletcher O, et al.: Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 2007, 447:1087-1093.
• [42]Fanale D, Amodeo V, Corsini LR, Rizzo S, Bazan V, Russo A: Breast cancer genome-wide association studies: there is strength in numbers. Oncogene 2012, 31:2121-2128.
• [43]He C, Chasman DI, Dreyfus J, Hwang SJ, Ruiter R, Sanna S, Buring JE, Fernandez-Rhodes L, Franceschini N, Hankinson SE, Hofman A, Lunetta KL, Palmieri G, Porcu E, Rivadeneira F, Rose LM, Splansky GL, Stolk L, Uitterlinden AG, Chanock SJ, Crisponi L, Demerath EW, Murabito JM, Ridker PM, Stricker BH, Hunter DJ: Reproductive aging associated common genetic variants and the risk of breast cancer. Breast Cancer Res 2012, 14:R54. BioMed Central Full Text
• [44]Hunter DJ, Kraft P, Jacobs KB, Cox DG, Yeager M, Hankinson SE, Wacholder S, Wang Z, Welch R, Hutchinson A, Wang J, Yu K, Chatterjee N, Orr N, Willett WC, Colditz GA, Ziegler RG, Berg CD, Buys SS, McCarty CA, Feigelson HS, Calle EE, Thun MJ, Hayes RB, Tucker M, Gerhard DS, Fraumeni JF Jr, Hoover RN, Thomas G, Chanock SJ: A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat Genet 2007, 39:870-874.
• [45]Long J, Cai Q, Sung H, Shi J, Zhang B, Choi JY, Wen W, Delahanty RJ, Lu W, Gao YT, Shen H, Park SK, Chen K, Shen CY, Ren Z, Haiman CA, Matsuo K, Kim MK, Khoo US, Iwasaki M, Zheng Y, Xiang YB, Gu K, Rothman N, Wang W, Hu Z, Liu Y, Yoo KY, Noh DY, Han BG, et al.: Genome-wide association study in East asians identifies novel susceptibility Loci for breast cancer. PLoS Genet 2012, 8:e1002532.
• [46]Sehrawat B, Sridharan M, Ghosh S, Robson P, Cass CE, Mackey JR, Greiner R, Damaraju S: Potential novel candidate polymorphisms identified in genome-wide association study for breast cancer susceptibility. Hum Genet 2011, 130:529-537.
• [47]Stacey SN, Manolescu A, Sulem P, Rafnar T, Gudmundsson J, Gudjonsson SA, Masson G, Jakobsdottir M, Thorlacius S, Helgason A, Aben KK, Strobbe LJ, Albers-Akkers MT, Swinkels DW, Henderson BE, Kolonel LN, Le Marchand L, Millastre E, Andres R, Godino J, Garcia-Prats MD, Polo E, Tres A, Mouy M, Saemundsdottir J, Backman VM, Gudmundsson L, Kristjansson K, Bergthorsson JT, Kostic J, et al.: Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer. Nat Genet 2007, 39:865-869.
• [48]Teraoka SN, Bernstein JL, Reiner AS, Haile RW, Bernstein L, Lynch CF, Malone KE, Stovall M, Capanu M, Liang X, Smith SA, Mychaleckyj J, Hou X, Mellemkjaer L, Boice JD Jr, Siniard A, Duggan D, Thomas DC: Single nucleotide polymorphisms associated with risk for contralateral breast cancer in the Women's Environment, Cancer, and Radiation Epidemiology (WECARE) Study. Breast Cancer Res 2011, 13:R114. BioMed Central Full Text
• [49]Vega A, Salas A, Milne RL, Carracedo B, Ribas G, Ruibal A, de Leon AC, Gonzalez-Hernandez A, Benitez J, Carracedo A: Evaluating new candidate SNPs as low penetrance risk factors in sporadic breast cancer: a two-stage Spanish case-control study. Gynecol Oncol 2009, 112:210-214.
• [50]Chu LW, Meyer TE, Li Q, Menashe I, Yu K, Rosenberg PS, Huang WY, Quraishi SM, Kaaks R, Weiss JM, Hayes RB, Chanock SJ, Hsing AW: Association between genetic variants in the 8q24 cancer risk regions and circulating levels of androgens and sex hormone-binding globulin. Cancer Epidemiol Biomarkers Prev 2010, 19:1848-1854.
• [51]Zanke BW, Greenwood CM, Rangrej J, Kustra R, Tenesa A, Farrington SM, Prendergast J, Olschwang S, Chiang T, Crowdy E, Ferretti V, Laflamme P, Sundararajan S, Roumy S, Olivier JF, Robidoux F, Sladek R, Montpetit A, Campbell P, Bezieau S, O'Shea AM, Zogopoulos G, Cotterchio M, Newcomb P, McLaughlin J, Younghusband B, Green R, Green J, Porteous ME, Campbell H, et al.: Genome-wide association scan identifies a colorectal cancer susceptibility locus on chromosome 8q24. Nat Genet 2007, 39:989-994.
• [52]Ahmadiyeh N, Pomerantz MM, Grisanzio C, Herman P, Jia L, Almendro V, He HH, Brown M, Liu XS, Davis M, Caswell JL, Beckwith CA, Hills A, Macconaill L, Coetzee GA, Regan MM, Freedman ML: 8q24 prostate, breast, and colon cancer risk loci show tissue-specific long-range interaction with MYC. Proc Natl Acad Sci U S A 2010, 107:9742-9746.
• [53]Brisbin AG, Asmann YW, Song H, Tsai YY, Aakre JA, Yang P, Jenkins RB, Pharoah P, Schumacher F, Conti DV, Duggan DJ, Jenkins M, Hopper J, Gallinger S, Newcomb P, Casey G, Sellers TA, Fridley BL: Meta-analysis of 8q24 for seven cancers reveals a locus between NOV and ENPP2 associated with cancer development. BMC Med Genet 2011, 12:156. BioMed Central Full Text
• [54]Nakajima T, Cheng T, Rohrwasser A, Bloem LJ, Pratt JH, Inoue I, Lalouel JM: Functional analysis of a mutation occurring between the two in-frame AUG codons of human angiotensinogen. J Biol Chem 1999, 274:35749-35755.
• [55]Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M: Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet 2008, 371:569-578.
• [56]Key TJ, Appleby PN, Reeves GK, Roddam A, Dorgan JF, Longcope C, Stanczyk FZ, Stephenson HE Jr, Falk RT, Miller R, Schatzkin A, Allen DS, Fentiman IS, Key TJ, Wang DY, Dowsett M, Thomas HV, Hankinson SE, Toniolo P, Akhmedkhanov A, Koenig K, Shore RE, Zeleniuch-Jacquotte A, Berrino F, Muti P, Micheli A, Krogh V, Sieri S, Pala V, Venturelli E, et al.: Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women. J Natl Cancer Inst 2003, 95:1218-1226.
• [57]Perkins CI, Hotes J, Kohler BA, Howe HL: Association between breast cancer laterality and tumor location, United States, 1994-1998. Cancer Causes Control 2004, 15:637-645.
• [58]Roychoudhuri R, Putcha V, Moller H: Cancer and laterality: a study of the five major paired organs (UK). Cancer Causes Control 2006, 17:655-662.
• [59]Parkash O: Lung cancer. A statistical study based on autopsy data from 1928 to 1972. Respiration 1977, 34:295-304.
• [60]Delahunt B, Bethwaite P, Nacey JN: Renal cell carcinoma in New Zealand: a national survival study. Urology 1994, 43:300-309.
• [61]Stone JM, Cruickshank DG, Sandeman TF, Matthews JP: Laterality, maldescent, trauma and other clinical factors in the epidemiology of testis cancer in Victoria. Australia. Br J Cancer 1991, 64:132-138.
• [62]Hallberg O, Johansson O: Sleep on the right side-Get cancer on the left? Pathophysiology 2010, 17:157-160.
• [63]Hsieh CC, Trichopoulos D: Breast size, handedness and breast cancer risk. Eur J Cancer 1991, 27:131-135.
• [64]Ing R, Petrakis NL, Ho JH: Unilateral breast-feeding and breast cancer. Lancet 1977, 2:124-127.
• [65]Assmann G, Koenig J, Pfreundschuh M, Epplen JT, Kekow J, Roemer K, Wieczorek S: Genetic variations in genes encoding RANK, RANKL, and OPG in rheumatoid arthritis: a case-control study. J Rheumatol 2010, 37:900-904.
• [66]Furuya T, Hakoda M, Ichikawa N, Higami K, Nanke Y, Yago T, Kamatani N, Kotake S: Associations between HLA-DRB1, RANK, RANKL, OPG, and IL-17 genotypes and disease severity phenotypes in Japanese patients with early rheumatoid arthritis. Clin Rheumatol 2007, 26:2137-2141.
• [67]Rhee EJ, Yun EJ, Oh KW, Park SE, Park CY, Lee WY, Park SW, Kim SW, Baek KH, Kang MI: The relationship between Receptor Activator of Nuclear Factor-kappaB Ligand (RANKL) gene polymorphism and aortic calcification in Korean women. Endocr J 2010, 57:541-549.
• [68]Pan R, Liu YZ, Deng HW, Dvornyk V: Association analyses suggest the effects of RANK and RANKL on age at menarche in Chinese women. Climacteric 2012, 15:75-81.
• [69]Chung PY, Beyens G, Riches PL, Van Wesenbeeck L, de Freitas F, Jennes K, Daroszewska A, Fransen E, Boonen S, Geusens P, Vanhoenacker F, Verbruggen L, Van Offel J, Goemaere S, Zmierczak HG, Westhovens R, Karperien M, Papapoulos S, Ralston SH, Devogelaer JP, Van Hul W: Genetic variation in the TNFRSF11A gene encoding RANK is associated with susceptibility to Paget's disease of bone. J Bone Miner Res 2010, 25:2592-2605.
• [70]Bonifaci N, Palafox M, Pellegrini P, Osorio A, Benitez J, Peterlongo P, Manoukian S, Peissel B, Zaffaroni D, Roversi G, Barile M, Viel A, Mariette F, Bernard L, Radice P, Kaufman B, Laitman Y, Milgrom R, Friedman E, Saez ME, Climent F, Soler MT, Diez O, Balmana J, Lasa A, Ramon Y, Cajal T, Miramar MD, De la Hoya M, Perez-Segura P, Caldes T, et al.: Evidence for a link between TNFRSF11A and risk of breast cancer. Breast Cancer Res Treat 2011, 129:947-954.