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ORIGINAL ARTICLE
Year : 2021  |  Volume : 17  |  Issue : 1  |  Page : 46-50

Evaluation of newly identified Ikaros family zinc finger 1 loci in colorectal cancer


1 School of Biotechnology, Shri Mata Vaishno Devi University, Katra, Jammu and Kashmir, India
2 Department of Biotechnology, Kashmir University, Srinagar, Jammu and Kashmir, India
3 Indian Council of Medical Research-Centre for Advance Research, Shri Mata Vaishno Devi University, Katra, Jammu and Kashmir, India
4 Department of Medicine, ASCOMS, Jammu, Jammu and Kashmir, India
5 Department of Radiotherapy, Government Medical College, Jammu, Jammu and Kashmir, India
6 Centre for Molecular Biology, Central University of Jammu, Jammu, Jammu and Kashmir, India
7 Department of Botany, Central University of Jammu, Jammu, Jammu and Kashmir, India

Date of Submission22-Jun-2020
Date of Decision14-Aug-2020
Date of Acceptance30-Sep-2020
Date of Web Publication15-Mar-2021

Correspondence Address:
Rakesh Kumar
Assistant Professor, School of Biotechnology Shri Mata Vaishno Devi University Katra., Jammu and Kashmir
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_844_20

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 > Abstract 


Aim: In this study, we evaluated the association of rs6964823 of the Ikaros Family Zinc Finger 1 (IKZF1) gene with the risk of colorectal cancer (CRC) within the population of Jammu and Kashmir (J and K).
Materials and Methods: The variant rs6964823 of the IKZF1 gene was genotyped using the TaqMan allele discrimination assay for 578 individuals (182 CRC cases and 396 healthy controls). The association of single-nucleotide polymorphisms with the disease was evaluated using logistic regression.
Results: It was observed that the variant rs6964823 (IKZF1) showed a significant association with an adjusted allelic odds ratio (OR) of 1.74 (1.34–2.27) at 95% confidence interval (CI), P ≤ 0.05. The dominant model (AA + AG vs. GG) was also applied, where the adjusted OR was 3.096 (2.011–4.76) at 95% CI, P > 0.05.
Conclusions: It was found that the variant rs6964823 of the IKZF1 gene is associated with a higher risk of CRC within the population of J and K.

Keywords: Colorectal cancer, Ikaros Zinc Finger 1, Jammu and Kashmir, rs6964823


How to cite this article:
Sharma B, Shah R, Jamwal RS, Verma S, Bhat A, Bhat GR, Bakshi D, Singh S, Angurana S, Bhat A, Vaishnavi S, Kumar R. Evaluation of newly identified Ikaros family zinc finger 1 loci in colorectal cancer. J Can Res Ther 2021;17:46-50

How to cite this URL:
Sharma B, Shah R, Jamwal RS, Verma S, Bhat A, Bhat GR, Bakshi D, Singh S, Angurana S, Bhat A, Vaishnavi S, Kumar R. Evaluation of newly identified Ikaros family zinc finger 1 loci in colorectal cancer. J Can Res Ther [serial online] 2021 [cited 2021 Jun 19];17:46-50. Available from: https://www.cancerjournal.net/text.asp?2021/17/1/46/311074




 > Introduction Top


Colorectal cancer (CRC) is the third most frequent and a leading cause of cancer-related morbidity and mortality worldwide.[1],[2] CRC evolves as a result of the progressive accumulation of genetic and epigenetic alterations in the colonic epithelium, which transforms them into colorectal adenomas and adenocarcinomas.[3] The incidence of CRC has increased yearly since the middle of the last century.[4] In 2018, it accounted for over 10% of all cancer incidences, with more than 1.8 million new cases and nearly 900,000 mortalities recorded worldwide.[2],[5] It affected males (10.9%) and females (9.5%) almost equally all over the world.[5]

In India, CRC claimed an estimated 43,090 lives (males: 28,591 [6.9%] and females: 14,499) in 2018.[5],[6] In the Union Territory of Jammu and Kashmir (J and K), increased incidences of the gastric, esophagus, and CRC have been reported in recent years.[7],[8] According to the hospital-based data analysis, CRC with an incident rate of 16.8% is the second most common cancer type, and a steady increase in morbidity and mortality is being noted simultaneously in the J and K region.[8] This may be a result of environmental factors involving modified lifestyle and intake of processed food items[7] which are mostly endocrine disruptors. An increase in body mass index (BMI) of the general population has led to obesity. Obesity plays a critical role in development and progression of CRC.[9] Various studies have proven the fact that in the Kashmir region, the increased incidence of the gastric, esophagus, and CRC is due to their lifestyle that includes chemicals (nitroso compounds, amines, and nitrates) in their food items.[10],[11] It is a well-established fact in the literature that westernization such as obesity and physical inactivity increases the incidence of CRC in many countries.[12] In addition to other socioeconomic factors, genetic pool of the studied population/s is conserved due to the ritual of endogamy.[13],[14] The main cause of CRC could be sporadic, inhereditary, or acquired mutation cancer.[15] The failure of DNA repair genes leading to apoptosis can also be related to the causes of the mutations,[16] Various studies reported that regulation of genetic and epigenetic alteration provide a better prognosis in the progression of CRCs.[3] The predominant population groups of J and K are endogamous.[12] A higher rate of endogamy leads to pooling of recessive genomic factors, leading to genetic diseases. This factor has been progressively recognized as a major contributory factor that can contribute to the development of CRC. The pathogenesis of CRC is known to result from the interplay of multiple environmental and inherited factors.[7],[11] The genome-wide association studies (GWASs) significantly increased our understanding of genetic predisposition to the expansion of CRC.[17],[18] Recent advances in GWAS have led to the successful identification of multiple common single-nucleotide polymorphisms (SNPs) associated with CRC risk.[19] The majority of the GWAS-identified CRC risk variants are involved in known biological pathways; however, a few highly significant ones reside in gene desert regions, and the mechanism by which these variants contribute to colorectal carcinogenesis remains unclear.[20] The study of SNPs provides an understanding of cancer susceptibility and their response to personalized treatment.[21],[22]

Transcription factors are common targets of epigenetic inactivation in human cancer.[23] The Ikaros Family Zinc Finger 1 (IKZF1) gene encodes a pivotal transcription factor that belongs to the zinc-finger DNA-binding protein family.[24] IKZF1 plays critical roles in regulating numerous biological events including immune system function and hematopoietic proliferation and differentiation.[25],[26],[27] Several alternatively spliced transcript variants encoding different isoforms have been described for this gene.[28] Colorectal cell lines study has shown the hypermethylation of the promoter region of the IKZF1 gene in more than 60% of primary CRC samples.[29]

In a previous study, our research group explored the variant rs6964823 of the IKZF1 gene which was found to be associated with greater risk factors in the progression of leukemia in similar population subset.[30] The locus and genotyping information for the selected SNP are given in [Table 1]. Nevertheless, the relationship between variant rs6964823 and susceptibility of CRC is still unfamiliar. We hypothesized that the variant rs6964823 of the IKZF1 gene identified in GWASs which plays a role in leukemia might also affect the susceptibility to CRC in the J and K population.
Table 1: Clinical characteristics for cases and controls

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 > Materials and Methods Top


Ethics statement

This study was approved by the Institutional Ethics Review Board (IERB) of Shri Mata Vaishno Devi University (SMVDU). All details were recorded in a predesigned pro forma and the written informed consent was obtained from each participant before conducting the study. All experimental procedures were conducted according to the guidelines and regulations set by the IERB, SMVDU.

Study subjects

The present study included 182 colorectal patients and 396 healthy controls (age and sex matched) comprising a total of 578 participants from the J and K region of India. All the cases recruited for the study were obtained from different hospitals and various clinics of J and K.

Blood samples

Peripheral blood was collected from all the participants after obtaining prior informed consent. Two to three milliliters of venous blood was collected in ethylenediaminetetraacetic acid Vacutainer tubes from all the participants.

DNA extraction

The genomic DNA was isolated from the venous blood samples, using the manufacturer's protocol of Qiagen™ DNA isolation kit (Catalog No. #51206, Hilden, Germany). The quantification of DNA was done using Eppendorf's bio-spectrophotometer (Hamburg, Germany) at wavelength 260 nm and 280 nm, and the ratio of OD260 nm/OD280 nm was taken as a criterion to check the purity of DNA.

Genotyping of rs6964823 of Ikaros family zinc finger 1

The TaqMan® assay was used for the genotyping of variant rs6964823 of IKZF1 as described in our previous studies.[31],[32] The volume of the total polymerase chain reaction (PCR) was 10 mL, comprising 2.5 mL of TaqMan® UNG Master Mix, 0.25 mL of probe, 3 mL DNA (5 ng/mL), and 4.25 mL nuclease-free water added together to make the final volume. The thermal conditions adopted were hold for 10 min at 95°C, 40 cycles at 95°C for 15s, and 60°C for 1 min. All the samples were run in a 96-well plate with three no-template controls. The post-PCR detection system is used to measure allele-specific fluorescence. A total of 100 random samples from colorectal were picked and regenotyped for cross-validation of the genotyping calls, and the concordance rate was found to be 100%.

Statistical analysis

The statistical analysis was mainly performed using the Statistical Package for the Social Sciences (SPSS version 20; SPSS, Chicago, IL, USA).[33] A comparative analysis of clinical parameters was performed. Chi-square test was done and genotype frequencies were tested for total Hardy–Weinberg equilibrium. The logistic regression model was used to estimate the odds ratio (OR) at a 95% confidence interval (CI). Statistical significance was considered when P ≤ 0.05. The power of the study was calculated using PS: Power and sample size calculation (PS version 3.1.6) software.[34] The in silico analysis of variant was done with exonic splicing enhancer Manufacturer of (ESE) finder (3.0)[35] and SNiPA v3.3 Snipa are Cold Spring Harbor Laboratory and Institute of Computational Biology.[36]

Protein-protein interaction network construction and gene function enrichment analysis

The Search Tool for the Retrieval of Interacting Genes (STRING) database was used to analyze the functional interactions of IKZF1 protein with other proteins.[37] The interactions with confidence scores ≥0.85 were retrieved and resulting protein-protein interaction network was screened for analysis. Then, a functional enrichment analysis of these genes using the STRING database was also done.


 > Results Top


Clinical characteristics for cases and controls

The clinicopathological characteristics of all the participants are shown in [Table 1].

Single-nucleotide polymorphisms analysis of rs6964823 of Ikaros family zinc finger 1

In total, there were 578 participants, out of which 182 were colorectal cases and 396 were healthy controls in the current study. The frequency of risk allele “A” observed for the variant rs6964923 of the IKZF1 gene was 0.387 in cases and 0.266 in controls. The allele frequency distribution for SNP is summarized in [Table 2]. The unadjusted allelic odds ratio (OR) was 1.74 (1.34–2.27 at 95% CI, P ≤ 0.05), which showed a strong association with CRC. Age, gender, BMI, alcohol, and smoking are included as covariates. The dominant model (AA + AG vs. GG) was applied to evaluate the maximum effect of risk allele A, where the adjusted OR was 3.096 (2.011–4.76), P > 0.05 [Table 3]. The variant rs6964923 of IKZF1 followed the HWE (P = 0.727). The calculated power of this study is above 90%.
Table 2: The locus and genotyping information for selected single-nucleotide polymorphisms at 7p12.2

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Table 3: Allelic frequency distribution of variant rs6964823 and risk in colorectal cancer

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Ikaros family zinc finger 1is associated with hematopoietic cell differentiation

In the current study, the STRING database was used to search for functional interaction of proteins with IKZF1. The five most related interaction proteins were CRBN, GATA1, P2RY8, PTPRC, and SPI1 [Figure 1]a. Further, GO (biological process) analysis showed that all proteins were involved in the lymphocyte differentiation process [Figure 1]b. GO (molecular function) analysis showed that these proteins have a transcription regulator activity [Figure 1]c. All these results indicate that IKZF1 plays a very important role in hematopoietic cell differentiation and transcription regulation.
Figure 1: Ikaros family zinc finger 1 is associated with hematopoietic cell differentiation. (a) Protein-protein interaction network of Ikaros Family Zinc (b and c) Functional enrichment analysis of HSD17B6 and related proteins in three modules: (b) for GO (biological process), (c) for GO (molecular function)

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 > Discussion Top


IKZF1 has been shown to have characteristics of a tumor suppressor gene that can arrest the uncontrolled growth and proliferation when introduced into an established mouse Ikaros null T-leukemia cell line.[38],[39] Indeed, loss of IKZF1 is an important step in the leukemic transformation in a cohort of patients with myeloproliferative neoplasms.[38] Bhat et al. (2019) suggested that the variant rs6964823 of the IKZF1 gene is not only associated independently in the predisposition of leukemic risk in northern India but also cumulatively with the variant rs10740055 of the ARID5B gene. However, the role of this variant in the predisposition of CRC is still unknown.

The IKZF1 gene encodes eight exons and can generate multiple isoforms by alternative splicing.[40] Exons 3–5 encode four N-terminal zinc fingers which are indispensable for IKZF1 DNA binding activity and Exon 7 encodes two C-terminal zinc fingers, leading to homological or heterogenetic dimerization between IKZF's isoforms.[41] Among the eight isoforms from RNA splicing, Ik4-Ik8 shows the dominant-negative effect due to the lack of N-terminal zinc fingers for DNA binding activity.[42]

The in silico analysis of variant rs6964823 was done with ESE finder (version 3.0)[35] and SNiPA (version 3.3).[36] Wherefrom the ESE prediction tool, we found that there is no change in splicing factor binding sites of ESE intronic site and SF2/ASF (IgM-BRCA1) [Figure S1]. Besides, linkage disequilibrium (LD) of the variant has shown no direct regulatory effect [Figure S2].



We observed the normalized effect size from GTex Portal (www.gtexportal.org) and the value observed for the variant in colorectal tissue was 0.58 and the P value observed was 2.8e-48 which is significant, to evaluate the expression of the variant rs6964823 of the IKZF, an increase in the expression of the gene which may imply the severity of colon cancer.

All these results indicate that IKZF1 plays a very important role in transcription regulation which can lead to the development of cancer. Various GWASs found that various variants of the IKZF1 gene are associated with different ethnic populations like Indian, Japanese, and Han Chinese population for leukemia.[27],[28] In the Kashmir region, the rs6964823 variant of the IKZF1 gene is significantly associated with leukemia.[28]

To the best of our knowledge, to date, no study has been conducted on the role of the rs6964823 of IKZF1 in CRC within the population of J and K. This is the first prelude study that investigated the possible correlation between the rs6964823 IKZF1 polymorphism and susceptibility to CRC.


 > Conclusions Top


Our findings suggest that variant rs6964823 of the IKZF1 gene may contribute to the risk of CRC in the J and K population, especially in patients with advanced age, alcohol consumption, and smoking habits.

IKZF1 polymorphism as genetic evidence supports the genomic association of colorectal carcinoma and, if investigated further in a large cohort, can prove to be a potential biomarker in the studied population.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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