There was a significant association observed between rs2066827 polymorphism and cancer risk (Table 2). The TG genotype carriers, compared to the TT genotype carriers, were less likely to develop cancer (fixed-effects pooled OR 0.92, 95% CI: 0.86–0.99; model, TG vs. TT, Figure 2). In the subgroup analyses by cancer type, a moderate decrease in the risk of ovarian cancer was seen among carriers with a TG genotype (fixed-effects pooled OR 0.85, 95% CI: 0.74–0.97; model, TG vs. TT, Figure 3). We finally stratified the studies by ethnicity, and found a slightly decreased risk of cancer associated with the TG genotype in Caucasians (fixed-effects pooled OR 0.91, 95% CI: 0.85–0.98; model, TG vs. TT, Table 2).
We detected significant between-study heterogeneity in the analyses using GG + TG vs. TT, and G vs. T models (P < 0.05, Table 2). We performed sensitivity analyses by sequentially omitting the studies included (one omitted each time). Two studies, by Mohamed et al24 and Francisco et al29, respectively, were identified as outliers. The results in GG + TG versus TT, and G versus T models were highly homogeneous when the outliers were excluded (available on request). But we noted that the exclusion resulted in significant alternations in the pooled ORs (available on request).
Publication bias is a potential problem when performing a meta-analysis. To determine the possible bias, we used Begg funnel plots and Egger test simultaneously. Both tests showed no evidence of significant bias (PBegg = 0.73, PEgger = 0.43, model: TG vs. TT) (Figure 4).
Cell cycle progression is mediated by cyclins and cyclin-dependent kinase complexes. The CDKN1B mammalian cell cycle protein has been identified as an inhibitor of cyclin-dependent kinases.36 Lack of CDKN1B is thought to be an important mechanism underlying carcinogenesis.37–40
Due to the influence of nonsynonymous SNPs on the amino acid sequence of protein, the role of a common SNP at codon 109 that encodes a nonsynonymous amino acid change of CDKN1B in the pathogenesis of human cancer has received widespread attention.19–23 Nevertheless, these genetic association studies produced highly controversial findings, failing to facilitate a full understanding of the mechanisms that underlie cancer. For instance, Li et al20 designed a hospital-based case–control study incorporating 713 patients with SCCHN and 1224 cancer-free control subjects of Caucasian origin, demonstrating no evidence for a major role of rs2066827 in the etiology of SCCHN. In a subsequent case–control study of 368 breast cancer patients and 467 controls of Asian origin, Ma et al21 did not observed a significantly increased or decreased risk of breast cancer. It is especially interesting that Figueiredo et al25 identified a modest protective effect on breast cancer associated with the G allele in a population-based study of 1115 cases and 710 controls of Caucasian ancestry. There are several possible causes related to the inconsistency. The first cause is the sampling difference. A study with a larger number is known to be more prone to reveal the true SNP–cancer association. The second reason may be due to the heterogeneous populations and ethnic variance. Possible consequences resulting from various genetic backgrounds include allele frequency variance, different gene–gene interactions and gene–environment interactions. The third cause might be the different cancer types. Human cancers at various sites may vary widely in terms of the etiology of pathology. In this study, we carried out a meta-analysis with an aim to examine the association between rs2066827 polymorphism and cancer risk.
In our meta-analysis of 9038 cancer cases and 11,596 controls participating in 17 studies, we demonstrated a weak protective effect on cancer in relation to the TG genotype. We also observed a moderate protective effect on ovarian cancer and a slight protective effect in Caucasians after stratification by cancer type and ethnicity, respectively. The most likely reason for absence of an association in Asians may relate to the significant difference in minor allele frequency (G). The frequency in the Asian populations was 3.4%, which was significantly lower compared to Caucasians (25.9%, P < 0.05). Another possible explanation is the wide disparity of total number (8279 cases and 6707 controls of Caucasian origin, 3217 cases and 2231 controls of Asian origin).
In a previous meta-analysis where a total of 8 studies with 3591 cases and 3799 controls were included, Wei et al41 failed to demonstrate any evidence in support of an association between rs2066827 polymorphism and cancer. In this published analysis, Wei et al included a study of 398 breast cancer cases and 372 controls,42 which was later updated by Figueiredo et al in a larger number.25 The results thus may be affected due to the overlapped data. Unlike the earlier meta-analysis, our analysis restricted to studies without HWE deviation indicated significant protective effects on cancer based on 13,244 additional subjects (5447 cases and 7797 controls). In addition, we found a novel association for ovarian cancer and Caucasians after excluding the overlapped data.
There are some strengths and limitations in our study. An important strength is the markedly expanded sample size which helped to identify some findings not suggested in the previous meta-analysis. Further, we included all studies with usable data without considering language. The exclusion of papers for linguistic reasons may lead to biased results.43 However, the current sample was too small to detect the possible effects for multiple cancer types and did not allow further stratification analyses by ethnicity for ovarian cancer and breast cancer. Thus, sample insufficiency is one of the limitations. Second, significant heterogeneity presented in some analyses. Exclusion of the identified outliers caused obvious changes in the risk estimates, suggesting that heterogeneity should be considered in interpreting some results. Finally, effects of common confounding factors, including age, gender, tobacco smoking and alcohol consumption, were not assessed in the present study because of data insufficiency.
In summary, our meta-analysis demonstrated some evidence that the rs2066827 polymorphism of the CDKN1B gene may protect against the development of human cancer, especially ovarian cancer and in Caucasians. Additional work with a larger number is recommended to better understand the potential functional role of this nonsynonymous polymorphism in distinct ethnic populations and various cancers.
1. Morgan DO. Principles of CDK regulation. Nature
2. Sherr CJ, Roberts JM. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev
3. Sherr CJ. Cancer cell cycles. Science
4. Wingate H, Bedrosian I, Akli S, et al. The low molecular weight (LMW) isoforms of cyclin E deregulate the cell cycle of mammary epithelial cells. Cell Cycle
5. Alkarain A, Slingerland J. Deregulation of p27 by oncogenic signaling and its prognostic significance in breast cancer. Breast Cancer Res
6. Tsihlias J, Kapusta LR, DeBoer G, et al. Loss of cyclin-dependent kinase inhibitor p27Kip1 is a novel prognostic factor in localized human prostate adenocarcinoma. Cancer Res
7. Mori M, Mimori K, Shiraishi T, et al. p27 expression and gastric carcinoma. Nat Med
8. Pruneri G, Pignataro L, Carboni N, et al. Clinical relevance of expression of the CIP/KIP cell-cycle inhibitors p21 and p27 in laryngeal cancer. J Clin Oncol
9. Loda M, Cukor B, Tam SW, et al. Increased proteasome-dependent degradation of the cyclin-dependent kinase inhibitor p27 in aggressive colorectal carcinomas. Nat Med
10. Porter PL, Malone KE, Heagerty PJ, et al. Expression of cell-cycle regulators p27Kip1 and cyclin E, alone and in combination, correlate with survival in young breast cancer patients. Nat Med
11. Landa I, Montero-Conde C, Malanga D, et al. Allelic variant at −79 (C > T) in CDKN1B (p27Kip1) confers an increased risk of thyroid cancer and alters mRNA levels. Endocr Relat Cancer
12. Chang BL, Zheng SL, Isaacs SD, et al. A polymorphism in the CDKN1B gene is associated with increased risk of hereditary prostate cancer. Cancer Res
13. Tomoda K, Kubota Y, Kato J. Degradation of the cyclin-dependent-kinase inhibitor p27Kip1 is instigated by Jab1. Nature
14. Chen J, Killary AM, Sen S, et al. Polymorphisms of p21 and p27 jointly contribute to an earlier age at diagnosis of pancreatic cancer. Cancer Lett
15. Goode EL, Fridley BL, Vierkant RA, et al. Candidate gene analysis using imputed genotypes: cell cycle single-nucleotide polymorphisms and ovarian cancer risk. Cancer Epidemiol Biomarkers Prev
16. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst
17. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials
18. Egger M, Davey Smith G, Schneider M, et al. Bias in meta-analysis detected by a simple, graphical test. BMJ
19. Kibel AS, Suarez BK, Belani J, et al. CDKN1A and CDKN1B polymorphisms and risk of advanced prostate carcinoma. Cancer Res
20. Li G, Sturgis EM, Wang LE, et al. Association between the V109G polymorphism of the p27 gene and the risk and progression of oral squamous cell carcinoma. Clin Cancer Res
2004; 10 (12 Pt 1):3996–4002.
21. Ma H, Jin G, Hu Z, et al. Variant genotypes of CDKN1A and CDKN1B are associated with an increased risk of breast cancer in Chinese women. Int J Cancer
22. Chen J, Amos CI, Merriman KW, et al. Genetic variants of p21 and p27 and pancreatic cancer risk in non-Hispanic Whites: a case-control study. Pancreas
23. Huang SP, Yu CC, Liu CC, et al. CDKN1B V109G polymorphism frequency and prostate cancer risk in Taiwan. Urol Int
24. Mohamed FZ, Hussien YM, AlBakry MM, et al. Role of DNA repair and cell cycle control genes in ovarian cancer susceptibility. Mol Biol Rep
25. Figueiredo JC, Knight JA, Cho S, et al. Polymorphisms cMyc-N11S and p27-V109G and breast cancer risk and prognosis. BMC Cancer
26. Yu JC, Ding SL, Chang CH, et al. Genetic susceptibility to the development and progression of breast cancer associated with polymorphism of cell cycle and ubiquitin ligase genes. Carcinogenesis
27. Liu F, Wei YG, Luo LM, et al. Genetic variants of p21 and p27 and hepatocellular cancer risk in a Chinese Han population: a case-control study. Int J Cancer
28. Driver KE, Song H, Lesueur F, et al. Association of single-nucleotide polymorphisms in the cell cycle genes with breast cancer in the British population. Carcinogenesis
29. Francisco G, Gonçalves FT, Luiz OC, et al. Polymorphisms in the p27kip-1 and prohibitin genes denote novel genes associated with melanoma risk in Brazil, a high ultraviolet index region. Melanoma Res
30. Gayther SA, Song H, Ramus SJ, et al. Tagging single nucleotide polymorphisms in cell cycle control genes and susceptibility to invasive epithelial ovarian cancer. Cancer Res
31. Jin X, Kang S, Wang N, et al. Single nucleotide polymorphisms in cell cycle regulator p21 and p27 genes are associated with susceptibility to epithelial ovarian cancer [Article in Chinese]. Chin J Obstet Gynecol
32. Li ZS, Ma YQ, Li BQ, et al. Study of correlation between polymorphisms of p21 and p27 genes and non-small cell lung cancer [Article in Chinese]. Chin J Cancer Prev Treat
33. Ma YQ, Yang XG, Liu H, et al. Influence of p21 and p27 gene polymorphisms on development and lymphatic metastasis of esophageal squamous cell carcinoma [Article in Chinese]. J Fourth Mil Med Univ
34. Pasquali D, Circelli L, Faggiano A, et al. CDKN1B V109G polymorphism a new prognostic factor in sporadic medullary thyroid carcinoma. Eur J Endocrinol
35. Sekiya T, Bronstein MD, Benfini K, et al. p27 variant and corticotropinoma susceptibility: a genetic and in vitro study. Endocr Relat Cancer
36. Pagano M, Tam SW, Theodoras AM, et al. Role of the ubiquitin-proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27. Science
37. Slingerland J, Pagano M. Regulation of the cdk inhibitor p27 and its deregulation in cancer. J Cell Physiol
38. Spataro VJ, Litman H, Viale G, et al. Decreased immunoreactivity for p27 protein in patients with early-stage breast carcinoma is correlated with HER-2/neu overexpression and with benefit from one course of perioperative chemotherapy in patients with negative lymph node status: results from International Breast Cancer Study Group Trial V. Cancer
39. Catzavelos C, Bhattacharya N, Ung YC, et al. Decreased levels of the cell-cycle inhibitor p27Kip1 protein: prognostic implications in primary breast cancer. Nat Med
40. Catzavelos C, Tsao MS, DeBoer G, et al. Reduced expression of the cell cycle inhibitor p27Kip1 in non-small cell lung carcinoma: a prognostic factor independent of Ras. Cancer Res
41. Wei F, Xu J, Tang L, et al. p27(Kip1) V109G polymorphism and cancer risk: a systematic review and meta-analysis. Cancer Biother Radiopharm
42. Onay VU, Briollais L, Knight JA, et al. SNP-SNP interactions in breast cancer susceptibility. BMC Cancer
43. Grégoire G, Derderian F, Le Lorier J. Selecting the language of the publications included in a meta-analysis: is there a Tower of Babel bias? J Clin Epidemiol