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Contribution of Cyclin Dependent Kinase Inhibitor 1A Genotypes to Childhood Acute Lymphocytic Leukemia Risk in Taiwan

CHAO-CHUN CHEN, CHUNG-LIN TSAI, JEN-SHENG PEI, HUEY-EN TZENG, PEI-CHEN HSU, DA-CHUAN CHENG, JIUNN-CHERNG LIN, CHIA-WEN TSAI, DA-TIAN BAU and WEN-SHIN CHANG
Cancer Genomics & Proteomics January 2025, 22 (1) 46-54; DOI: https://doi.org/10.21873/cgp.20486

Abstract

Background/Aim: The disruption of cell-cycle control can lead to an imbalance in cell proliferation, often accompanied by genomic instability, which in turn can facilitate carcinogenesis. This study aimed to examine the impact of CDKN1A rs1801270 and rs1059234 polymorphisms on the risk of childhood acute lymphocytic leukemia (ALL) in Taiwan. Materials and Methods: The genotypes of CDKN1A rs1801270 and rs1059234 in 266 childhood ALL cases and 266 controls were determined using PCR-RFLP techniques. Results: The genotypic and allelic frequencies for CDKN1A rs1801270 and rs1059234 did not significantly differ between childhood ALL cases and controls (all p>0.05). However, stratified analysis revealed that the CDKN1A rs1801270 AA variant was associated with a reduced risk of childhood ALL in males (OR=0.40, 95%CI=0.20-0.82, p=0.0178). Additionally, the AC and AA genotypes of rs1801270 were linked to a lower risk classification for childhood ALL and longer survival times (OR=0.57 and 0.31, 95%CI=0.33-0.97 and 0.18-0.56, p=0.0538 and 0.0001, respectively). No significant associations were found for rs1059234 in the stratified analyses (p>0.05 for all). Conclusion: Although CDKN rs1801270 and rs1059234 genotypes were not associated with an overall risk of childhood ALL, CDKN1A rs1801270 polymorphism may serve as a protective predictor in males and as a potential marker for better prognosis of childhood ALL. Validation in larger and more diverse populations is necessary to confirm the feasibility of this predictor.

Key Words:

Acute lymphoblastic leukemia (ALL) is the most common hematological cancer in children and is characterized by the malignancy of white blood cells (1-3). This form of leukemia predominantly affects children aged 2-5 years, making it the most prevalent pediatric hematological malignancy (4, 5). ALL can arise from both T-cell and B-cell progenitors, with B-cell progenitor cases accounting for over 85% of diagnoses (6). Despite extensive research, the pathogenesis and etiology of childhood ALL remain largely unclear. However, it is generally accepted that a combination of genetic variations and environmental factors contributes to its development (7-9).

Recent evidence suggests that inherited genomic alterations, such as single nucleotide polymorphisms (SNPs), may act as predictive markers for individual susceptibility to childhood ALL (10-15). Despite advances in genomic research, the genetic factors linked to childhood ALL remain largely undefined. Further investigation into these genomic factors is essential for improving early detection and prediction of the disease.

The p21Cip1 protein is encoded by the CDKN1A gene located on chromosome 6p21. Two potentially functional common SNPs have been identified in CDKN1A: a serine (base C) to arginine (base A) substitution at codon 31 (rs1801270) and a single-base C to T transition 20 bp downstream of the stop codon (rs1059234) (16). These polymorphisms are hypothesized to alter p21 function (16). However, the role of CDKN1A in leukemia, particularly in childhood ALL, has not been extensively studied.

Up to date, several epidemiological studies have investigated the association between CDKN1A polymorphisms and susceptibility to various cancers, including breast (17), lung (18, 19), oral (20), esophageal (21), gastric (22, 23), hepatocellular (24), pancreatic (25), ovarian (26, 27), cervical (28) endometrial (29, 30), and bladder cancer (31). Some studies found associations between CDKN1A polymorphisms and increased cancer risk, while others reported no significant associations with breast (32), oral (33), nasopharyngeal (34), esophageal (35), colorectal (36, 37), ovarian (27), and bladder cancer (38). Overall, the role of CDKN1A polymorphisms in genetic susceptibility to various types of cancer remains unclear, with conflicting findings across studies.

In 2022, we investigated the role of CDKN1B genotypes in childhood ALL and found no association between the CDKN1B rs34330 or rs2066827 genotype and the risk of childhood ALL in Taiwan (13). Based on this context, the current study aims to examine the potential association between the CDKN1A rs1801270 and rs1059234 genotypes and susceptibility to childhood ALL in Taiwan. Additionally, this study will explore the interactions of these CDKN1A genotypes with factors such as age, sex, immunophenotype, risk classification, and survival time.

Materials and Methods

Childhood ALL cases and healthy controls. Childhood ALL cases were diagnosed by expert pediatric oncologists. All recruited cases completed a questionnaire with assistance from their parents or guardians and provided blood samples. Healthy controls, who did not have cancer, were matched to cases by age (within 2 years) and sex. All participants were Taiwanese. This study received approval and oversight from the Institutional Review Board of the China Medical University Hospital (CMUH111-REC1-038). The overall flow chart of the study is illustrated in Figure 1.

Figure 1.
Figure 1.

The overall flow chart of the study.

CDKN1A genotyping design and settings. The genotyping methodology for CDKN1A rs1801270 and rs1059234 was performed as previously described (37, 39), and the physical locations of CDKN1A genotypes are illustrated in Figure 2. Briefly, for CDKN1A rs1801270, PCR was conducted using the primers 5′-GTCAGAACCGGCTGGGGATG-3′ and 5′-CTCCTCCCAACT CATCCCGG-3′. For CDKN1A rs1059234, the primers 5′-TCCAA GAGGAAGCCCTAATC-3′ and 5′-AAAGGAGAACACGGGA TGAG-3′ were used.

Figure 2.
Figure 2.

The physical locations of CDKN1A rs1801270 and rs1059234 genotypes on chromosome 6.

The PCR cycling conditions were set as: one cycle at 94°C for 5 min; 35 cycles of 94°C for 20 s, 58°C for 20 s, and 72°C for 20 s; and a final extension at 72°C for 10 min. The restriction enzymes Blp I and Pst I (New England BioLabs, Ipswich, MA, USA) were employed to digest the PCR products of CDKN1A rs1801270 and rs1059234, respectively, at 37°C for 16 h. The full digested products were then analyzed by electrophoresis on a 3% agarose gel. After enzyme digestion and agarose gel separation, the CC, AC, and AA genotypes for CDKN1A rs1801270 will present 63+186, 63+186+249, and 249 bps, respectively. As for CDKN1A rs1059234, the CC, CT and TT genotypes will present 39+257, 39+257+296, and 296 bps, respectively.

Statistical analysis. Genotyping data for 266 childhood ALL patients and 266 healthy controls were successfully obtained and are undergoing final analysis. Unpaired Student’s t-test was used to assess age differences between the childhood ALL cases and controls. Pearson’s Chi-square test was employed to evaluate the distribution of various CDKN1A genotypes. Associations between specific CDKN1A genotypes and childhood ALL risk were determined by calculating odds ratios (ORs) with corresponding 95% confidence intervals (CIs) as previously described (40-42). A p-Value less than 0.05 was considered statistically significant.

Results

Comparisons of demographics between case and control groups. There were no significant differences in age and sex between the ALL case and control groups (p>0.05), as these variables were well-matched in the study design (Table I). However, childhood ALL cases had significantly higher white blood cell counts compared to healthy controls (p<0.0001). Among the ALL patients, 85.3% (227) were of the B subtype and 14.7% (39) were of the T subtype. Additionally, 48.9% (130) were classified as standard risk, 25.2% (67) as high risk, and 25.9% (69) as very high risk. Regarding survival time, 25.9% of the patients survived less than 5 years, while 74.1% survived for more than 5 years (Table I).

View this table:
Table I.

Distribution of demographics of the 266 patients with childhood acute lymphoblastic leukemia and the 266 matched controls.

Association between CDKN1A genotypes and childhood ALL risk. Firstly, the genotype distributions of CDKN1A rs1801270 and rs1059234 in the control group were consistent with the Hardy-Weinberg equilibrium (pHWE=0.7844 and 0.4443, respectively). Secondly, there were no significant differences in the frequencies of CDKN1A rs1801270 or rs1059234 genotypes between the childhood ALL and control groups (p for trend=0.5459 and 0.5186, respectively) (Table II). Specifically, the heterozygous CA and homozygous AA genotypes at CDKN1A rs1801270 were not associated with an increased risk of childhood ALL (OR=0.95 and 0.77, 95%CI=0.64-1.42 and 0.47-1.26, p=0.8789 and 0.3584, respectively). Likewise, the variant CT and TT genotypes at CDKN1A rs1059234 did not show an association with childhood ALL risk (OR=0.93 and 0.75, 95%CI=0.62-1.39 and 0.45-1.24, p=0.7906 and 0.3230, respectively). Additionally, recessive and dominant genotypic model analyses also revealed no significant associations (data not shown).

View this table:
Table II.

Distribution of CDKN1A genotypic patterns among the 266 patients with childhood acute lymphoblastic leukemia and 266 healthy controls.

Contribution of CDKN1A variant alleles to childhood ALL risk. To further corroborate the findings presented in Table II, we conducted a statistical analysis of allelic frequency distributions for CDKN1A rs1801270 and rs1059234. The results indicated that neither the A allele of CDKN1A rs1801270 nor the T allele of CDKN1A rs1059234 was significantly associated with altered risk of childhood ALL (OR=0.89 and 0.88, 95%CI=0.70-1.13 and 0.69-1.12, p=0.3565 and 0.3253) (Table III).

View this table:
Table III.

Distribution of CDKN1A allelic frequencies among the 266 patients with childhood acute lymphoblastic leukemia and 266 healthy controls.

Combinatory impact of CDKN1A genotypes with sex on childhood ALL risk. After examining the distribution of CDKN1A rs1801270 and rs1059234 genotypes, we evaluated the combined effects of CDKN1A genotypes and sex on the risk of childhood ALL. For CDKN1A rs1801270, the genotypes appeared to have a protective effect in males (p for trend=0.0384), but not in females (p for trend=0.2985). Specifically, the homozygous AA genotype showed a protective association in males (OR=0.40, 95%CI=0.20-0.82, p=0.0178), whereas the heterozygous CA genotype did not (OR=0.69, 95%CI=0.41-1.16, p=0.2056) (Table IV). In contrast, neither the heterozygous nor the homozygous variant genotypes at CDKN1A rs1059234 were associated with altered risk of childhood ALL in either males or females (Table V).

View this table:
Table IV.

Distribution of CDKN1A rs1801270 genotypes among childhood acute lymphoblastic leukemia and 266 healthy controls after stratification by sex.

View this table:
Table V.

Distribution of CDKN1A rs1059234 genotypes among childhood acute lymphoblastic leukemia and 266 healthy controls after stratification by sex.

Correlation of CDKN1A genotypes with childhood ALL immunophenotype, risk classification, and survival time. We further investigated the potential impact of CDKN1A rs1801270 and rs1059234 genotypes on childhood ALL immunophenotype, risk classification, and survival time. The analysis revealed that the CDKN1A rs1801270 variant genotypes (AC+AA) were associated with a standard (lower) risk classification for childhood ALL (OR=0.57, 95%CI=0.33-0.97) and longer survival time (OR=0.31, 95%CI=0.18-0.56, p=0.0001) (Table VI). In contrast, CDKN1A rs1059234 genotypes did not show a significant effect on childhood ALL immunophenotype, risk classification, or survival time (Table VII).

View this table:
Table VI.

Distribution of CDKN1A rs1801270 genotypes among the 266 patients with childhood acute lymphoblastic leukemia stratified by immunophenotype, risk classification, and survival time.

View this table:
Table VII.

Distribution of CDKN1A rs1059234 genotypes among the 266 patients with childhood acute lymphoblastic leukemia stratified by immunophenotype, risk classification, and survival time.

Discussion

In this study, we aimed to assess the impact of CDKN1A rs1801270 and rs1059234 genotypes on ALL risk within a representative Taiwanese population, comprising 266 childhood ALL patients and an equal number of healthy controls (Table I). The analysis revealed no significant differences in the distribution of CDKN1A rs1801270 or rs1059234 genotypes between childhood ALL cases and controls (Table II and Table III). Notably, the homozygous AA genotype of CDKN1A rs1801270 was linked to a reduced risk of childhood ALL in males, but not in females (Table IV). Furthermore, the variant AC and AA genotypes of CDKN1A rs1801270 were associated with a higher risk classification and shorter survival time in childhood ALL patients (Table VI). These novel findings provide valuable insights for prognosis prediction. They also support the hypothesis that CDKN1A may play a significant role in the etiology of ALL, though further research is needed to elucidate the underlying mechanisms

Given the limited reports on the role of CDKN1A genotypes in childhood ALL, we will discuss studies focusing on CDKN1A genotypes in ALL without age restriction. In 1999, Kawamura and his colleagues investigated CDKN1A mutations in a cohort of 51 males and 17 females from the Japanese population, concluding that CDKN1A mutations were not involved in the pathogenesis of T-cell ALL (43). In 2007, Healy and his collaborators found that genotypes of three SNPs in the promoter region (T-1284C rs733590, T-899G rs762624, T-791C rs2395655) were not associated with childhood ALL risk in a French-Canadian cohort comprising 141 males, 99 females, and 277 controls (44). Conversely, in 2020, Garavand and his colleagues reported that the A allele of CDKN1A rs1801270 was associated with increased risk of ALL in a study involving 115 ALL cases and 115 healthy controls from the Iranian population (45). Notably, our study found that the AA genotype of CDKN1A rs1801270 appeared protective, although this association did not achieve statistical significance (Table II and Table III). The discrepancies between our findings and those of Garavand and his colleagues. may be due to differences in the populations studied and sample sizes. Garavand’s study included ALL patients aged 10 to 70 years, unlike our focus on childhood ALL. We also analyzed the combined effects of CDKN1A genotypes and onset age on childhood ALL risk, finding no significant differences between younger (<3.5 years) and older (≥3.5 years) groups (data not shown). Overall, these findings warrant further validation in diverse populations with well recorded samples.

It is noteworthy that the distribution patterns of CDKN1A genotypes vary significantly across different ethnic groups. For example, the frequency of the CDKN1A rs1801270 A allele is only 0.0680 in European populations, where 250,862 individuals have been studied. In contrast, this allele has a frequency of 0.4563 in East Asian populations, based on a study of 4,528 subjects (46). In African and Latin American populations, the minor allele A has frequencies of 0.1966 (8,614 samples) and 0.2622 (4,172 samples), respectively. Consequently, the CDKN1A rs1801270 A allele may have a more significant impact as a cancer risk predictor in Asian populations.

Research has explored the association of CDKN1A rs1801270 and rs1059234 genotypes with the risk of various solid tumors. Studies have investigated these genotypes in relation to breast cancer (17, 32), lung cancer (18, 19), oral cancer (20, 33), nasopharyngeal cancer (34), esophageal cancer (21, 35), gastric cancer (22, 23), colorectal cancer (36, 37), hepatocellular carcinoma (24), pancreatic cancer (25), ovarian cancer (26, 27), cervical cancer (28), endometrial cancer (29, 30), and bladder cancer (31, 38). Additionally, the interaction between CDKN1A rs1801270 and MDM2 genotypes has been implicated in acute myeloid leukemia susceptibility (47). Variability in findings across studies may be attributed to ethnic differences and cancer type specificity.

This hospital-based case-control study has several limitations that warrant consideration. First, unlike other types of solid tumors, pediatric ALL presents challenges in collecting comprehensive environmental risk factor data, particularly maternal exposures such as radiation and chemicals. Second, the age-matched control group may not perfectly correspond to the cases, as older or even adult subjects might have a lower probability of being misclassified as false negatives. Despite having a representative sample size of 266 cases and 266 controls, which provides over 80% power for a two-sided significance test (α=0.05), this sample size may be insufficient for detecting low-penetrance effects of specific genotypes in stratified analyses. Therefore, larger sample sizes and more rigorously designed studies are needed to generate more definitive evidence. Lastly, the study lacks phenotype and functional data that could further elucidate the role of CDKN1A genotypes in childhood ALL.

In summary, our study showed that the genotypes of CDKN1A rs1801270 and rs1059234 do not serve as predictive markers for childhood ALL risk in Taiwan. However, the variant AC and AA genotypes of CDKN1A rs1801270 may act as protective factors for males, correlate with standard (lower) risk classifications, and are associated with longer survival times.

Acknowledgements

The Authors are grateful to the Tissue-bank of China Medical University Hospital and doctors/nurses for their blood sample and questionnaire collection. This study was supported by research grants from Taichung Veterans General Hospital (TCVGH-VHCY1118603), Taoyuan General Hospital, Ministry of Health and Welfare (PTH112077), China Medical University Hospital (DMR-113-112) and National Science and Technology Council (NSTC 112-2635-B-039-003).

Footnotes

  • Conflicts of Interest

    All the Authors declare no conflicts of interest regarding this study.

  • Authors’ Contributions

    Research design: Chen CC, Tsai CL, Bau DT; patient and questionnaire summaries: Chen CC, Pei JS, Tzeng HE, Hsu PC; experimental work: Chang WS, Tsai CW; statistical analysis: Pei JS, Chang WS, Lin JC, Cheng DC; Tables and Figures organization: Tsai CL; manuscript writing: Chen CC, Pei JS, Bau DT; manuscript checking and discussing: Chen CC, Tsai CL, Pei JS, Tzeng HE, Hsu PC, Cheng DC, Lin JC, Tsai CW, Bau DT, Chang WS.

  • Received July 31, 2024.
  • Revision received September 25, 2024.
  • Accepted October 1, 2024.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

References

  1. ↵
    1. Al-Zayan NR,
    2. Ashour MJ,
    3. Abuwarda HN,
    4. Sharif FA
    : ARID5B, IKZF1, GATA3, CEBPE, and CDKN2A germline polymorphisms and predisposition to childhood acute lymphoblastic leukemia. Pediatr Hematol Oncol 41(2): 103-113, 2024. DOI: 10.1080/08880018.2023.2234946
    OpenUrlCrossRefPubMed
    1. He J,
    2. Munir F,
    3. Catueno S,
    4. Connors JS,
    5. Gibson A,
    6. Robusto L,
    7. McCall D,
    8. Nunez C,
    9. Roth M,
    10. Tewari P,
    11. Garces S,
    12. Cuglievan B,
    13. Garcia MB
    : Biological markers of high-risk childhood acute lymphoblastic leukemia. Cancers (Basel) 16(5): 858, 2024. DOI: 10.3390/cancers16050858
    OpenUrlCrossRefPubMed
  3. ↵
    1. de Smith AJ,
    2. Jiménez-Morales S,
    3. Mejía-Aranguré JM
    : The genetic risk of acute lymphoblastic leukemia and its implications for children of Latin American origin. Front Oncol 13: 1299355, 2024. DOI: 10.3389/fonc.2023.1299355
    OpenUrlCrossRefPubMed
  4. ↵
    1. Hayashi H,
    2. Makimoto A,
    3. Yuza Y
    : Treatment of pediatric acute lymphoblastic leukemia: a historical perspective. Cancers (Basel) 16(4): 723, 2024. DOI: 10.3390/cancers16040723
    OpenUrlCrossRefPubMed
  5. ↵
    1. Graff Z,
    2. Burke MJ,
    3. Gossai N
    : Novel therapies for pediatric acute lymphoblastic leukemia. Curr Opin Pediatr 36(1): 64-70, 2024. DOI: 10.1097/MOP.0000000000001316
    OpenUrlCrossRefPubMed
  6. ↵
    1. Wang P,
    2. Deng Y,
    3. Yan X,
    4. Zhu J,
    5. Yin Y,
    6. Shu Y,
    7. Bai D,
    8. Zhang S,
    9. Xu H,
    10. Lu X
    : The role of ARID5B in acute lymphoblastic leukemia and beyond. Front Genet 11: 598, 2020. DOI: 10.3389/fgene.2020.00598
    OpenUrlCrossRefPubMed
  7. ↵
    1. Gándara-Mireles JA,
    2. Lares-Asseff I,
    3. Reyes Espinoza EA,
    4. Córdova Hurtado LP,
    5. Payan Gándara H,
    6. Botello Ortiz M,
    7. Loera Castañeda V,
    8. Patrón Romero L,
    9. Almanza Reyes H
    : Nutritional status as a risk factor for doxorubicin cardiotoxicity in Mexican children with acute lymphoblastic leukemia. Nutr Cancer 76(10): 952-962, 2024. DOI: 10.1080/01635581.2024.2378502
    OpenUrlCrossRefPubMed
    1. Yang X,
    2. Yang L,
    3. Luo A,
    4. Liu S,
    5. Zhang X,
    6. Liu X,
    7. Liu X,
    8. Luo A,
    9. Cai M,
    10. Yan Y,
    11. Wu X,
    12. Huang K,
    13. Xu L,
    14. Jiang H
    : IKZF3 polymorphisms contribute to the increased risk of acute lymphoblastic leukemia in children. Cancer 130(6): 973-984, 2024. DOI: 10.1002/cncr.35129
    OpenUrlCrossRefPubMed
  9. ↵
    1. Cheung YT,
    2. To KK,
    3. Hua R,
    4. Lee CP,
    5. Chan AS,
    6. Li CK
    : Association of markers of inflammation on attention and neurobehavioral outcomes in survivors of childhood acute lymphoblastic leukemia. Front Oncol 13: 1117096, 2023. DOI: 10.3389/fonc.2023.1117096
    OpenUrlCrossRefPubMed
  10. ↵
    1. Chen CC,
    2. Chang WS,
    3. Pei JS,
    4. Kuo CC,
    5. Wang CH,
    6. Wang YC,
    7. Hsu PC,
    8. He JL,
    9. Gu J,
    10. Bau DT,
    11. Tsai CW
    : Non-homologous end-joining genotype, mRNA expression, and DNA repair capacity in childhood acute lymphocytic leukemia. Cancer Genomics Proteomics 21(2): 144-157, 2024. DOI: 10.21873/cgp.20436
    OpenUrlAbstract/FREE Full Text
    1. Hsu P,
    2. Chen C,
    3. Yang Y,
    4. Shih H,
    5. Chin Y,
    6. Pei J,
    7. Chang W,
    8. Tsai C,
    9. Kuo C,
    10. Bau D
    : Interleukin-8 Rs4073 genotypes as prognostic predictors for childhood acute lymphocytic leukemia. Anticancer Res 43(12): 5359-5366, 2023. DOI: 10.21873/anticanres.16739
    OpenUrlAbstract/FREE Full Text
    1. Pei JS,
    2. Chang WS,
    3. Chen CC,
    4. Mong MC,
    5. Hsu SW,
    6. Hsu PC,
    7. Hsu YN,
    8. Wang YC,
    9. Tsai CW,
    10. Bau DT
    : Novel contribution of long non-coding RNA MEG3 genotype to prediction of childhood leukemia risk. Cancer Genomics Proteomics 19(1): 27-34, 2022. DOI: 10.21873/cgp.20301
    OpenUrlAbstract/FREE Full Text
  13. ↵
    1. Pei JS,
    2. Chang WS,
    3. Hsu PC,
    4. Chen CC,
    5. Yang YC,
    6. Hsu SW,
    7. Hsu YN,
    8. Wang YC,
    9. Wang CH,
    10. Tsai CW,
    11. Bau DT
    : Contribution of cyclin-dependent kinase inhibitor 1B genotypes to childhood leukemia risk. In Vivo 36(4): 1637-1642, 2022. DOI: 10.21873/invivo.12874
    OpenUrlAbstract/FREE Full Text
    1. Chen CC,
    2. Tzeng HE,
    3. Kuo CC,
    4. Lim SNS,
    5. Hsu PC,
    6. Hsu YN,
    7. Chin YT,
    8. Chang WS,
    9. Wang CH,
    10. Tsai CW,
    11. Pei JS,
    12. Bau DT
    : Significant contribution of interleukin-18 genotypes to childhood acute lymphocytic leukemia risk in Taiwanese. Anticancer Res 42(11): 5283-5290, 2022. DOI: 10.21873/anticanres.16035
    OpenUrlAbstract/FREE Full Text
  15. ↵
    1. Pei JS,
    2. Chen CC,
    3. Chang WS,
    4. Wang YC,
    5. Chen JC,
    6. Hsiau YC,
    7. Hsu PC,
    8. Hsu YN,
    9. Tsai CW,
    10. Bau DT
    : Significant associations of lncRNA H19 genotypes with susceptibility to childhood leukemia in Taiwan. Pharmaceuticals (Basel) 14(3): 235, 2021. DOI: 10.3390/ph14030235
    OpenUrlCrossRefPubMed
  16. ↵
    1. Mousses S,
    2. Ozcelik H,
    3. Lee PD,
    4. Malkin D,
    5. Bull SB,
    6. Andrulis IL
    : Two variants of the CIP1/WAF1 gene occur together and are associated with human cancer. Hum Mol Genet 4(6): 1089-1092, 1995. DOI: 10.1093/hmg/4.6.1089
    OpenUrlCrossRefPubMed
  17. ↵
    1. Datkhile KD,
    2. Bhosale SJ,
    3. Durgawale PP,
    4. Jagdale NJ,
    5. More AL,
    6. Gudur RA,
    7. Gudur AK,
    8. Patil SR
    : TP53 (rs1042522, rs28934571) and TP21 (rs1801270, rs1059234) polymorphisms and risk of breast cancer among rural women of Maharashtra: Findings from a hospital based case- control study. Asian Pac J Cancer Prev 24(5): 1611-1619, 2023. DOI: 10.31557/APJCP.2023.24.5.1611
    OpenUrlCrossRefPubMed
  18. ↵
    1. Zheng YL,
    2. Kosti O,
    3. Loffredo CA,
    4. Bowman E,
    5. Mechanic L,
    6. Perlmutter D,
    7. Jones R,
    8. Shields PG,
    9. Harris CC
    : Elevated lung cancer risk is associated with deficiencies in cell cycle checkpoints: genotype and phenotype analyses from a case-control study. Int J Cancer 126(9): 2199-2210, 2010. DOI: 10.1002/ijc.24771
    OpenUrlCrossRefPubMed
  19. ↵
    1. Choi YY,
    2. Kang HK,
    3. Choi JE,
    4. Jang JS,
    5. Kim EJ,
    6. Cha SI,
    7. Lee WK,
    8. Kam S,
    9. Kim CH,
    10. Han SB,
    11. Jung TH,
    12. Park JY
    : Comprehensive assessment of P21 polymorphisms and lung cancer risk. J Hum Genet 53(1): 87-95, 2008. DOI: 10.1007/s10038-007-0222-6
    OpenUrlCrossRefPubMed
  20. ↵
    1. Yadav DS,
    2. Chattopadhyay I,
    3. Verma A,
    4. Devi TR,
    5. Singh LC,
    6. Sharma JD,
    7. Kataki A,
    8. Saxena S,
    9. Kapur S
    : A pilot study evaluating genetic alterations that drive tobacco- and betel quid-associated oral cancer in Northeast India. Tumour Biol 35(9): 9317-9330, 2014. DOI: 10.1007/s13277-014-2222-4
    OpenUrlCrossRefPubMed
  21. ↵
    1. Li G,
    2. Song Q,
    3. Jiang Y,
    4. Cai A,
    5. Tang Y,
    6. Tang N,
    7. Yi D,
    8. Zhang R,
    9. Wei Z,
    10. Liu D,
    11. Chen J,
    12. Zhang Y,
    13. Liu L,
    14. Wu Y,
    15. Zhang B,
    16. Yi D
    : Cumulative evidence for associations between genetic variants and risk of esophageal cancer. Cancer Epidemiol Biomarkers Prev 29(4): 838-849, 2020. DOI: 10.1158/1055-9965.EPI-19-1281
    OpenUrlAbstract/FREE Full Text
  22. ↵
    1. Dmitrieva AI,
    2. Serebryakova VA,
    3. Rakitin SS,
    4. Kudyakov LA,
    5. Novitskii VV,
    6. Yankovich KI,
    7. Sevostyanova NV
    : Study of the association of polymorphisms of p53 and p21 with the risk of development of stomach cancer. Bull Exp Biol Med 164(1): 95-98, 2017. DOI: 10.1007/s10517-017-3932-6
    OpenUrlCrossRefPubMed
  23. ↵
    1. Wang X,
    2. Lin Y,
    3. Lan F,
    4. Yu Y,
    5. Ouyang X,
    6. Liu W,
    7. Xie F,
    8. Wang X,
    9. Huang Q
    : BAX and CDKN1A polymorphisms correlated with clinical outcomes of gastric cancer patients treated with postoperative chemotherapy. Med Oncol 31(11): 249, 2014. DOI: 10.1007/s12032-014-0249-4
    OpenUrlCrossRefPubMed
  24. ↵
    1. Liu F,
    2. Wei YG,
    3. Luo LM,
    4. Wang WT,
    5. Yan LN,
    6. Wen TF,
    7. Xu MQ,
    8. Yang JY,
    9. Li B
    : Genetic variants of p21 and p27 and hepatocellular cancer risk in a Chinese Han population: A case-control study. Int J Cancer 132(9): 2056-2064, 2013. DOI: 10.1002/ijc.27885
    OpenUrlCrossRefPubMed
  25. ↵
    1. Chen J,
    2. Amos CI,
    3. Merriman KW,
    4. Wei Q,
    5. Sen S,
    6. Killary AM,
    7. Frazier ML
    : Genetic variants of p21 and p27 and pancreatic cancer risk in non-Hispanic Whites: a case-control study. Pancreas 39(1): 1-4, 2010. DOI: 10.1097/MPA.0b013e3181bd51c8
    OpenUrlCrossRefPubMed
  26. ↵
    1. Zavarykina TM,
    2. Tyulyandina AS,
    3. Khokhlova SV,
    4. Khabas GN,
    5. Asaturova AV,
    6. Nosova YA,
    7. Brenner PK,
    8. Kapralova MA,
    9. Atkarskaya MV,
    10. Khodyrev DS,
    11. Burdennyi AM,
    12. Loginov VI,
    13. Stenina MB,
    14. Sukhikh GT
    : Association of molecular genetic markers of TP53, MDM2, and CDKN1A genes with progression-free survival of patients with ovarian cancer after platinum-based chemotherapy. Bull Exp Biol Med 169(4): 486-490, 2020. DOI: 10.1007/s10517-020-04915-5
    OpenUrlCrossRefPubMed
  27. ↵
    1. Goode EL,
    2. Fridley BL,
    3. Vierkant RA,
    4. Cunningham JM,
    5. Phelan CM,
    6. Anderson S,
    7. Rider DN,
    8. White KL,
    9. Pankratz VS,
    10. Song H,
    11. Hogdall E,
    12. Kjaer SK,
    13. Whittemore AS,
    14. DiCioccio R,
    15. Ramus SJ,
    16. Gayther SA,
    17. Schildkraut JM,
    18. Pharaoh PP,
    19. Sellers TA
    : Candidate gene analysis using imputed genotypes: cell cycle single-nucleotide polymorphisms and ovarian cancer risk. Cancer Epidemiol Biomarkers Prev 18(3): 935-944, 2009. DOI: 10.1158/1055-9965.EPI-08-0860
    OpenUrlAbstract/FREE Full Text
  28. ↵
    1. Tian Q,
    2. Lu W,
    3. Chen H,
    4. Ye F,
    5. Xie X
    : The nonsynonymous single-nucleotide polymorphisms in codon 31 of p21 gene and the susceptibility to cervical cancer in Chinese women. Int J Gynecol Cancer 19(6): 1011-1014, 2009. DOI: 10.1111/IGC.0b013e3181a8b950
    OpenUrlAbstract/FREE Full Text
  29. ↵
    1. Cai H,
    2. Xiang YB,
    3. Qu S,
    4. Long J,
    5. Cai Q,
    6. Gao J,
    7. Zheng W,
    8. Shu XO
    : Association of genetic polymorphisms in cell-cycle control genes and susceptibility to endometrial cancer among Chinese women. Am J Epidemiol 173(11): 1263-1271, 2011. DOI: 10.1093/aje/kwr002
    OpenUrlCrossRefPubMed
  30. ↵
    1. Roh JW,
    2. Kim JW,
    3. Park NH,
    4. Song YS,
    5. Park IA,
    6. Park SY,
    7. Kang SB,
    8. Lee HP
    : p53 and p21 genetic polymorphisms and susceptibility to endometrial cancer1. Gynecol Oncol 93(2): 499-505, 2004. DOI: 10.1016/j.ygyno.2004.02.005
    OpenUrlCrossRefPubMed
  31. ↵
    1. Chen WC,
    2. Wu HC,
    3. Hsu CD,
    4. Chen HY,
    5. Tsai FJ
    : p21 gene codon 31 polymorphism is associated with bladder cancer. Urol Oncol 7(2): 63-66, 2002. DOI: 10.1016/s1078-1439(01)00152-1
    OpenUrlCrossRefPubMed
  32. ↵
    1. Akhter N,
    2. Dar SA,
    3. Haque S,
    4. Wahid M,
    5. Jawed A,
    6. Akhtar MS,
    7. Alharbi RA,
    8. Sindi AAA,
    9. Alruwetei A,
    10. Zubair Choudhry HM,
    11. Ahmad A
    : Crosstalk of Cyclin-dependent kinase inhibitor 1A (CDKN1A) gene polymorphism with p53 and CCND1 polymorphism in breast cancer. Eur Rev Med Pharmacol Sci 25(12): 4258-4273, 2021. DOI: 10.26355/eurrev_202106_26131
    OpenUrlCrossRefPubMed
  33. ↵
    1. Bau DT,
    2. Tsai MH,
    3. Lo YL,
    4. Hsu CM,
    5. Tsai Y,
    6. Lee CC,
    7. Tsai FJ
    : Association of p53 and p21(CDKN1A/WAF1/CIP1) polymorphisms with oral cancer in Taiwan patients. Anticancer Res 27(3B): 1559-1564, 2007.
    OpenUrlAbstract/FREE Full Text
  34. ↵
    1. Soares S,
    2. Craveiro R,
    3. Catarino R,
    4. Breda E,
    5. Medeiros R,
    6. Bravo I
    : The role of nt590 P21 gene polymorphism in the susceptibility to nasopharyngeal cancer. Exp Oncol 36(1): 44-47, 2014.
    OpenUrlPubMed
  35. ↵
    1. Kaya Z,
    2. Karan BM,
    3. Almalı N
    : CDKN1A (p21 gene) polymorphisms correlates with age in esophageal cancer. Mol Biol Rep 49(1): 249-258, 2022. DOI: 10.1007/s11033-021-06865-1
    OpenUrlCrossRefPubMed
  36. ↵
    1. Alvizo-Rodríguez CR,
    2. Flores-López BA,
    3. Ayala-Madrigal ML,
    4. Partida-Pérez M,
    5. Macías-Gómez NM,
    6. Peregrina-Sandoval J,
    7. Suárez-Villanueva AS,
    8. Moreno-Ortiz JM,
    9. Cervantes-Ortiz S,
    10. Maciel-Gutiérre VM,
    11. Gutiérrez-Angulo M
    : Interaction of CCND2, CDKN1A, and POLD3 variants in Mexican patients with colorectal cancer. Turk J Gastroenterol 33(6): 525-531, 2022. DOI: 10.5152/tjg.2022.21223
    OpenUrlCrossRefPubMed
  37. ↵
    1. Cacina C,
    2. Yaylim-Eraltan I,
    3. Arikan S,
    4. Saglam EK,
    5. Zeybek U,
    6. Isbir T
    : Association between CDKN1A Ser31Arg and C20T gene polymorphisms and colorectal cancer risk and prognosis. In Vivo 24(2): 179-183, 2010.
    OpenUrlAbstract/FREE Full Text
  38. ↵
    1. Koga F,
    2. Kitahara S,
    3. Arai K,
    4. Honda M,
    5. Sumi S,
    6. Yoshida K
    : Negative p53/positive p21 immunostaining is a predictor of favorable response to chemotherapy in patients with locally advanced bladder cancer. Jpn J Cancer Res 91(4): 416-423, 2000. DOI: 10.1111/j.1349-7006.2000.tb00961.x
    OpenUrlCrossRefPubMed
  39. ↵
    1. Ying TH,
    2. Tseng CJ,
    3. Tsai SJ,
    4. Hsieh SC,
    5. Lee HZ,
    6. Hsieh YH,
    7. Bau DT
    : Association of p53 and CDKN1A genotypes with endometriosis. Anticancer Res 31(12): 4301-4306, 2011.
    OpenUrlAbstract/FREE Full Text
  40. ↵
    1. Yang MD,
    2. Lin KC,
    3. Lu MC,
    4. Jeng LB,
    5. Hsiao CL,
    6. Yueh TC,
    7. Fu CK,
    8. Li HT,
    9. Yen ST,
    10. Lin CW,
    11. Wu CW,
    12. Pang SY,
    13. Bau DT,
    14. Tsai FJ
    : Contribution of matrix metalloproteinases-1 genotypes to gastric cancer susceptibility in Taiwan. Biomedicine (Taipei) 7(2): 10, 2017. DOI: 10.1051/bmdcn/2017070203
    OpenUrlCrossRefPubMed
    1. Bau DT,
    2. Tsai CW,
    3. Chang WS,
    4. Yang JS,
    5. Liu TY,
    6. Lu HF,
    7. Wang YW,
    8. Tsai FJ
    : Genetic susceptibility to prostate cancer in Taiwan: A genome-wide association study. Mol Carcinog 63(4): 617-628, 2024. DOI: 10.1002/mc.23676
    OpenUrlCrossRefPubMed
  42. ↵
    1. Chen LH,
    2. Tsai YF,
    3. Wu WT,
    4. Chiu KL,
    5. Tsai CW,
    6. Chang WS,
    7. Li CH,
    8. Yang JS,
    9. Mong MC,
    10. Hsia TC,
    11. Bau DT
    : Association of matrix metalloproteinase-9 genotypes with lung cancer risk in Taiwan. Anticancer Res 44(5): 1845-1852, 2024. DOI: 10.21873/anticanres.16986
    OpenUrlAbstract/FREE Full Text
  43. ↵
    1. Kawamura M,
    2. Ohnishi H,
    3. Guo SX,
    4. Sheng XM,
    5. Minegishi M,
    6. Hanada R,
    7. Horibe K,
    8. Hongo T,
    9. Kaneko Y,
    10. Bessho F,
    11. Yanagisawa M,
    12. Sekiya T,
    13. Hayashi Y
    : Alterations of the p53, p21, p16, p15 and RAS genes in childhood T-cell acute lymphoblastic leukemia. Leuk Res 23(2): 115-126, 1999. DOI: 10.1016/s0145-2126(98)00146-5
    OpenUrlCrossRefPubMed
  44. ↵
    1. Healy J,
    2. Bélanger H,
    3. Beaulieu P,
    4. Larivière M,
    5. Labuda D,
    6. Sinnett D
    : Promoter SNPs in G1/S checkpoint regulators and their impact on the susceptibility to childhood leukemia. Blood 109(2): 683-692, 2007. DOI: 10.1182/blood-2006-02-003236
    OpenUrlAbstract/FREE Full Text
  45. ↵
    1. Lotfi Garavand A,
    2. Mohammadi M,
    3. Mohammadzadeh S
    : Evaluation of TP53 Codon 72, P21 Codon 31, and MDM2 SNP309 polymorphisms in Iranian patients with acute lymphocytic leukemia. Rep Biochem Mol Biol 9(1): 26-32, 2020. DOI: 10.29252/rbmb.9.1.26
    OpenUrlCrossRefPubMed
  46. ↵
    Reference SNP (rs) report rs1801270. Available at: https://www.ncbi.nlm.nih.gov/snp/rs1801270 [Last accessed on July 30, 2024]
  47. ↵
    1. Ebid GT,
    2. Sedhom IA,
    3. El-Gammal MM,
    4. Moneer MM
    : MDM2 T309G has a synergistic effect with P21 ser31arg single nucleotide polymorphisms on the risk of acute myeloid leukemia. Asian Pac J Cancer Prev 13(9): 4315-4320, 2012. DOI: 10.7314/apjcp.2012.13.9.4315
    OpenUrlCrossRefPubMed
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Contribution of Cyclin Dependent Kinase Inhibitor 1A Genotypes to Childhood Acute Lymphocytic Leukemia Risk in Taiwan
CHAO-CHUN CHEN, CHUNG-LIN TSAI, JEN-SHENG PEI, HUEY-EN TZENG, PEI-CHEN HSU, DA-CHUAN CHENG, JIUNN-CHERNG LIN, CHIA-WEN TSAI, DA-TIAN BAU, WEN-SHIN CHANG
Cancer Genomics & Proteomics Jan 2025, 22 (1) 46-54; DOI: 10.21873/cgp.20486
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