#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Clinical and Functional Importance of Selected CASP8 and CASP9 Polymorphisms in Breast Carcinoma


Authors: V. Brynychová 1,2;  R. Václavíková 1;  K. Kubáčková 3;  M. Mrhalová 4;  R. Kodet 4;  K. Rauš 5;  D. Vrána 6;  J. Gatěk 7;  M. Bendová 8;  P. Souček 1
Authors‘ workplace: Oddělení toxikogenomiky, Státní zdravotní ústav, Praha 1;  3. lékařská fakulta UK v Praze 2;  Onkologická klinika 2. LF UK a FN Motol, Praha 3;  Ústav patologie a molekulární medicíny, 2. LF UK a FN Motol, Praha 4;  Ústav pro péči o matku a dítě, Praha 5;  Onkologická klinika LF UP a FN Olomouc 6;  Chirurgické oddělení, Nemocnice Atlas, Zlín 7;  Gynekologicko-porodnická klinika 3. LF UK a FN Královské Vinohrady, Praha 8
Published in: Klin Onkol 2016; 29(6): 445-453
Category: Original Articles
doi: https://doi.org/10.14735/amko2016445

Overview

Background:
Caspase-8 and caspase-9 (encoded by CASP8 and CASP9) are executive caspases of programmed cell death (apoptosis). Dysregulation of apoptosis plays an important role in cancer development, progression, and resistance to anticancer therapy. The goal of this work was to evaluate potential associations between polymorphisms in CASP8 and CASP9, previously linked to breast cancer risk, and the transcript levels of these genes (including their alternative anti-apoptotic variants) in tumor tissues and the clinical characteristics of the patients.

Material and Methods:
Sanger sequencing, high resolution melting (HRM) analysis, and allelic discrimination were used to identify polymorphisms in DNA samples isolated from tumor tissues and peripheral blood lymphocytes of 60 breast carcinoma patients. Total transcript levels of CASP8 and CASP9, and levels of alternative splicing variants CASP8L and CASP9B, were quantified by real-time PCR in tumor tissues. Clinically interesting associations were validated in DNA from lymphocytes of 615 breast carcinoma patients.

Results:
A haplotype in CASP9 composed of three polymorphisms rs4645978-rs2020903-rs4646034 was significantly associated with CASP9 expression in tumors, with the expression of the progesterone receptor and ERBB2, and with the TNBC subtype of breast carcinoma in the validation study. The associations between the rs3834129 polymorphism in CASP8 and stage of disease, rs6435074 with grade, expression of estrogen receptor and ERBB2, and rs6723097 with ERBB2 expression have not yet been validated. However, rs6723097 was associated with disease-free survival in patients treated with hormonal therapy.

Conclusion:
This study reveals a previously unknown and presumably functional (in silico) association between a haplotype in CASP9 and molecular and clinical phenotypes of breast carcinoma. The potential clinical utility of this association for prognostication of breast carcinoma should be evaluated by independent studies.

Key words:
breast carcinoma – caspases – polymorphisms – functional – clinical – importance

This work was supported by grant of the CU Grant Agency No. 1444313, and grant of the Internal Grant Agency of the Czech Ministry of Health No. 15-25618A.

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.

Submitted:
3. 3. 2016

Accepted:
26. 10. 2016


Sources

1. Svod.cz [internetová stránka]. Český národní webový portál epidemiologie nádorů. Masarykova univerzita, Česká republika; [aktualizováno 6. prosince 2015; citováno 1. února 2016]. Dostupný z: www.svod.cz.

2. Michailidou K, Hall P, Gonzalez-Neira A et al. Large-scale genotyping identifies 41 new loci associated with breast cancer risk. Nature Genetics 2013; 45 (4): 353–361. doi: 10.1038/ng.2563.

3. Ghavami S, Hashemi M, Ande SR et al. Apoptosis and cancer: mutations within caspase genes. J Med Genet 2009; 46 (8): 497–510. doi: 10.1136/jmg.2009.066944.

4. Stephens PJ, Tarpey PS, Davies H et al. The landscape of cancer genes and mutational processes in breast cancer. Nature 2012; 486 (7403): 400–404. doi: 10.1038/nature11017.

5. Cox A, Dunning AM, Garcia-Closas M et al. A common coding variant in CASP8 is associated with breast cancer risk. Nature Genetics 2007; 39 (3): 352–358.

6. Shephard ND, Abo R, Rigas SH et al. A breast cancer risk haplotype in the caspase-8 gene. Cancer Research 2009; 69 (7): 2724–2728. doi: 10.1158/0008-5472.CAN-08-4266.

7. Sergentanis TN, Economopoulos KP. Association of two CASP8 polymorphisms with breast cancer risk: a meta-analysis. Breast Cancer Res Treat 2010; 120 (1): 229–234. doi: 10.1007/s10549-009-0471-5.

8. Turnbull C, Ahmed S, Morrison J et al. Genome-wide association study identifies five new breast cancer susceptibility loci. Nature Genetics 2010; 42 (6): 504–507. doi: 10.1038/ng.586.

9. Zhang B, Beeghly-Fadiel A, Long J et al. Genetic variants associated with breast-cancer risk: comprehensive research synopsis, meta-analysis, and epidemiological evidence. Lancet Oncol 2011; 12 (5): 477–488. doi: 10.1016/S1470-2045 (11) 70076-6.

10. Camp NJ, Parry M, Knight S et al. Fine-mapping CASP8 risk variants in breast cancer. Cancer Epidemiol Biomarkers Prev 2012; 21 (1): 176–181. doi: 10.1158/1055-9965.EPI-11-0845.

11. Sun T, Gao Y, Tan W et al. A six-nucleotide insertion-deletion polymorphism in the CASP8 promoter is associated with susceptibility to multiple cancers. Nat Genet 2007; 39 (5): 605–613.

12. Horiuchi T, Himeji D, Tsukamoto H et al. Dominant expression of a novel splice variant of caspase-8 in human peripheral blood lymphocytes. Biochem Biophys Res Commun 2000; 272 (3): 877–881.

13. Himeji D, Horiuchi T, Tsukamoto H et al. Characterization of caspase-8L: a novel isoform of caspase-8 that behaves as an inhibitor of the caspase cascade. Blood 2002; 99 (11): 4070–4078.

14. Theodoropoulos GE, Michalopoulos NV, Pantou MP et al. Caspase 9 promoter polymorphisms confer increased susceptibility to breast cancer. Cancer Genetics 2012; 205 (10): 508–512. doi: 10.1016/j.cancergen.2012.08.001.

15. Srinivasula SM, Ahmad M, Guo Y et al. Identification of an endogenous dominant-negative short isoform of caspase-9 that can regulate apoptosis. Cancer Research 1999; 59 (5): 999–1002.

16. Hubackova M, Vaclavikova R, Ehrlichova M et al. Association of superoxide dismutases and NAD (P) H quinone oxidoreductases with prognosis of patients with breast carcinomas. Int J Cancer 2012; 130 (2): 338–348. doi: 10.1002/ijc.26006.

17. Brynychová V, Hlaváč V, Ehrlichová M et al. Importance of transcript levels of caspase-2 isoforms S and L for breast carcinoma progression. Future Oncol 2013; 9 (3): 427–438. doi: 10.2217/fon.12.200.

18. Tavassoli FA, Devilee P eds. Pathology & genetics: tumours of the breast and female genital organs. Vol. 4. Lyon: IARC 2003.

19. Goldhirsch A, Winer EP, Coates AS et al. Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013. Ann Oncol 2013; 24 (9): 2206–2223. doi: 10.1093/annonc/mdt303.

20. Topić E, Gluhak J. Isolation of restrictible DNA. Eur J Clin Chem Clin Biochem 1991; 29 (5): 327–330.

21. Vu NT, Park MA, Shultz JC et al. hnRNP U enhances caspase-9 splicing and is modulated by AKT-dependent phosphorylation of hnRNPL. J Biol Chem 2013; 288 (12): 8575–8584. doi: 10.1074/jbc.M112.443333.

22. Ward LD, Kellis M. HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acid Research 2012; 40: D930–D934. doi: 10.1093/nar/gkr917.

23. Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Statist Soc B 1995; 57 (1): 289–300.

24. Kouros-Mehr H, Slorach EM, Sternlicht MD et al. GATA-3 maintains the differentiation of the luminal cell fate in the mammary gland. Cell 2006; 127 (5): 1041–1055.

25. Wang D, Lu P, Zhang H et al. Oct-4 and Nanog promote the epithelial-mesenchymal transition of breast cancer stem cells and are associated with poor prognosis in breast cancer patients. Oncotarget 2014; 5 (21): 10803–10815.

26. Rihani A, De Wilde B, Zeka F et al. CASP8 SNP D302H (rs1045485) is associated with worse survival in MYCN-amplified neuroblastoma patients. PLoS One 2014; 9 (12): e114696. doi: 10.1371/journal.pone.0114696.

27. Lin WY, Camp NJ, Ghoussaini M et al. Identification and characterization of novel associations in the CASP8/ALS2CR12 region on chromosome 2 with breast cancer risk. Hum Mol Genet 2015; 24 (1): 285–298. doi: 10.1093/hmg/ddu431.

28. Stacey SN, Helgason H, Gudjonsson SA et al. New basal cell carcinoma susceptibility loci. Nat Commun 2015; 6: 6825. doi: 10.1038/ncomms7825.

29. Nehra R, Riggins RB, Shajahan AN et al. BCL2 and CASP8 regulation by NF-κB differentially affect mitochondrial function and cell fate in antiestrogen-sensitive and-resistant breast cancer cells. FASEB J 2010; 24 (6): 2040–2055. doi: 10.1096/fj.09-138305.

Labels
Paediatric clinical oncology Surgery Clinical oncology
Login
Forgotten password

Enter the email address that you registered with. We will send you instructions on how to set a new password.

Login

Don‘t have an account?  Create new account

#ADS_BOTTOM_SCRIPTS#