Issue
The effects of CDKN2A rs3731249, rs11515, and rs3088440 polymorphisms on cancer risk
Corresponding Author(s) : Y-J. Liu
Cellular and Molecular Biology,
Vol. 63 No. 3: Issue 3
Abstract
Many studies have been carried out to examine whether there is an association between CDKN2A polymorphisms and cancer risk, but the results from these studies were controversial. In the present study, we performed a meta-analysis to clarify whether there is an association of CDKN2A polymorphisms and cancer risk. Published reports were searched in PubMed and Google Scholar. ORs with 95% CIs were calculated in the dominant models. Twenty six case-control studies that met the inclusion criteria were included in the final meta-analysis. Overall, we found that rs3731249, rs11515, and rs3088440 polymorphisms were not associated with cancer risk (OR=1.27, 95%CI: 0.79-2.03; OR=0.91, 95%CI: 0.79-1.03; OR=1.02, 95%CI: 0.95-1.09). However, CDKN2A rs3731249 polymorphism was significantly associated with ovarian cancer risk (OR=0.78, 95%CI: 0.65-0.95). A significant association was observed in Asian with rs11515 polymorphism (OR=0.48, 95%CI: 0.28-0.83). This meta-analysis shows that CDKN2A rs3731249 polymorphism was significantly associated with ovarian cancer risk. In addition, CDKN2A rs11515 polymorphism might associate with cancer risk in Asians.
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- Bredberg A. Cancer: more of polygenic disease and less of multiple mutations? A quantitative viewpoint. Cancer. 2011;117(3):440-5.
- Nelson AA, Tsao H. Melanoma and genetics. Clin Dermatol. 2009;27(1):46-52.
- Nobori T, Miura K, Wu DJ, Lois A, Takabayashi K, Carson DA. Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers. Nature. 1994;368(6473):753-6.
- Kumar R, Smeds J, Berggren P, Straume O, Rozell BL, Akslen LA, et al. A single nucleotide polymorphism in the 3'untranslated region of the CDKN2A gene is common in sporadic primary melanomas but mutations in the CDKN2B, CDKN2C, CDK4 and p53 genes are rare. Int J Cancer, 2001;95: 388-393
- McCloud JM, Sivakumar R, Greenhough A, Elder J, Jones PW, Deakin M, et al. p16INK4a polymorphism: associations with tumour progression in patients with sporadic colorectal cancer. Int J Oncol, 2004;25: 1447-52
- Bertram CG, Gaut RM, Barrett JH, Pinney E, Whitaker L, Turner F, et al. An assessment of the CDKN2A variant Ala148Thr as a nevus/melanoma susceptibility allele. J Invest Dermatol, 2002;119: 961-5
- Geddert H, Kiel S, Zotz RB, Zhang J, Willers R, Gabbert HE, et al. Polymorphism of p16 INK4A and cyclin D1 in adenocarcinomas of the upper gastrointestinal tract. J Cancer Res Clin Oncol, 2005;131: 803-8
- Hung RJ, Boffetta P, Canzian F, Moullan N, Szeszenia-Dabrowska N, Zaridze D, et al. Sequence variants in cell cycle control pathway, X-ray exposure, and lung cancer risk: a multicenter case-control study in Central Europe. Cancer Res, 2006;66: 8280-6
- Spica T, Portela M, Gérard B, Formicone F, Descamps V, Crickx B, et al. The A148T variant of the CDKN2A gene is not associated with melanoma risk in the French and Italian populations. J Invest Dermatol, 2006;126: 1657-60
- Debniak T, Scott RJ, Huzarski T, Byrski T, Rozmiarek A, Debniak B, et al. CDKN2A common variant and multi-organ cancer risk--a population-based study. Int J Cancer, 2006;118: 3180-2
- Canova C, Hashibe M, Simonato L, Nelis M, Metspalu A, Lagiou P, et al. Genetic associations of 115 polymorphisms with cancers of the upper aerodigestive tract across 10 European countries: the ARCAGE project. Cancer Res, 2009;69: 2956-65
- Bakos RM, Besch R, Zoratto GG, Godinho JM, Mazzotti NG, Ruzicka T, et al. The CDKN2A p.A148T variant is associated with cutaneous melanoma in Southern Brazil. Exp Dermatol, 2011;20: 890-3
- Thakur N1, Hussain S, Nasare V, Das BC, Basir SF, Bharadwaj M. Association analysis of p16 (CDKN2A) and RB1 polymorphisms with susceptibility to cervical cancer in Indian population. Mol Biol Rep, 2012;39: 407-414
- Azimzadeh P, Romani S, Mohebbi SR, Mahmoudi T, Vahedi M, Fatemi SR, et al. Association of polymorphisms in microRNA-binding sites and colorectal cancer in an Iranian population. Cancer Genet, 2012;205: 501-7
- Jin L, Xu L, Song X, Wei Q, Sturgis EM, Li G. Genetic variation in MDM2 and p14ARF and susceptibility to salivary gland carcinoma. PLoS One, 2012;7: e49361
- Pinheiro UB, de Carvalho Fraga CA, Mendes DC, Marques-Silva L, Farias LC, de Souza MG, et al: p16 (CDKN2A) SNP rs11515 was not associated with head and neck carcinoma. Tumour Biol, 2014;35: 6113-8
- Barbieri RB, Bufalo NE, Secolin R, Assumpçí£o LV, Maciel RM, Cerutti JM, et al. Polymorphisms of cell cycle control genes influence the development of sporadic medullary thyroid carcinoma. Eur J Endocrinol, 2014;171: 761-7
- Zheng Y, Shen H, Sturgis EM, Wang LE, Shete S, Spitz MR, et al. Haplotypes of two variants in p16 (CDKN2/MTS-1/INK4a) exon 3 and risk of squamous cell carcinoma of the head and neck: a case-control study. Cancer Epidemiol Biomarkers Prev, 2002;11: 640-5
- Yan L, Na W, Shan K, Xiao-Wei M, Wei G, Shu-Cheng C. p16(CDKN2) gene polymorphism: association with histologic subtypes of epithelial ovarian cancer in China. Int J Gynecol Cancer, 2008;18: 30-5
- Tuna G, Küçükhüseyin O, Arıkan S, Kaytan Sağlam E, Güler E, Cacına C, et al: Do CDKN2 p16 540 C>G, CDKN2 p16 580 C>T, and MDM2 SNP309 T>G gene variants act on colorectal cancer development or progression? DNA Cell Biol, 2013;32: 400-8
- Chansaenroj J, Theamboonlers A, Junyangdikul P, Swangvaree S, Karalak A, Chinchai T, et al. Polymorphisms in TP53 (rs1042522), p16 (rs11515 and rs3088440) and NQO1 (rs1800566) genes in Thai cervical cancer patients with HPV 16 infection. Asian Pac J Cancer Prev, 2013;14: 341-6
- Maccioni L, Rachakonda PS, Bermejo JL, Planelles D, Requena C, Hemminki K, et al. Variants at the 9p21 locus and melanoma risk. BMC Cancer, 2013;13: 325
- Debniak T, Scott RJ, Huzarski T, Byrski T, Rozmiarek A, Debniak B, et al. CDKN2A common variants and their association with melanoma risk: a population-based study. Cancer Res, 2005;65: 835-9
- Wang SS, Cozen W, Severson RK, Hartge P, Cerhan JR, Davis S, et al. Cyclin D1 splice variant and risk for non-Hodgkin lymphoma. Hum Genet, 2006;120: 297-300
- Landi S, Gemignani F, Canzian F, Gaborieau V, Barale R, Landi D, et al. DNA repair and cell cycle control genes and the risk of young-onset lung cancer. Cancer Res, 2006;66: 11062-9
- Gayther SA, Song H, Ramus SJ, Kjaer SK, Whittemore AS, Quaye L, et al. Tagging single nucleotide polymorphisms in cell cycle control genes and susceptibility to invasive epithelial ovarian cancer. Cancer Res, 2007;67: 3027-35
- Driver KE, Song H, Lesueur F, Ahmed S, Barbosa-Morais NL, Tyrer JP, et al. Association of single-nucleotide polymorphisms in the cell cycle genes with breast cancer in the British population. Carcinogenesis, 2008;29: 333-41
- Polakova V, Pardini B, Naccarati A, Landi S, Slyskova J, Novotny J, et al. Genotype and haplotype analysis of cell cycle genes in sporadic colorectal cancer in the Czech Republic. Hum Mutat, 2009;30: 661-8
- Quaye L, Tyrer J, Ramus SJ, Song H, Wozniak E, DiCioccio RA, et al. Association between common germline genetic variation in 94 candidate genes or regions and risks of invasive epithelial ovarian cancer. PLoS One, 2009;4: e5983
- Collado M, Blasco MA, Serrano M. Cellular senescence in cancer and aging. Cell. 2007;130(2):223-33.
- Voorhoeve PM, Agami R. The tumor-suppressive functions of the human INK4A locus. Cancer Cell. 2003;4(4):311-9.
- Merlo A, Herman JG, Mao L, Lee DJ, Gabrielson E, Burger PC, et al. 5' CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers. Nat Med. 1995;1(7):686-92.
- Samowitz WS, Albertsen H, Herrick J, Levin TR, Sweeney C, Murtaugh MA, et al. Evaluation of a large, population-based sample supports a CpG island methylator phenotype in colon cancer. Gastroenterology. 2005;129(3):837-45.
- Bihl MP, Foerster A, Lugli A, Zlobec I. Characterization of CDKN2A(p16) methylation and impact in colorectal cancer: systematic analysis using pyrosequencing. J Transl Med. 2012;10:173.
- Lou-Qian Z, Rong Y, Ming L, Xin Y, Feng J, Lin X. The prognostic value of epigenetic silencing of p16 gene in NSCLC patients: a systematic review and meta-analysis. PLoS One. 2013;8(1):e54970.
- Jiang W, Wang PG, Zhan Y, Zhang D. Prognostic value of p16 promoter hypermethylation in colorectal cancer: a meta-analysis. Cancer Invest. 2014;32(2):43-52.
References
Bredberg A. Cancer: more of polygenic disease and less of multiple mutations? A quantitative viewpoint. Cancer. 2011;117(3):440-5.
Nelson AA, Tsao H. Melanoma and genetics. Clin Dermatol. 2009;27(1):46-52.
Nobori T, Miura K, Wu DJ, Lois A, Takabayashi K, Carson DA. Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers. Nature. 1994;368(6473):753-6.
Kumar R, Smeds J, Berggren P, Straume O, Rozell BL, Akslen LA, et al. A single nucleotide polymorphism in the 3'untranslated region of the CDKN2A gene is common in sporadic primary melanomas but mutations in the CDKN2B, CDKN2C, CDK4 and p53 genes are rare. Int J Cancer, 2001;95: 388-393
McCloud JM, Sivakumar R, Greenhough A, Elder J, Jones PW, Deakin M, et al. p16INK4a polymorphism: associations with tumour progression in patients with sporadic colorectal cancer. Int J Oncol, 2004;25: 1447-52
Bertram CG, Gaut RM, Barrett JH, Pinney E, Whitaker L, Turner F, et al. An assessment of the CDKN2A variant Ala148Thr as a nevus/melanoma susceptibility allele. J Invest Dermatol, 2002;119: 961-5
Geddert H, Kiel S, Zotz RB, Zhang J, Willers R, Gabbert HE, et al. Polymorphism of p16 INK4A and cyclin D1 in adenocarcinomas of the upper gastrointestinal tract. J Cancer Res Clin Oncol, 2005;131: 803-8
Hung RJ, Boffetta P, Canzian F, Moullan N, Szeszenia-Dabrowska N, Zaridze D, et al. Sequence variants in cell cycle control pathway, X-ray exposure, and lung cancer risk: a multicenter case-control study in Central Europe. Cancer Res, 2006;66: 8280-6
Spica T, Portela M, Gérard B, Formicone F, Descamps V, Crickx B, et al. The A148T variant of the CDKN2A gene is not associated with melanoma risk in the French and Italian populations. J Invest Dermatol, 2006;126: 1657-60
Debniak T, Scott RJ, Huzarski T, Byrski T, Rozmiarek A, Debniak B, et al. CDKN2A common variant and multi-organ cancer risk--a population-based study. Int J Cancer, 2006;118: 3180-2
Canova C, Hashibe M, Simonato L, Nelis M, Metspalu A, Lagiou P, et al. Genetic associations of 115 polymorphisms with cancers of the upper aerodigestive tract across 10 European countries: the ARCAGE project. Cancer Res, 2009;69: 2956-65
Bakos RM, Besch R, Zoratto GG, Godinho JM, Mazzotti NG, Ruzicka T, et al. The CDKN2A p.A148T variant is associated with cutaneous melanoma in Southern Brazil. Exp Dermatol, 2011;20: 890-3
Thakur N1, Hussain S, Nasare V, Das BC, Basir SF, Bharadwaj M. Association analysis of p16 (CDKN2A) and RB1 polymorphisms with susceptibility to cervical cancer in Indian population. Mol Biol Rep, 2012;39: 407-414
Azimzadeh P, Romani S, Mohebbi SR, Mahmoudi T, Vahedi M, Fatemi SR, et al. Association of polymorphisms in microRNA-binding sites and colorectal cancer in an Iranian population. Cancer Genet, 2012;205: 501-7
Jin L, Xu L, Song X, Wei Q, Sturgis EM, Li G. Genetic variation in MDM2 and p14ARF and susceptibility to salivary gland carcinoma. PLoS One, 2012;7: e49361
Pinheiro UB, de Carvalho Fraga CA, Mendes DC, Marques-Silva L, Farias LC, de Souza MG, et al: p16 (CDKN2A) SNP rs11515 was not associated with head and neck carcinoma. Tumour Biol, 2014;35: 6113-8
Barbieri RB, Bufalo NE, Secolin R, Assumpçí£o LV, Maciel RM, Cerutti JM, et al. Polymorphisms of cell cycle control genes influence the development of sporadic medullary thyroid carcinoma. Eur J Endocrinol, 2014;171: 761-7
Zheng Y, Shen H, Sturgis EM, Wang LE, Shete S, Spitz MR, et al. Haplotypes of two variants in p16 (CDKN2/MTS-1/INK4a) exon 3 and risk of squamous cell carcinoma of the head and neck: a case-control study. Cancer Epidemiol Biomarkers Prev, 2002;11: 640-5
Yan L, Na W, Shan K, Xiao-Wei M, Wei G, Shu-Cheng C. p16(CDKN2) gene polymorphism: association with histologic subtypes of epithelial ovarian cancer in China. Int J Gynecol Cancer, 2008;18: 30-5
Tuna G, Küçükhüseyin O, Arıkan S, Kaytan Sağlam E, Güler E, Cacına C, et al: Do CDKN2 p16 540 C>G, CDKN2 p16 580 C>T, and MDM2 SNP309 T>G gene variants act on colorectal cancer development or progression? DNA Cell Biol, 2013;32: 400-8
Chansaenroj J, Theamboonlers A, Junyangdikul P, Swangvaree S, Karalak A, Chinchai T, et al. Polymorphisms in TP53 (rs1042522), p16 (rs11515 and rs3088440) and NQO1 (rs1800566) genes in Thai cervical cancer patients with HPV 16 infection. Asian Pac J Cancer Prev, 2013;14: 341-6
Maccioni L, Rachakonda PS, Bermejo JL, Planelles D, Requena C, Hemminki K, et al. Variants at the 9p21 locus and melanoma risk. BMC Cancer, 2013;13: 325
Debniak T, Scott RJ, Huzarski T, Byrski T, Rozmiarek A, Debniak B, et al. CDKN2A common variants and their association with melanoma risk: a population-based study. Cancer Res, 2005;65: 835-9
Wang SS, Cozen W, Severson RK, Hartge P, Cerhan JR, Davis S, et al. Cyclin D1 splice variant and risk for non-Hodgkin lymphoma. Hum Genet, 2006;120: 297-300
Landi S, Gemignani F, Canzian F, Gaborieau V, Barale R, Landi D, et al. DNA repair and cell cycle control genes and the risk of young-onset lung cancer. Cancer Res, 2006;66: 11062-9
Gayther SA, Song H, Ramus SJ, Kjaer SK, Whittemore AS, Quaye L, et al. Tagging single nucleotide polymorphisms in cell cycle control genes and susceptibility to invasive epithelial ovarian cancer. Cancer Res, 2007;67: 3027-35
Driver KE, Song H, Lesueur F, Ahmed S, Barbosa-Morais NL, Tyrer JP, et al. Association of single-nucleotide polymorphisms in the cell cycle genes with breast cancer in the British population. Carcinogenesis, 2008;29: 333-41
Polakova V, Pardini B, Naccarati A, Landi S, Slyskova J, Novotny J, et al. Genotype and haplotype analysis of cell cycle genes in sporadic colorectal cancer in the Czech Republic. Hum Mutat, 2009;30: 661-8
Quaye L, Tyrer J, Ramus SJ, Song H, Wozniak E, DiCioccio RA, et al. Association between common germline genetic variation in 94 candidate genes or regions and risks of invasive epithelial ovarian cancer. PLoS One, 2009;4: e5983
Collado M, Blasco MA, Serrano M. Cellular senescence in cancer and aging. Cell. 2007;130(2):223-33.
Voorhoeve PM, Agami R. The tumor-suppressive functions of the human INK4A locus. Cancer Cell. 2003;4(4):311-9.
Merlo A, Herman JG, Mao L, Lee DJ, Gabrielson E, Burger PC, et al. 5' CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers. Nat Med. 1995;1(7):686-92.
Samowitz WS, Albertsen H, Herrick J, Levin TR, Sweeney C, Murtaugh MA, et al. Evaluation of a large, population-based sample supports a CpG island methylator phenotype in colon cancer. Gastroenterology. 2005;129(3):837-45.
Bihl MP, Foerster A, Lugli A, Zlobec I. Characterization of CDKN2A(p16) methylation and impact in colorectal cancer: systematic analysis using pyrosequencing. J Transl Med. 2012;10:173.
Lou-Qian Z, Rong Y, Ming L, Xin Y, Feng J, Lin X. The prognostic value of epigenetic silencing of p16 gene in NSCLC patients: a systematic review and meta-analysis. PLoS One. 2013;8(1):e54970.
Jiang W, Wang PG, Zhan Y, Zhang D. Prognostic value of p16 promoter hypermethylation in colorectal cancer: a meta-analysis. Cancer Invest. 2014;32(2):43-52.