Volume 11, Issue 2 (Vol.11 No.2 Jul 2022)                   rbmb.net 2022, 11(2): 336-343 | Back to browse issues page


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Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
Abstract:   (1995 Views)
Background: Pancreatic cancer (PC) is among the most aggressive tumors with a poor prognosis, indicating the need for the identification of a novel prognostic biomarker for risk stratifications. Recent genome-wide association studies have demonstrated common genetic variants in a region on chromosome 9p21 associated with an increased risk of different malignancies.

Methods: In the present study, we explore the possible relationship between genetic variant, rs10811661, and gene expression of CDKN2B in 75 pancreatic cancer patients, and 188 healthy individuals. DNAs were extracted and genotyping and gene expression were performed by TaqMan real-time PCR and RT-PCR, respectively. Logistic regression was used to assess the association between risk and genotypes, while the significant prognostic variables in the univariate analysis were included in multivariate analyses.

Results: The patients with PDAC had a higher frequency of a TT genotype for rs10811661 than the control group. Also, PDAC patients with dominant genetic model, (TT + TC), was associated with increased risk of developing PDAC (OR= 14.71, 95% CI [1.96-110.35], p= 0.009). Moreover, patients with CC genotype had a higher expression of CDKN2B, in comparison with TT genotype.

Conclusions: Our findings demonstrated that CDKN2A/B was associated with the risk of developing PDAC, supporting further investigations in the larger and multicenter setting to validate the potential value of this gene as an emerging marker for PDAC.
Full-Text [PDF 251 kb]   (1377 Downloads)    
Type of Article: Original Article | Subject: Molecular Biology
Received: 2022/03/23 | Accepted: 2022/03/27 | Published: 2022/08/7

References
1. Arnold M, Rutherford MJ, Bardot A, Ferlay J, Andersson TML, Myklebust TÅ, et al. Progress in cancer survival, mortality, and incidence in seven high-income countries 1995-2014 (ICBP SURVMARK-2): a population-based study. Lancet Oncol. 2019;20(11):1493-1505. [DOI:10.1016/S1470-2045(19)30456-5]
2. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394-424. [DOI:10.3322/caac.21492] [PMID]
3. Dhillon J, Betancourt M. Pancreatic Ductal Adenocarcinoma. Monogr Clin Cytol. 2020;26:74-91. [DOI:10.1159/000455736] [PMID]
4. Pereira SP, Oldfield L, Ney A, Hart PA, Keane MG, Pandol SJ, et al. Early detection of pancreatic cancer. Lancet Gastroenterol Hepatol. 2020;5(7):698-710. [DOI:10.1016/S2468-1253(19)30416-9]
5. Brand RE, Lerch MM, Rubinstein WS, Neoptolemos JP, Whitcomb DC, Hruban RH, et al. Advances in counselling and surveillance of patients at risk for pancreatic cancer. Gut. 2007;56(10):1460-9. [DOI:10.1136/gut.2006.108456] [PMID] [PMCID]
6. Campa D, Pastore M, Gentiluomo M, Talar-Wojnarowska R, Kupcinskas J, Malecka-Panas E, et al. Functional single nucleotide polymorphisms within the cyclin-dependent kinase inhibitor 2A/2B region affect pancreatic cancer risk. Oncotarget. 2016;7(35):57011-57020. [DOI:10.18632/oncotarget.10935] [PMID] [PMCID]
7. Guo G, Chmielecki J, Goparaju C, Heguy A, Dolgalev I, Carbone M, et al. Whole-exome sequencing reveals frequent genetic alterations in BAP1, NF2, CDKN2A, and CUL1 in malignant pleural mesothelioma. Cancer Res. 2015;75(2):264-9. [DOI:10.1158/0008-5472.CAN-14-1008] [PMID]
8. Hesari, A, Maleksabet, A, Tirkani, AN, et al. Evaluation of the two polymorphisms rs1801133 in MTHFR and rs10811661 in CDKN2A/B in breast cancer. J Cell Biochem. 2019; 120: 2090- 2097. [DOI:10.1002/jcb.27517] [PMID]
9. ShahidSales S, Mehramiz M, Ghasemi F, Aledavood A, Shamsi M, Hassanian SM, et al. A genetic variant in CDKN2A/B gene is associated with the increased risk of breast cancer. J Clin Lab Anal. 32(1):e22190. [DOI:10.1002/jcla.22190] [PMID] [PMCID]
10. Rahmani F, Avan A, Amerizadeh F, Ferns GA, Talebian S, Shahidsales S. The association of a genetic variant in CDKN2A/B gene and the risk of colorectal cancer. EXCLI J. 2020;19:1316-1321.
11. Ghobadi N, Mehramiz M, ShahidSales S, Rezaei Brojerdi A, Anvari K, Khazaei M, et al. A genetic variant in CDKN2A/2B locus was associated with poor prognosis in patients with esophageal squamous cell carcinoma. Journal of Cellular Physiology. 2019;234(4):5070-6. [DOI:10.1002/jcp.27310] [PMID]
12. Vijayakrishnan J, Henrion M, Moorman AV, Fiege B, Kumar R, da Silva Filho MI, et al. The 9p21.3 risk of childhood acute lymphoblastic leukaemia is explained by a rare high-impact variant in CDKN2A. Sci Rep. 2015;5:15065. [DOI:10.1038/srep15065] [PMID] [PMCID]
13. Rezaee M, Akbari H, Momeni-Moghaddam MA, Moazzen F, Salehi S, et al. Association of C677T (rs1081133) and A1298C (rs1801131) Methylenetetrahydrofolate Reductase Variants with Breast Cancer Susceptibility Among Asians: A Systematic Review and Meta-Analysis. Biochem Genet. 2021;59(2): 367-97. [DOI:10.1007/s10528-020-10020-z] [PMID]
14. Bishop DT, Demenais F, Goldstein AM, Bergman W, Bishop JN, Bressac-de Paillerets B, et al. Geographical variation in the penetrance of CDKN2A mutations for melanoma. J Natl Cancer Inst. 2002;94(12):894-903. [DOI:10.1093/jnci/94.12.894] [PMID]
15. Overbeek KA, Rodríguez-Girondo MD, Wagner A, van der Stoep N, van den Akker PC, Oosterwijk JC, et al. Genotype-phenotype correlations for pancreatic cancer risk in Dutch melanoma families with pathogenic CDKN2A variants. J Med Genet. 2021;58(4):264-269. [DOI:10.1136/jmedgenet-2019-106562] [PMID] [PMCID]
16. Goldstein AM, Fraser MC, Struewing JP, Hussussian CJ, Ranade K, Zametkin DP, et al. Increased risk of pancreatic cancer in melanoma-prone kindreds with p16INK4 mutations. N Engl J Med. 1995;333(15):970-4. [DOI:10.1056/NEJM199510123331504] [PMID]
17. Goggins M, Overbeek KA, Brand R, Syngal S, Del Chiaro M, Bartsch DK, et al. Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium. Gut. 2020;69(1):7-17. [DOI:10.1136/gutjnl-2019-319352] [PMID] [PMCID]
18. Ghiorzo P, Fornarini G, Sciallero S, Battistuzzi L, Belli F, Bernard L, et al. CDKN2A is the main susceptibility gene in Italian pancreatic cancer families. J Med Genet. 2012;49(3):164-70. [DOI:10.1136/jmedgenet-2011-100281] [PMID]
19. Ghiorzo P, Fornarini G, Sciallero S, Battistuzzi L, Belli F, Bernard L, et al. CDKN2A is the main susceptibility gene in Italian pancreatic cancer families. J Med Genet. 2012;49(3):164-70. [DOI:10.1136/jmedgenet-2011-100281] [PMID]
20. Biankin AV, Waddell N, Kassahn KS, Gingras MC, Muthuswamy LB, Johns AL, et al. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature. 2012;491:399-405. [DOI:10.1038/nature11547] [PMID] [PMCID]
21. Grarup N, Rose CS, Andersson EA, Andersen G, Nielsen AL, Albrechtsen A, et al. Studies of association of variants near the HHEX, CDKN2A/B, and IGF2BP2 genes with type 2 diabetes and impaired insulin release in 10,705 Danish subjects: validation and extension of genome-wide association studies. Diabetes. 2007;56(12):3105-11. [DOI:10.2337/db07-0856] [PMID]
22. Horikoshi M, Hara K, Ito C, Shojima N, Nagai R, Ueki K, et al. Variations in the HHEX gene are associated with increased risk of type 2 diabetes in the Japanese population. Diabetologia. 2007;50(12):2461-6. [DOI:10.1007/s00125-007-0827-5] [PMID]
23. Cauchi S, Meyre D, Durand E, Proença C, Marre M, Hadjadj S, et al. Post genome-wide association studies of novel genes associated with type 2 diabetes show gene-gene interaction and high predictive value. PloS one. 2008;3(5):e2031. [DOI:10.1371/journal.pone.0002031] [PMID] [PMCID]
24. Tarnowski M, Malinowski D, Safranow K, Dziedziejko V, Pawlik A. CDC123/CAMK1D gene rs12779790 polymorphism and rs10811661 polymorphism upstream of the CDKN2A/2B gene in women with gestational diabetes. J Perinatol. 2017;37(4):345-348. [DOI:10.1038/jp.2016.249] [PMID]
25. Sherr CJ. Cancer cell cycles. Science. 1996;274(5293):1672-7. [DOI:10.1126/science.274.5293.1672] [PMID]
26. Pomerantz J, Schreiber-Agus N, Liégeois NJ, Silverman A, Alland L, Chin L, et al. The Ink4a tumor suppressor gene product, p19Arf, interacts with MDM2 and neutralizes MDM2's inhibition of p53. Cell. 1998;92(6):713-23. [DOI:10.1016/S0092-8674(00)81400-2]
27. Stott FJ, Bates S, James MC, McConnell BB, Starborg M, Brookes S, et al. The alternative product from the human CDKN2A locus, p14(ARF), participates in a regulatory feedback loop with p53 and MDM2. EMBO J. 1998;17(17):5001-14. [DOI:10.1093/emboj/17.17.5001] [PMID] [PMCID]
28. Klump B, Hsieh CJ, Nehls O, Dette S, Holzmann K, Kiesslich R, et al. Methylation status of p14ARF and p16INK4a as detected in pancreatic secretions. Br J Cancer. 2003;88(2):217-22. [DOI:10.1038/sj.bjc.6600734] [PMID] [PMCID]
29. Yap KL, Li S, Muñoz-Cabello AM, Raguz S, Zeng L, Mujtaba S, et al. Molecular interplay of the noncoding RNA ANRIL and methylated histone H3 lysine 27 by polycomb CBX7 in transcriptional silencing of INK4a. Mol Cell. 2010;38(5):662-674. [DOI:10.1016/j.molcel.2010.03.021] [PMID] [PMCID]
30. Popov N, Gil J. Epigenetic regulation of the INK4b-ARF-INK4a locus: in sickness and in health. Epigenetics. 2010;5(8):685-690. [DOI:10.4161/epi.5.8.12996] [PMID] [PMCID]
31. ShahidSales S, Mehramiz M, Ghasemi F, Aledavood A, Shamsi M, Hassanian SM, et al. A genetic variant in CDKN2A/B gene is associated with the increased risk of breast cancer. J Clin Lab Anal. 2018;32(1):e22190. [DOI:10.1002/jcla.22190] [PMID] [PMCID]
32. Kong Y, Sharma RB, Ly S, Stamateris RE, Jesdale WM, Alonso LC. CDKN2A/B T2D Genome-Wide Association Study Risk SNPs Impact Locus Gene Expression and Proliferation in Human Islets. Diabetes. 2018;67(5):872-884. [DOI:10.2337/db17-1055] [PMID] [PMCID]
33. Ghanbari M, Franco OH, Looper HWJd, Hofman A, Erkeland SJ, Dehghan A. Genetic Variations in MicroRNA-Binding Sites Affect MicroRNA-Mediated Regulation of Several Genes Associated with Cardio-metabolic Phenotypes. Circ Cardiovasc Genet. 2015;8(3):473-86. [DOI:10.1161/CIRCGENETICS.114.000968] [PMID]
34. Ye Z-M, Li L-J, Luo M-B, Qing H-Y, Zheng J-H, Zhang C, et al. A systematic review and network meta-analysis of single nucleotide polymorphisms associated with pancreatic cancer risk. Aging (Albany NY). 2020;12(24):25256-25274. [DOI:10.18632/aging.104128] [PMID] [PMCID]

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