The influence of CASP8 D302H gene variant in colorectal cancer risk and prognosis

Canan Cacina; Saime Turan Sürmen; Soykan Arıkan; Sadrettin Pençe; İlhan Yaylım

doi:10.1515/tjb-2022-0042

Article Open Access

The influence of CASP8 D302H gene variant in colorectal cancer risk and prognosis

Canan Cacina , Saime Turan Sürmen , Soykan Arıkan , Sadrettin Pençe and İlhan Yaylım

Published/Copyright: April 21, 2023

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From the journal Turkish Journal of Biochemistry Volume 48 Issue 3

Abstract

Objectives

Apoptosis is defined as programmed cell death, which regulates cellular functions and various physiological responses. Several studies reported that Caspase genes play important roles in the apoptosis and inflammation process. Caspase-8 (CASP8) is a member of the cysteine protease family and a key regulator gene in the induction of apoptosis. In present study, we aimed to investigate the possible associations between the CASP8; D302H (G>C) gene polymorphism and colorectal cancer risk and prognosis.

Methods

The CASP8; D302H genotypes were determined in 75 colorectal cancer patients and 122 healthy controls. Polymerase Chain Reaction-Restriction Fragment Length Polymorphism method (PCR-RFLP) was used to detect the CASP8; D302H gene variation in the study group.

Results

We found that individuals carrying the GC genotype of CASP8; D302H gene variation had significantly lower colorectal cancer risk compared with those carrying CC and GG genotypes (OR=0.539; p=0.045). In addition, we analyzed the clinicopathological characteristics of patients and noticed a significant correlation between the C allele frequency and moderately differentiated tumor parameter (p<0.05).

Conclusions

The CASP8; D302H gene polymorphism GC genotype might be associated with a reduced risk of colorectal cancer but further studies in a larger population are needed most effective evaluation of the CASP8; D302H gene variation in colorectal cancer development.

Keywords: apoptosis; caspase-8; colorectal cancer; gene variation; prognosis

Introduction

Colorectal cancer (CRC) is a common type of malignancy with an increasing incidence tendency, in terms of both morbidity and mortality [1]. The pathogenesis of CRC is induced by multiple variables such as genetic, epigenetic factors, and alterations in protein expression also it is known that influenced by host immune reactions [2, 3]. Advanced scientific improvements have led to the investigation of novel biomarkers to clarify the possible risks of diseases and enhance our understanding of health problems and predict therapeutic approaches [2, 3].

Apoptosis is programmed cell death also a crucial mechanism to maintain homeostatic balance between cell growth, division, and death [4, 5]. Dysregulation of this death mechanism, which consists of the receptors, ligands, adaptors, and caspases, induces carcinogenesis by activating cell proliferation and genetic variations also promotes resistance to therapy [5, 6].

Caspases (cysteine aspartyl proteases) are key regulators of apoptosis, which hydrolyze aspartic acid peptide bonds within crucial intracellular molecules to induce cell death [7], [8], [9], [10]. Several reports have concluded that the caspases influence immunological functions, cell proliferation, and migration [11]. According to studies, apoptosis is regulated by two basic pathways, which are defined as the internal pathway (mitochondria-related) and the external (extrinsic) pathway. The extrinsic pathway includes proteins, which were identified as tumor necrosis factor (TNF) family (TRAIL-R1, TRAIL-R2), membranous receptor Fas/CD95, and death receptors (DRs) [11]. Caspase-8 (CASP-8) initiates the extrinsic apoptotic pathway by activating tumor necrosis factor receptor 1 (TNFR)1, cell surface death receptor (FAS), and (DRs) [12, 13].

Studies have reported that the binding of receptor-ligand complex, catalytically induces Caspase-8 through homo-oligomerization/dimerization, subsequently, the activated Caspase-8 transfers the death signal to mainly important executor caspases such as Caspase-3, which then cleave several cellular proteins to complete the apoptosis-inducing process [14].

The first genome-wide association studies (GWAS) enable to the identification of many genomic polymorphisms and mutations, which are potentially associated with cancer risk and development [15]. The human CASP8 gene is located on human chromosome 2q33–34 and it has at least 11 exons spanning ∼30 kb, which contains highly polymorphic regions [16]. CASP8; D302H (aspartate to histidine, G>C; rs1045485) gene polymorphism has been analyzed in many types of cancers [17], [18], [19], [20], [21]. Although in several studies researchers concluded that the substitution of an amino acid (the aspartate to histidine) at the D302H region theoretically might influence the auto processing of Caspase-8 and molecular interactions, the mechanism is yet to be confirmed by several studies, which are conducted in different populations [21].

To the best of our knowledge, there was no study that mainly focused on CASP8; D302H gene variation and colorectal cancer risk in the Turkish population, so our purpose in the present study was to investigate the possible correlations between the CASP8; D302H gene polymorphism and colorectal cancer risk.

Materials and methods

Sample groups

In the present study, 75 colorectal cancer patients and 122 healthy individuals were analyzed. The whole cases were selected from Istanbul Education and Research Hospital. This case-control study was approved by the Istanbul University Faculty of Medicine Ethical Committee and the research protocol was consistent with the World Medical Association Declaration of Helsinki (Ethical Principles for Medical Research Involving Human Subjects). The Power and Sample Size Calculation Program software were used to evaluate effective sample size and the data size was consistent. The peripheral blood samples were taken into EDTA containing tubes from individuals who have given informed consent. The patient samples were obtained before chemotherapeutic or radiation therapy. The verification analysis of histological grade was determined through the assessment of differentiation.

Extraction of DNA

A common and reliable technique, salting-out was used for extracting genomic DNA from blood samples [22]. Briefly, 5–10 mL of fresh blood samples were transferred to 50 mL falcon tubes and the cell lysis buffer was added and incubated for 10 min. After centrifugation, the supernatant was discarded. These steps were done twice. White blood cell lysis, 10 % SDS, and proteinase K (20 mg/mL) were included in the pellet and incubated in a water bath at 56 °C overnight. Then, 9.5 M ammonium acetate was added, and the samples were shaken a few times and centrifuged. The supernatant was taken into a clean tube and 99 % ethanol was added. After this step, visible DNA threads were taken with a clean tip and stored at appropriate pH and temperature until analysis.

SNP genotyping

The Caspase-8; D302H gene variation was detected by PCR–RFLP (polymerase chain reaction–restriction fragment length polymorphism) method. We used to following primer sequences: 5′-CATTTTGAGATCAAGCCCCG-3′ (forward) and 5′-CCCTTGTCTCCATGGGAGAGGA-3′ (reverse) for the amplification. The PCR reaction started with the initial DNA denaturation step at 95 °C for 5 min, followed by 35 cycles at (95 °C for 45 s, 60 °C for 45 s, 72 °C for 45 s). The final extension step was at 72 °C for 4 min. Caspase-8; D302H polymorphism, 132-bp PCR products were digested by BstUI (MBI Fermantas) at 37 °C for 3 h. After incubation, all of the digested products were visualized in 3 % agarose gel containing ethidium bromide, and band sizes were determined with markers of 50 bp. The GG genotype generated two fragments of 112, 20 bp, and the CC genotype individuals were identified by the presence of 132 bp in the agarose gel [21].

Statistical analysis

The data were evaluated with SPSS version 21 for Windows (SPSS Inc, Chicago, IL, USA). Numerical results were defined as mean, standard deviation, and percentage. The determination of CASP8; D302H genotype frequencies in the patients and the healthy group were performed by using the chi-square test. Odds ratios (ORs) with 95 % confidence intervals (CIs) were calculated for risk estimation. A p-value less than 0.05 was considered significant. The distribution of allele and genotype frequencies was determined according to Hardy-Weinberg equilibrium (HWE) in the study population (p>0.05).

Results

The characteristics of colorectal cancer patients were given in Table 1. We didn’t find statistically significant differences in terms of age, family history, or smoking status parameters among the study groups in the present study. The mean age of participants was 59.31 ± 13.1 years in cases and 53.11 ± 10.39 in healthy individuals respectively. The distribution of CASP8; D302H polymorphism genotype and allele frequencies in study groups were given in Table 2. The CASP8; D302H (GG, GC and CC) genotypes frequencies were observed as (54.1 , 45.1, 0.8 %) in controls and (66.7 , 30.7, 2.7 %) in patients respectively. In present study, we found that the individuals with GC (heterozygote) genotype had significantly lower colorectal cancer risk compared with those carrying CC and GG genotypes of CASP8; D302H polymorphism (OR=0.539; p=0.045) (Table 3).

Table 1:

Characteristics of patients with colorectal carcinoma (%).

	Patients, %
T stage
T1 + T2	26.9
T3 + T4	73.1
Lymph node status
N0	42.3
N1 + N2 + N3	57.7
Differentiation
Well	28.6
Moderate poor	71.4
Distant metastasis
Absence	81.5
Presence	18.5
Perineural invasion
Absence	53.8
Presence	46.2
Angiolymphatic invasion
Absence	61.6
Presence	38.4

Table 2:

Genotype and allele frequencies of cases and controls.

Genotype and allele	Patients n=75, %	Controls n=122, %	p-Value
GG	50 (66.7)	66 (54.1)	p>0.05
GC	23 (30.7)	55 (45.1)
CC	2 (2.7)	1 (0.8)
G Allele	123 (82)	187 (76.6)	0.207
C Allele	27 (18)	57 (23.3)	0.207

n, number of individuals, chi-square (χ2) test was used between the groups. p-values less than 0.05 denote statistical significance.

Table 3:

The risk of colorectal cancer associated with CASP8 D302H.

	Patients, n (%)	Controls, n (%)	OR	(95 % CI)	p-Value
GG + GC	73 (97.3)	121 (99.2)	0.302	0.027–3.385	0.559
CC	2 (2.7)	1 (0.8)	0.302	0.027–3.385	0.559
CC + GC	25 (33.3)	56 (45.9)	0.589	0.324–1.071	0.082
GG	50 (66.7)	66 (54.1)	0.589	0.324–1.071	0.082
GG + CC	52 (69.3)	67 (54.9)	0.539	0.294–0.988	0.045^a
GC	23 (30.7)	55 (45.1)	0.539	0.294–0.988	0.045^a

OR, odds ratio; CI, confidence interval. ^ap-Value <0.05 denoted statistical significance.

On the other hand, we detected the CC genotype in only two patients and this rare genotype was observed in only one healthy individual. For this reason, carrying the CC + GC genotypes (C recessive allele) of CASP8; D302H polymorphism were compared with possessing the GG (homozygote of dominant allele) genotype to evaluate whether a statistical link between cases and controls in terms of allele and genotype distributions, but we did not observe any significant differences. In addition, we investigated the potential correlations between the CASP8; D302H, allele frequencies, and the prognostic features of cases. The data was shown in Table 4. We observed that possessing the C allele of CASP8; D302H polymorphism was associated with moderately differentiated tumor parameter (OR=1.17; p<0.05) but there was not any statistical significance between the CASP8; D302H gene variation and other histopathologic characteristics of the patients.

Table 4:

Distribution of the CASP8 D302H genotypes with different histopathological parameters.

Tumor characteristics	GG + GC, %	CC, %	p-Value	CC + GC, %	GG, %	p-Value
*T Stage*
T1 + T2	29.2	n/a	p>0.05	22.2	29.4	p>0.05
T3 + T4	70.8	100	p>0.05	77.8	70.6	p>0.05
Lymph node status
N0	45.8	n/a	p>0.05	22.2	52.9	p>0.05
N1 + N2 + N3	54.2	100	p>0.05	77.8	47.1	p>0.05
Differentiation
Well	30.8	n/a	p>0.05	n/a	42.1	0.029 ^a
Moderate poor	69.2	100	p>0.05	100	57.9	0.029 ^a
Distant metastasis
Absence	80	100	p>0.05	80.0	82.4	p>0.05
Presence	20	n/a	p>0.05	20.0	17.6	p>0.05
Perineural invasion
Absence	45.8	50	p>0.05	50.0	43.8	p>0.05
Presence	54.2	50	p>0.05	50.0	56.3	p>0.05
Angiolymphatic invasion
Absence	62.5	50	p>0.05	60.0	62.5	p>0.05
Presence	37.5	50	p>0.05	40.0	37.5	p>0.05

n/a, not available. ^ap-Value <0.05 denoted statistical significance.

Discussion

Colorectal cancer (CRC) incidence has increased in recent decades. The progression of colorectal cancer malignancy is a multistep process, which consists of alterations in molecular mechanisms, instability between cell growth and apoptosis, and long-term accumulation of genetic aberrations [23, 24].

Caspase genes, promote cellular maturation and reconstruction by initiating the apoptosis of old cells or that could not able to perform their functions, so they maintain the balance between cell life and death [25, 26]. The Caspase-8 (CASP8) gene has critical roles in the regulation of apoptosis and inflammatory process [27]. Although several studies reported that the loss of Caspase-8 expression is not detected in most epithelial-derived cancers such as colon carcinoma, gastric cancer, and breast cancer, many reports concluded, that the CASP8 mutations have been observed in 5 % of invasive colorectal carcinomas (but not adenomas) and these genetic variations might lead to the loss of CASP8 apoptotic function. Moreover, they affect the pathogenesis of colorectal carcinomas [28, 29].

According to the importance of Caspase genes in carcinogenesis, we evaluated the CASP8; D302H gene variation in colorectal cancer risk and also aimed to reveal if there were any associations with the clinicopathological characteristic of the patients. We observed that individuals carrying the GC genotype of CASP8; D302H polymorphism had significantly reduced colorectal cancer risk compared with those carrying CC and GG genotypes (p=0.045). When we stratified histopathological features of the patients and analyzed them according to genotype and allele frequencies, we found that the possessing of the C allele was associated with moderate tumor differentiation parameter (OR=1.17, 95 % CI=1.177–2.535; p<0.05).

The CASP8; D302H gene polymorphism has been analyzed in different types of cancers [17], [18], [19], [20], [21], but in the literature, there was a limited study that directly focused on the CASP8; D302H gene variation and colorectal cancer risk. In a study, which was conducted to evaluate the CASP8; D302H (rs1045485), CASP8; (rs3834129) gene variants and risk of CRC in the UK population, Pittman et al. concluded that there was no association between both variants and risk of CRC progression in their data analysis [30]. In another study, Hashemi et al. designed an investigation to assess the possible roles of CASP8; rs1045485 G>C, rs3834129, rs3769818 G>A, rs6723097 A>C, rs3769821 T>C, rs13113T>A, rs3769825 G>A, rs2293554 A>C, and rs10931936 C>T polymorphisms in susceptibility of cancers. They reported that the CASP8; (rs3834129) polymorphism was associated with the reduced risk of gastrointestinal, digestive tract, colorectal, breast, and lung cancers and concluded the CASP8; D302H polymorphism was related to the decreased risk of overall cancer [31]. Vahednia et al. conducted a study in the Iranian population and found that the CC and GC genotypes of CASP8; D302H polymorphism were significantly increased in healthy controls compared to breast cancer patients. As a result, they concluded the C allele of CASP8; D302H has a protective impact on breast cancer risk in the Iranian population [21].

In a meta-analysis, which was conducted by Zhang et al., they reported that the CASP8; D302H gene variation was significantly associated with decreased breast cancer risk in the population of the UK, Germany, and Poland but they did not observe a significant relationship in Finland or USA populations [32].

Bethke et al. conducted a study to test the possible effect of CASP8; D302H polymorphism in the risk of glioma. They concluded that carrying the rare allele of D302H variation was associated with an increased risk of glioma [33]. Similarly, they designed a study to analyze the CASP8; D302H polymorphism and susceptibility of meningioma through investigation of five independent series of case-control studies. They did not find a statistically significant correlation between the carrying CASP8; 302H variant and the risk of meningioma [34]. On the other hand, Lubahn et al. analyzed three independent series of aggressive prostate cancer cases and control studies. They observed that the H allele of CASP8; D302H polymorphism was related to decreased risk of aggressive prostate cancer [35].

In conclusion, this is the first study, which was investigated the association between the CASP8; D302H gene polymorphism and colorectal cancer risk in the Turkish population. Although the GC genotype of CASP8; D302H gene variation was observed as significantly associated with reduced risk of colorectal cancer, our study has a limitation that needs to be mentioned. This was a preliminary report and the size number of the study group was relatively small, so larger population data might provide to determine underlying mechanisms of CASP8; D302H polymorphism in the colorectal cancer risk and prognosis.

Corresponding author: Canan Cacina, Molecular Medicine, Istanbul University, Fatih 34452, Türkiye, E-mail: canan.cacina@istanbul.edu.tr

Acknowledgments

We would like to thank Prof. Dr. Chonlaphat Sukasem and his team members from the Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand, for providing DNA with known genotypes using PCR-SSOP method.

Research funding: Short Term Grant, Universiti Sains Malaysia (304 / PFARMASI / 6315398).
Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
Competing interests: Authors state no conflict of interest.
Informed consent: Informed consent was obtained from all individuals included in this study.
Ethical approval: Medical Review & Ethics Committee (MREC) (NMRR-19-4092-45982) and Human Research Ethics Committee Universiti Sains Malaysia (JEPEM) (USM/JEPeM/20050287).

References

1. Sawicki, T, Ruszkowska, M, Danielewicz, A, Niedźwiedzka, E, Arłukowicz, T, Przybyłowicz, KE. A review of colorectal cancer in terms of epidemiology, risk factors, development, symptoms and diagnosis. Cancers (Basel) 2021;13:2025. https://doi.org/10.3390/cancers13092025.Search in Google Scholar PubMed PubMed Central

2. Nishihara, R, Glass, K, Mima, K, Hamada, T, Nowak, JA, Qian, ZR, et al.. Biomarker correlation network in colorectal carcinoma by tumor anatomic location. BMC Bioinform 2017;18:304. https://doi.org/10.1186/s12859-017-1718-5.Search in Google Scholar PubMed PubMed Central

3. Nambiar, PR, Gupta, RR, Misra, V. An “Omics” based survey of human colon cancer. Mutat Res 2010;693:3–18. https://doi.org/10.1016/j.mrfmmm.2010.07.008.Search in Google Scholar PubMed

4. Obeng, E. Apoptosis (programmed cell death) and its signals - a review. Braz J Biol 2021;81:1133–43. https://doi.org/10.1590/1519-6984.228437.Search in Google Scholar PubMed

5. Melet, A, Song, K, Bucur, O, Jagani, Z, Grassian, AR, Khosravi-Far, R. Apoptotic pathways in tumor progression and therapy. Adv Exp Med Biol 2008;615:47–79. https://doi.org/10.1007/978-1-4020-6554-5_4.Search in Google Scholar PubMed

6. van Noesel, MM, Versteeg, R. Pediatric neuroblastomas: genetic and epigenetic ‘danse macabre’. Gene 2004;325:1–15. https://doi.org/10.1016/j.gene.2003.09.042.Search in Google Scholar PubMed

7. Ghavami, S, Hashemi, M, Ande, SR, Yeganeh, B, Xiao, W, Eshraghi, M, et al.. Apoptosis and cancer: mutations within caspase genes. J Med Genet 2009;46:497–510. https://doi.org/10.1136/jmg.2009.066944.Search in Google Scholar PubMed

8. Ghavami, S, Hashemi, M, Kadkhoda, K, Alavian, SM, Bay, GH, Los, M. Apoptosis in liver diseases--detection and therapeutic applications. Med Sci Monit 2005;11:RA337–45.Search in Google Scholar

9. Los, M, Wesselborg, S, Schulze-Osthoff, K. The role of caspases in development, immunity, and apoptotic signal transduction: lessons from knockout mice. Immunity 1999;10:629–39. https://doi.org/10.1016/s1074-7613(00)80062-x.Search in Google Scholar PubMed

10. Zaman, S, Wang, R, Gandhi, V. Targeting the apoptosis pathway in hematologic malignancies. Leuk Lymphoma 2014;55:1980–92. https://doi.org/10.3109/10428194.2013.855307.Search in Google Scholar PubMed PubMed Central

11. Frejlich, E, Rudno-Rudzińska, J, Janiszewski, K, Salomon, L, Kotulski, K, Pelzer, O, et al.. Caspases and their role in gastric cancer. Adv Clin Exp Med 2013;22:593–602.Search in Google Scholar

12. Boatright, KM, Salvesen, GS. Mechanisms of caspase activation. Curr Opin Cell Biol 2003;15:725–31. https://doi.org/10.1016/j.ceb.2003.10.009.Search in Google Scholar PubMed

13. Kruidering, M, Evan, GI. Caspase-8 in apoptosis: the beginning of “the end”. IUBMB Life 2000;50:85–90. https://doi.org/10.1080/713803693.Search in Google Scholar PubMed

14. Thornberry, NA, Lazebnik, Y. Caspases: enemies within. Science 1998;281:1312–6. https://doi.org/10.1126/science.281.5381.1312.Search in Google Scholar PubMed

15. Sud, A, Kinnersley, B, Houlston, RS. Genome-wide association studies of cancer: current insights and future perspectives. Nat Rev Cancer 2017;17:692–704. https://doi.org/10.1038/nrc.2017.82.Search in Google Scholar PubMed

16. Grenet, J, Teitz, T, Wei, T, Valentine, V, Kidd, VJ. Structure and chromosome localization of the human CASP8 gene. Gene 1999;226:225–32. https://doi.org/10.1016/s0378-1119(98)00565-4.Search in Google Scholar PubMed

17. Yin, M, Yan, J, Wei, S, Wei, Q. CASP8 polymorphisms contribute to cancer susceptibility: evidence from a meta-analysis of 23 publications with 55 individual studies. Carcinogenesis 2010;31:850–7. https://doi.org/10.1093/carcin/bgq047.Search in Google Scholar PubMed PubMed Central

18. Cox, A, Dunning, AM, Garcia-Closas, M, Balasubramanian, S, Reed, MW, Pooley, KA, et al.. Breast Cancer Association Consortium. A common coding variant in CASP8 is associated with breast cancer risk. Nat Genet 2007;39:352–8. https://doi.org/10.1038/ng1981.Search in Google Scholar PubMed

19. Frank, B, Bermejo, JL, Hemminki, K, Klaes, R, Bugert, P, Wappenschmidt, B, et al.. Re: association of a common variant of the CASP8 gene with reduced risk of breast cancer. J Natl Cancer Inst 2005;97:1012. https://doi.org/10.1093/jnci/dji178.Search in Google Scholar PubMed

20. MacPherson, G, Healey, CS, Teare, MD, Balasubramanian, SP, Reed, MW, Pharoah, PDP, et al.. Association of a common variant of the CASP8 gene with reduced risk of breast cancer. J Natl Cancer Inst 2004;96:1866–9. https://doi.org/10.1093/jnci/dji001.Search in Google Scholar PubMed

21. Vahednia, E, Shandiz, FH, Bagherabad, MB, Moezzi, A, Afzaljavan, F, Tajbakhsh, A, et al.. The impact of CASP8 rs10931936 and rs1045485 polymorphisms as well as the haplotypes on breast cancer risk: a case-control study. Clin Breast Cancer 2019;19:e563–77. https://doi.org/10.1016/j.clbc.2019.02.011.Search in Google Scholar PubMed

22. Miller, SA, Dykes, DD, Polesky, HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988;16:1215. https://doi.org/10.1093/nar/16.3.1215.Search in Google Scholar PubMed PubMed Central

23. Hao, X, Du, M, Bishop, AE, Talbot, IC. Imbalance between proliferation and apoptosis in the development of colorectal carcinoma. Virchows Arch 1998;433:523–7. https://doi.org/10.1007/s004280050284.Search in Google Scholar PubMed

24. Valle, L. Genetic predisposition to colorectal cancer: where we stand and future perspectives. World J Gastroenterol 2014;20:9828–49. https://doi.org/10.3748/wjg.v20.i29.9828.Search in Google Scholar PubMed PubMed Central

25. Elmore, S. Apoptosis: a review of programmed cell death. Toxicol Pathol 2007;35:495–516. https://doi.org/10.1080/01926230701320337.Search in Google Scholar PubMed PubMed Central

26. Evan, GI, Vousden, KH. Proliferation, cell cycle and apoptosis in cancer. Nature 2001;411:342–8. https://doi.org/10.1038/35077213.Search in Google Scholar PubMed

27. Shalini, S, Dorstyn, L, Dawar, S, Kumar, S. Old, new and emerging functions of caspases. Cell Death Differ 2015;22:526–39. https://doi.org/10.1038/cdd.2014.216.Search in Google Scholar PubMed PubMed Central

28. Kim, HS, Lee, JW, Soung, YH, Park, WS, Kim, SY, Lee, JH, et al.. Inactivating mutations of caspase-8 gene in colorectal carcinomas. Gastroenterology 2003;125:708–15. https://doi.org/10.1016/s0016-5085(03)01059-x.Search in Google Scholar PubMed

29. Soung, YH, Lee, JW, Kim, SY, Sung, YJ, Park, WS, Nam, SW, et al.. Caspase-8 gene is frequently inactivated by the frameshift somatic mutation 1225_1226delTG in hepatocellular carcinomas. Oncogene 2005;24:141–7. https://doi.org/10.1038/sj.onc.1208244.Search in Google Scholar PubMed

30. Pittman, AM, Broderick, P, Sullivan, K, Fielding, S, Webb, E, Penegar, S, et al.. CASP8 variants D302H and -652 6N ins/del do not influence the risk of colorectal cancer in the United Kingdom population. Br J Cancer 2008;98:1434–6. https://doi.org/10.1038/sj.bjc.6604314.Search in Google Scholar PubMed PubMed Central

31. Hashemi, M, Aftabi, S, Moazeni-Roodi, A, Sarani, H, Wiechec, E, Ghavami, S. Association of CASP8 polymorphisms and cancer susceptibility: a meta-analysis. Eur J Pharmacol 2020;881:173201. https://doi.org/10.1016/j.ejphar.2020.173201.Search in Google Scholar PubMed

32. Zhang, Y, Li, W, Hong, Y, Wu, G, He, K, Liu, D. A systematic analysis of the association studies between CASP8 D302H polymorphisms and breast cancer risk. J Genet 2017;96:283–9. https://doi.org/10.1007/s12041-017-0774-y.Search in Google Scholar PubMed

33. Bethke, L, Sullivan, K, Webb, E, Murray, A, Schoemaker, M, Auvinen, A, et al.. The common D302H variant of CASP8 is associated with risk of glioma. Cancer Epidemiol Biomarkers Prev 2008;17:987–9. https://doi.org/10.1158/1055-9965.epi-07-2807.Search in Google Scholar

34. Bethke, L, Sullivan, K, Webb, E, Murray, A, Schoemaker, M, Auvinen, A, et al.. CASP8 D302H and meningioma risk: an analysis of five case-control series. Cancer Lett 2009;273:312–5. https://doi.org/10.1016/j.canlet.2008.08.010.Search in Google Scholar PubMed

35. Lubahn, J, Berndt, SI, Jin, CH, Klim, A, Luly, J, Wu, WS, et al.. Association of CASP8 D302H polymorphism with reduced risk of aggressive prostate carcinoma. Prostate 2010;70:646–53. https://doi.org/10.1002/pros.21098.Search in Google Scholar PubMed PubMed Central

Received: 2022-02-11

Accepted: 2022-07-07

Published Online: 2023-04-21

This work is licensed under the Creative Commons Attribution 4.0 International License.

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https://doi.org/10.1515/tjb-2022-0042

Keywords for this article

apoptosis; caspase-8; colorectal cancer; gene variation; prognosis

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