AccScience Publishing / TD / Volume 3 / Issue 1 / DOI: 10.36922/td.1480
Cite this article
67
Download
720
Views
Journal Browser
Volume | Year
Issue
Search
News and Announcements
View All
ORIGINAL RESEARCH ARTICLE

Haplotype analysis and linkage disequilibrium of BRCA genes in glioblastoma: Impact on treatment response

Mohamed K. Khalifa1 Amira M. Nageeb2 Magdy M. Mohamed3 Lobna R. Ezz El Arab4 Menha Swellam2*
Show Less
1 Molecular Pathology Laboratory, Children’s Cancer Hospital, Cairo, Egypt
2 Department of Biochemistry, Biotechnology Research Institute, High Throughput Molecular and Genetic Laboratory, Central Laboratories Network and the Centers of Excellence, National Research Centre, Giza, Egypt
3 Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt
4 Department of Clinical Oncology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
Tumor Discovery 2024, 3(1), 1480 https://doi.org/10.36922/td.1480
Submitted: 9 August 2023 | Accepted: 30 November 2023 | Published: 15 February 2024
© 2024 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
Abstract

Glioblastoma (GBM) is an aggressive primary brain tumor prevalent in adults, characterized as a common malignant neoplasm of the human central nervous system with the worst survival rate among cancers. Treatment of GBM involves the addition of the alkylating agent temozolomide (TMZ) to radiotherapy, which improves overall survival by preventing replication through alkyl group-mediated DNA cross-linking. Genes related to homologous recombination (HR)-dependent DNA repair, such as the breast cancer susceptibility genes (BRCA), specifically BRCA1 or BRCA2, contribute to cellular resistance to alkylating agents. We aimed to perform a haplotype-based study on the frequencies of BRCA1 mutations in GBM patients compared to healthy individuals and investigate their linkage disequilibrium (LD) with the data population. Blood samples from GBM patients (n = 15) and healthy controls (n = 25) were sequenced using the Ion Torrent PGM platform to identify the BRCA1 mutation. Subsequently, the reported variants were submitted to the LDlink tool for haplotype analysis, and their association with treatment response was assessed. Our results revealed that the BRCA1 haplotype block consisted of seven SNPs, whose frequencies were reported with strong LD when compared to all available population data. This block was found to be represented by eight haplotypes. Five of these haplotypes were previously reported (four haplotypes were commonly reported, and one was rare), while the remaining three haplotypes were newly reported in this study. The relationship between newly reported haplotypes and response to treatment revealed that patients with these haplotypes responded to TMZ either as a complete or partial response. In addition, one haplotype in the heterozygote form was reported in the control case. In conclusion, haplotype analysis for BRCA genes in GBM cases can aid in predicting treatment responses and identifying cancer risk factors in individuals.

Keywords
Breast cancer susceptibility genes
Haplotype
Next-generation sequencing
Sequencing
Breast cancer
Funding
Science and Technology Development Fund (STDF) through Capacity Building Grant Fund (CBG)
References
  1. Thakkar JP, Dolecek TA, Horbinski C, et al. Epidemiologic and molecular prognostic review of glioblastoma. Cancer Epidemiol Biomarkers Prev. 2014;23(10):1985-1996. doi: 10.1158/1055-9965.EPI-14-0275

 

  1. Ostrom QT, Gittleman H, Xu J, et al. CBTRUS statistical report: Primary brain and other central nervous system tumors diagnosed in the United States in 2009-2013. Neuro Oncol. 2016;18(suppl_5):v1-v75. doi: 10.1093/neuonc/now207

 

  1. Kleihues P, Ohgaki H. Phenotype vs genotype in the evolution of astrocytic brain tumors. Toxicol Pathol. 2000;28(1):164-170. doi: 10.1177/019262330002800121

 

  1. Al-Holou WN, Hodges TR, Everson RG, et al. Perilesional resection of glioblastoma is independently associated with improved outcomes. Neurosurgery. 2020;86(1):112-121. doi: 10.1093/neuros/nyz008

 

  1. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987-996. doi: 10.1056/NEJMoa043330

 

  1. Huang B, Yu Z, Liang L. Effect of long-term adjuvant temozolomide chemotherapy on primary glioblastoma patient survival. BMC Neurol. 2021;21:424. doi: 10.1186/s12883-021-02461-9

 

  1. Guo C, Yang Q, Xu P, et al. Adjuvant temozolomide chemotherapy with or without interferon alfa among patients with newly diagnosed high-grade gliomas: A randomized clinical trial. JAMA Netw Open. 2023;6(1):e2253285. doi: 10.1001/jamanetworkopen.2022.53285

 

  1. HGMD. Available from: https://www.hgmd.cf.ac.uk/ac/ introduction.php?lang=english

 

  1. Kondo N, Takahashi A, Ono K, Ohinishi T. DNA damage induced by alkylating agents and repair pathways. J Nucleic Acids. 2010;2010:543531. doi: 10.4061/2010/543531

 

  1. Quiros S, Roos WP, Kaina B. Rad51 and BRCA2--New molecular targets for sensitizing glioma cells to alkylating anticancer drugs. PLoS One. 2011;6:e27183. doi: 10.1371/journal.pone.0027183

 

  1. Short SC, Giampieri S, Worku M, et al. Rad51 inhibition is an effective means of targeting DNA repair in glioma models and CD133+ tumor-derived cells. Neuro Oncol. 2011;13:487-499. doi: 10.1093/neuonc/nor010

 

  1. Zhang N, Wu X, Yang L, et al. FoxM1 Inhibition sensitizes resistant glioblastoma cells to temozolomide by downregulating the expression of DNA-repair gene Rad51. Clin Cancer Res. 2012;18(21):5961-5971. doi: 10.1158/1078-0432.CCR-12-0039

 

  1. Trujillano D, Weiss MER, Schneider J, et al. Next-generation sequencing of the BRCA1 and BRCA2 genes for the genetic diagnostics of hereditary breast and/or ovarian cancer. J Mol Diagn. 2015;17:162-170. doi: 10.1016/j.jmoldx.2014.11.004

 

  1. Lord CJ, Ashworth A. PARP inhibitors: Synthetic lethality in the clinic. Science. 2017;355(6330):1152-1158. doi: 10.1126/science.aam7344

 

  1. Taza F, Holler A, Fu W, et al. Differential activity of PARP inhibitors in BRCA1-versus BRCA2-altered metastatic castration-resistant prostate cancer. JCO Precis Oncol. 2021;5:1200-1220. doi: 10.1200/PO.21.00070

 

  1. Gupta SK, Smith EJ, Mladek AC, et al. PARP inhibitors for sensitization of alkylation chemotherapy in glioblastoma: Impact of blood-brain barrier and molecular heterogeneity. Front Oncol. 2019;8:670. doi: 10.3389/fonc.2018.00670

 

  1. Boukerroucha M, Josse C, Segers K, et al. BRCA1 germline mutation and glioblastoma development: Report of cases. BMC Cancer. 2015;15:181. doi: 10.1186/s12885-015-1205-1

 

  1. Galisa SLG, Jacob PL, de Farias AA, et al. Haplotypes of single cancer driver genes and their local ancestry in a highly admixed long-lived population of Northeast Brazil. Genet Mol Biol. 2022;45(1):e20210172. doi: 10.1590/1678-4685-GMB-2021-0172

 

  1. Wang S, Qian F, Zheng Y, et al. Genetic variants demonstrating flip-flop phenomenon and breast cancer risk prediction among women of African ancestry. Breast Cancer Res Treat. 2018;168:703-712. doi: 10.1007/s10549-017-4638-1

 

  1. Carrot-Zhang J, Chambwe N, Damrauer JS, et al. Comprehensive analysis of genetic ancestry and its molecular correlates in cancer. Cancer Cell. 2020;37:639- 654.e6. doi: 10.1016/j.ccell.2020.04.012

 

  1. Ostrom QT, Egan KM, Nabors LB, et al. Glioma risk associated with extent of estimated European genetic ancestry in African-Americans and Hispanics. Int J Cancer. 2020;146:739-748. doi: 10.1002/ijc.32318

 

  1. Wen PY, Macdonald DR, Reardon DA, et al. Updated response assessment criteria for high-grade gliomas: Response assessment in neuro-oncology working group. J Clin Oncol. 2010;28(11):1963-1972. doi: 10.1200/JCO.2009.26.3541

 

  1. Aykan NF, Özatlı T. Objective response rate assessment in oncology: Current situation and future expectations. World J Clin Oncol. 2020;11(2):53-73. doi: 10.5306/wjco.v11.i2.53

 

  1. Terkelsen T, Christensen LL, Fenton D, et al. Population frequencies of pathogenic alleles of BRCA1 and BRCA2: Analysis of 173 Danish breast cancer pedigrees using the BOADICEA model. Fam Cancer. 2019;18:381-388. doi: 10.1007/s10689-019-00141-9

 

  1. Nageeb A, Mohamed M, Ezz El Arab LR, Khalifa MK, Swellam M. Next generation sequencing of BRCA genes in glioblastoma multiform Egyptian patients: A pilot Study. Arch Physiol Biochem. 2020;128:809-817. doi: 10.1080/13813455.2020.1729814

 

  1. Massarat AR, Lamkin M, Reeve C, Williams AL, D’Antonio M, Gymrek M. Haptools: A toolkit for admixture and haplotype analysis. Bioinformatics. 2023;39(3):btad104. doi: 10.1093/bioinformatics/btad104

 

  1. Freedman ML, Penney KL, Stram DO, et al. Common variation in BRCA2 and breast cancer risk: A haplotype-based analysis in the multiethnic cohort. Hum Mol Genet. 2004;13:2431-2441. doi: 10.1093/hmg/ddh270

 

  1. Bhamidipati D, Haro-Silerio JI, Yap TA, Ngoi N. PARP inhibitors: Enhancing efficacy through rational combinations. Br J Cancer. 2023;129:904-916. doi: 10.1038/s41416-023-02326-7

 

  1. Gill SJ, Travers J, Pshenichnaya I, et al. Combinations of PARP inhibitors with temozolomide drive PARP1 trapping and apoptosis in Ewing’s sarcoma. PLoS One. 2015;10:e0140988. doi: 10.1371/journal.pone.0140988

 

  1. Sim HW, McDonald KL, Lwin Z, et al. A randomized phase II trial of veliparib, radiotherapy, and temozolomide in patients with unmethylated MGMT glioblastoma: The VERTU study. Neuro Oncol. 2021;23:1736-1749. doi: 10.1093/neuonc/noab111

 

  1. Pishvaian MJ, Slack RS, Jiang W, et al. A phase 2 study of the PARP inhibitor veliparib plus temozolomide in patients with heavily pretreated metastatic colorectal cancer. Cancer. 2018;124:2337-2346. doi: 10.1002/cncr.31309

 

  1. Xu J, Keenan TE, Overmoyer B, et al. Phase II trial of veliparib and temozolomide in metastatic breast cancer patients with and without BRCA1/2 mutations. Breast Cancer Res Treat. 2021;189:641-651. doi: 10.1007/s10549-021-06292-7

 

  1. Ding J, Wu S, Zhang C, et al. BRCA1 identified as a modulator of temozolomide resistance in P53 wild-type GBM using a high-throughput shRNA-based synthetic lethality screening. Am J Cancer Res. 2019;9(11):2428-2441.

 

  1. De Asis Tuazon A, Lott P, Bohórquez M, et al. Haplotype analysis of the internationally distributed BRCA1 c.3331_3334delCAAG founder mutation reveals a common ancestral origin in Iberia. Breast Cancer Res. 2020;22:108. doi: 10.1186/s13058-020-01341-3

 

  1. Vassilakopoulou M, Won M, Curran WJ, et al. BRCA1 protein expression predicts survival in glioblastoma patients from an NRG oncology RTOG cohort. Oncology. 2021;99(9):580-588. doi: 10.1159/000516168
Conflict of interest
The authors declare that they have no competing interests.
Share
Back to top
Tumor Discovery, Electronic ISSN: 2810-9775 Published by AccScience Publishing