GENETIC RISK FOR BREAST CANCER DEVELOPMENT

Main Article Content

Dr. Kausar Abbas Saldera
Dr. Taseer Ahmed Khan
Dr. Syed Mehboob Alam

Keywords

Genetic, Breast Cancer ATM, CHEK2, BARD1

Abstract

Objective: studies in the relation of moderate risk susceptibility genes in the onset of breast ca


Methods: Systematic random samples are done on selected Breast cancer patients from tertiary care hospitals in Karachi. The sample size was calculated using an online sample size calculator, Open Epi version 3.01 for case-controls, after inserting a 9.6% proportion of late menopause among cases, at a 5% margin of error and 95% confidence interval. The required sample size for our study was 74 with 37 participants in each group, but we took 100 samples in each group, making it a total of 200. This type of moderate-risk gene research and population-based study in correlation with high-risk gene variation is being conducted first time in the Pakistani population, therefore to see more effective results, we increase the sample size. Subjects were divided into two groups: Cases Group, which included 100 Known Naïve cases of Breast Ca (Females), and Control Group, which included 100 healthy individuals.


Results: The results of our study were from 100 breast cancer patients from a homogeneous population (Sindh). We found a correlation between age at diagnosis, family history, and mutation detection rate. Though our study has a limited number of patients, a low frequency of mutation in ATM, CHEK2, and BARD1 genes was reported.


 Conclusion: Around 20% of hereditary breast cancer is account for variants in the high and moderate breast cancer susceptibility genes BRCA1, BRCA2, TP53, CHEK2, and RAD51C, in Pakistan (Muhammad et al, 2018). Convincingly identified five moderate-risk breast cancer susceptibility genes are: CHEK2, ATM, BRIP1, PALB2, and NBS1 (Rashid et al. 2013). Attempts should be made to develop a real-time assay for the diagnosis of mutations in moderate-risk (ATM, BARD1, and CHEK2) genes.

Abstract 123 | pdf Downloads 40

References

1. Adamovich,A.I.; Banerjee,T.; Wingo, M.; Duncan, K.; Ning, J.; Rodrigues, F.M.; Huang, K.L.; Lee, C.; Chen, F.; Ding, L.; et al. Functional analysis of BARD1 missense variants in homology-directed repair and damage sensitivity. PLoS Genet. 2019, 15, e1008049. [CrossRef]
2. Anand, R.; Ranjha, L.; Cannavo, E.; Cejka, P. Phosphorylated CtIP Functions as a Co-factor of the MRE11-RAD50-NBS1 Endonuclease in DNA End Resection. Mol. Cell 2016, 64, 940–950. [CrossRef] [PubMed]
3. Antonelli M., Strappazzon F., Arisi I., Brandi R., D’Onofrio M., Sambucci M., Manic G., Vitale I., Barilà D., Stagni V. ATM kinase sustains breast cancer stem-like cells by promoting ATG4C expression and autophagy. Oncotarget. 2017;8:21692–21709. doi: 10.18632/oncotarget. 15537. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
4. Azarm, K.; Smith, S. Nuclear PARPs and genome integrity. Genes Dev. 2020, 34, 285–301. [CrossRef]
5. Bhat, K.P.; Cortez, D. RPA and RAD51: Fork reversal, fork protection, and genome stability. Nat. Struct. Mol. Biol. 2018, 25, 446–453. [CrossRef]
6. Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2018, 68, 394–424. [CrossRef] [PubMed]
7. Chaffee,K.G.; Oberg,A.L.; McWilliams,R.R.; Majithia,N.; Allen,B.A.; Kidd,J.; Singh, N.; Hartman, A.R.; Wenstrup, R.J.; Petersen, G.M. Prevalence of germ-line mutations in cancer genes among pancreatic cancer patients with a positive family history. Genet. Med. 2018, 20, 119–127. [CrossRef] [PubMed]
8. Cimmino, F.; Avitabile, M.; Diskin, S.J.; Vaksman, Z.; Pignataro, P.; Formicola, D.; Cardinale, A.; Testori, A.; Koster, J.; de Torres, C.; et al. Fine mapping of 2q35 high-risk neuroblastoma locus reveals independent functional risk variants and suggests full-length BARD1 as a tumor suppressor. Int. J. Cancer 2018, 143, 2828–2837. [CrossRef] [PubMed]
9. Cimmino, F.; Avitabile, M.; Lasorsa, V.A.; Pezone, L.; Cardinale, A.; Montella, A.; Cantalupo, S.; Iolascon, A.; Capasso, M. Functional characterization of full-length BARD1 strengthens its role as a tumor suppressor in neuroblastoma. J. Cancer 2020, 11, 1495–1504. [CrossRef]
10. Cimmino, F.; Formicola, D.; Capasso, M. Dualistic role of BARD1 in cancer. Genes 2017, 8, 375. [CrossRef] [PubMed]
11. Cury,N.M.;Brotto,D.B.;deAraujo,L.F.;Rosa,R.C.A.;Texeira,L.A.;Plaça,J.R.;Marques,A.A.;Peronni,K.C.; de Cássia Ruy, P.; Molfetta, G.A.; et al. Germline variants in DNA repair genes associated with hereditary breast and ovarian cancer syndrome: Analysis of a 21 gene panel in the Brazilian population. BMC Med. Genom. 2020, 13, 21.
12. Dev, H.; Chiang, T.W.W.; Lescale, C.; de Krijger, I.; Martin, A.G.; Pilger, D.; Coates, J.; Sczaniecka-Clift, M.; Wei, W.; Ostermaier, M.; et al. The shielding complex promotes DNA end-joining and counters homologous recombination in BRCA1-null cells. Nat. Cell Biol. 2018, 20, 954–965. [CrossRef]
13. Eliopoulos A.G., Havaki S., Gorgoulis V. DNA Damage Response and Autophagy: A Meaningful Partnership. Front. Genet. 2016;7:204. doi 10.3389/fgene.2016.00204. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
14. Feliubadaló,L.;Tonda,R.;Gausachs,M.;Trotta,J.R.;Castellanos,E.;López-Doriga,A.;Teulé,À.;Tornero,E.; Del Valle, J.; Gel, B.; et al. Benchmarking of Whole Exome Sequencing and Ad Hoc Designed Panels for Genetic Testing of Hereditary Cancer. Sci. Rep. 2017, 7, 37984. [CrossRef] [PubMed]
15. Fu, W.; Zhu, J.; Xiong, S.W.; Jia, W.; Zhao, Z.; Zhu, S.B.; Hu, J.H.; Wang, F.H.; Xia, H.; He, J.; et al.BARD1 Gene Polymorphisms Confer Nephroblastoma Susceptibility. EBioMedicine 2017, 16, 101–105. [CrossRef]
16. Gass,J.;Tatro,M.;Blackburn,P.;Hines,S.;Atwal,P.S.Nonsensevariantc.1921C>Tinapatientwithrecurrent breast cancer. Clin. Case Rep. 2017, 5, 104–107. [CrossRef] [PubMed]
17. Guo Q., Wang S., Xu H., Li X., Guan Y., Yi F., Zhou T., Jiang B., Bai N., Ma M., et al. ATM—CHK 2-Beclin 1 axis promotes autophagy to maintain ROS homeostasis under oxidative stress. EMBO J. 2020;39:e103111. doi: 10.15252/embj.2019103111. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
18. Guo, Z.P.; Hu, Y.C.; Xie, Y.; Jin, F.; Song, Z.Q.; Liu, X.D.; Ma, T.; Zhou, P.K.MLN4924suppressestheBRCA1 complex and synergizes with PARP inhibition in NSCLC cells. Biochem. Biophys. Res. Commun. 2017, 483, 223–229. [CrossRef]
19. Hamdi, Y.; Boujemaa, M.; Rekaya, M.B.; Hamda, C.B.; Mighri, N.; El Benna, H.; Mejri, N.; Labidi, S.; Daoud, N.; Naouali, C.; et al. Family specific genetic predisposition to breast cancer: Results from Tunisian whole exome sequenced breast cancer cases. J. Transl. Med. 2018, 16, 158. [CrossRef] [PubMed]
20. Hou, S.; Jin, W.; Xiao, W.; Deng, B.; Wu, D.; Zhi, J.; Wu, K.; Cao, X.; Chen, S.; Ding, Y.; et al. Integrin α5 promotes migration and cisplatin resistance in esophageal squamous cell carcinoma cells. Am. J. Cancer Res. 2019, 9, 2774–2788.
21. Huang, F.L.; Yu, S.J.Esophagealcancer: Risk factors, genetic association, and treatment.Asian J.Surg.2018, 41, 210–215. [CrossRef]
22. Irminger-Finger, I.; Ratajska, M.; Pilyugin, M. New concepts on BARD1: Regulator of BRCA pathways and beyond. Int. J. Biochem. Cell Biol. 2016, 72, 1–17. [CrossRef] [PubMed]
23. Lasorsa,V.A.;Formicola,D.;Pignataro,P.;Cimmino,F.;Calabrese,F.M.;Mora,J.;Esposito,M.R.;Pantile,M.; Zanon, C.; De Mariano, M.; et al. Exome and deep sequencing of clinically aggressive neuroblastoma reveal somatic mutations affecting key pathways in cancer progression. Oncotarget 2016, 7, 21840–21852. [CrossRef]
24. Lee J.-H., Paull T.T. Mitochondria at the crossroads of ATM-mediated stress signaling and regulation of reactive oxygen species. Redox Biol. 2020;32:101511. doi: 10.1016/ j.redox.2020.101511. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
25. Liang N., He Q., Liu X., Sun H. Multifaceted roles of ATM in autophagy: From nonselective autophagy to selective autophagy. Cell Biochem. Funct. 2019;37:177–184. doi: 10.1002/ cbf.3385. [PubMed] [CrossRef] [Google Scholar]
26. Liao, Y.; Yuan, S.; Chen, X.; Zhu, P.; Li, J.; Qin, L.; Liao, W. Up-regulation of BRCA1-associated RING Domain 1 promotes hepatocellular carcinoma progression by targeting Akt signaling. Sci. Rep. 2017, 7, 7649. [CrossRef] [PubMed]
27. Lubecka, K.; Flower, K.; Beetch, M.; Qiu, J.; Kurzava, L.; Buvala, H.; Ruhayel, A.; Gawrieh, S.; Liangpunsakul, S.; Gonzalez, T.; et al. Loci-specific differences in blood DNA methylation in HBV-negative populations at risk for hepatocellular carcinoma development. Epigenetics 2018, 13, 605–626. [CrossRef]
28. Mateo, J.; Lord, C.J.; Serra, V.; Tutt, A.; Balmaña, J.; Castroviejo-Bermejo, M.; Cruz, C.; Oaknin, A.; Kaye, S.B.; De Bono, J.S. A decade of clinical development of PARP inhibitors in perspective. Ann. Oncol. 2019, 30, 1437–1447. [CrossRef]
29. Moslemi M., Moradi Y., Dehghanbanadaki H., Afkhami H., Khaledi M., Sedighimehr N., Fathi J., Sohrabi E. The association between ATM variants and risk of breast cancer: A systematic review and meta-analysis. BMC Cancer. 2021;21:27. doi 10.1186/s12885-020-07749-6. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
30. Noordermeer, S.M. The shieldin complex mediates 53BP1-dependent DNA repair. Nature 2018, 560, 117–121. [CrossRef]
31. Oldridge, D.A.; Truong, B.; Russ, D.; DuBois, S.G.; Vaksman, Z.; Mosse, Y.P.; Diskin, S.J.; Maris, J.M.; Matthay, K.K. Differences in genomic profiles and outcomes between thoracic and adrenal neuroblastoma. J. Natl. Cancer Inst. 2019, 111, 1192–1201. [CrossRef] [PubMed]
32. Ozden,O.;Bishehsari,F.;Bauer,J.;Park,S.H.;Jana,A.;Baik,S.H.;Sporn,J.C.;Staudacher,J.J.;Yazici,C.; Krett, N.; et al. Expression of an oncogenic BARD1 splice variant impairs homologous recombination and predicts response to PARP-1 inhibitor therapy in colon cancer. Sci. Rep. 2016, 6, 26273. [CrossRef] [PubMed]
33. Pilyugin, M.; Descloux, P.; André,P.A.; Laszlo,V.; Dome, B.; Hegedus, B.; Sardy, S.; Janes,S.; Bianco, A.; Laurent, G.J.; et al. BARD1 serum autoantibodies for the detection of lung cancer. PLoS ONE 2017, 12, e0182356. [CrossRef] [PubMed]
34. Qi Y., Qiu Q., Gu X., Tian Y., Zhang Y. ATM mediates spermidine-induced mitophagy via PINK1 and Parkin regulation in human fibroblasts. Sci. Rep. 2016;6:24700. doi: 10.1038/ srep24700. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
35. Rawla, P.; Sunkara, T.; Barsouk, A. Epidemiology of colorectal cancer: Incidence, mortality, survival, and risk factors. Prz. Gastroenterol. 2019, 14, 89–103. [CrossRef]
36. Rezaeian A.-H., Khanbabaei H., Calin G.A. Therapeutic Potential of the miRNA-ATM Axis in the Management of Tumor Radioresistance. Cancer Res. 2019;80:139–150. doi: 10.1158/0008-5472.CAN-19-1807. [PubMed] [CrossRef] [Google Scholar]
37. Rezaeian A.-H., Li C.-F., Wu C.-Y., Zhang X., DeLacerda J., You M.J., Han F., Cai Z., Jeong Y.S., Jin G., et al. A hypoxia-responsive TRAF6–ATM–H2AX signaling axis promotes HIF1α activation, tumorigenesis, and metastasis. Nat. Cell Biol. 2017;19:38–51. doi: 10.1038/ ncb3445. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
38. Sakka, L.; Delétage, N.; Chalus, M.; Aissouni, Y.; Sylvain-Vidal, V.; Gobron, S.; Coll, G. Assessment of citalopram and escitalopram on neuroblastoma cell lines. Cell toxicity and gene modulation. Oncotarget 2017, 8, 42789–42807. [CrossRef] [PubMed]
39. Shi, J.; Yu, Y.; Jin, Y.; Lu, J.; Zhang, J.; Wang, H.; Han, W.; Chu, P.; Tai, J.; Chen, F.; et al. Functional Polymorphisms in BARD1 association with neuroblastoma in a regional Han Chinese population. J. Cancer 2019, 10, 2153–2160. [CrossRef]
40. Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2020. CA Cancer J. Clin. 2020, 70, 7–30. [CrossRef]
41. Stagni V., Cirotti C., Barilà D. Ataxia-Telangiectasia Mutated Kinase in the Control of Oxidative Stress, Mitochondria, and Autophagy in Cancer: A Maestro with a Large Orchestra. Front. Oncol. 2018;8:73. doi: 10.3389/fonc.2018.00073. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
42. Stagni V., Ferri A., Cirotti C., Barilà D. ATM Kinase-Dependent Regulation of Autophagy: A Key Player in Senescence? Front. Cell Dev. Biol. 2021;8:599048. doi: 10.3389 /fcell. 2020.599048. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
43. Stewart, M.D.; Zelin, E.; Dhall, A.; Walsh, T.; Upadhyay, E.; Corn, J.E.; Chatterjee, C.; King, M.C.; Klevit, R.E. BARD1 is necessary for ubiquitylation of nucleosomal histone H2A and transcriptional regulation of estrogen metabolism genes. Proc. Natl. Acad. Sci. USA 2018, 115, 1316–1321. [CrossRef]
44. Sun, J.; Meng, H.; Yao, L.; Lv, M.; Bai, J.; Zhang, J.; Wang, L.; Ouyang, T.; Li, J.; Wang, T.; et al. Germline Mutations in Cancer Susceptibility Genes in a Large Series of Unselected Breast Cancer Patients. Clin. Cancer Res. 2017, 23, 6113–6119. [CrossRef] [PubMed]
45. Suszynska,M.;Kluzniak,W.;Wokolorczyk,D.;Jakubowska,A.;Huzarski,T.;Gronwald,J.;Debniak,T.; Szwiec, M.; Ratajska, M.; Klonowska, K.; et al. Is A Low/Moderate Breast Cancer Risk Gene: Evidence Based on An. Association Study of the Central European p.Q564X Recurrent Mutation. Cancers 2019, 11, 740.
46. Swatek, K.N.; Komander, D. Ubiquitin modifications. Cell Res. 2016, 26, 399–422. [CrossRef] [PubMed]
47. Szybowska,M.; Mete,O.; Weber, E.; Silver, J.; Kim, R.H. euroendocrineneo plasms associated with germ line pathogenic variants in the homologous recombination pathway. Endocr. Pathol. 2019, 30, 237–245. [CrossRef]
48. Takagi, M.; Yoshida, M.; Nemoto, Y.; Tamaichi, H.; Tsuchida, R.; Seki, M.; Uryu, K.; Nishii, R.; Miyamoto, S.; Saito, M.; et al. Loss of DNA Damage Response in Neuroblastoma and Utility of a PARP Inhibitor. J. Natl. Cancer Inst. 2017, 109. [CrossRef] [PubMed]
49. Toh, M.R.; Chong, S.T.; Chan, S.H.; Low, C.E.; Ishak, N.D.B.; Lim, J.Q.; Courtney, E.; Ngeow, J. Functional analysis of clinical BARD1 germline variants. Cold Spring Harb. Mol. Case Stud. 2019, 5. [CrossRef]
50. Tonini, G.P.; Capasso, M. Genetic predisposition and chromosome instability in neuroblastoma. Cancer Metastasis Rev. 2020, 39, 275–285. [CrossRef] [PubMed]
51. Tripathi D.N., Zhang J., Jing J., Dere R., Walker C.L. A new role for ATM in selective autophagy of peroxisomes (pexophagy) Autophagy. 2016;12:711–712. doi 10.1080/1 5548627. 2015. 1123375. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
52. Venier, R.E.; Maurer, L.M.; Kessler, E.M.; Ranganathan, S.; McGough, R.L.; Weiss, K.R.; Malek, M.M.; Meade, J.; Tersak, J.M.; Bailey, K.M. A germline BARD1 mutation in a patient with Ewing sarcoma: Implications for familial testing and counseling. Pediatr. Blood Cancer 2019, 66, e27824. [CrossRef]
53. Yang,Q.;Pan,Q.;Li,C.;Xu,Y.;Wen,C.;Sun,F.NRAGEisinvolvedinhomologousrecombinationrepairto resists the DNA-damaging chemotherapy and composes a ternary complex with RNF8-BARD1 to promote cell survival in squamous esophageal tumorigenesis. Cell Death Differ. 2016, 23, 1406–1416. [CrossRef]
54. Zhang, R.; Zou, Y.; Zhu, J.; Zeng, X.; Yang, T.; Wang, F.; He, J.; Xia, H. The Association between GWAS-identified BARD1 Gene SNPs and Neuroblastoma Susceptibility in a Southern Chinese Population. Int. J. Med. Sci. 2016, 13, 133–138. [CrossRef] [PubMed]
55. Zhang, T.; Wang, X.; Yue, Z. Identification of c and I date genes related to pancreatic cancer based on analysis of gene co-expression and protein-protein interaction network. Oncotarget 2017, 8, 71105–71116. [CrossRef]
56. Zhao, W.; Steinfeld, J.B.; Liang, F.; Chen, X.; Maranon, D.G.; Ma, C.J.; Kwon, Y.; Rao, T.; Wang, W.; Sheng, C.; et al. BRCA1-BARD1 promotes RAD51-mediated homologous DNA pairing. Nature 2017, 550, 360–365. [CrossRef]
57. Zhao, W.; Wiese, C.; Kwon, Y.; Hromas, R.; Sung, P. The BRCA Tumor Suppressor Network in Chromosome Damage Repair by Homologous Recombination. Annu. Rev. Biochem. 2019, 88, 221–245. [CrossRef] [PubMed]