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ORIGINAL RESEARCH ARTICLE
Examining BRCA1 and BRCA2 Mutations in Gastric Cancer Using Next Generation Sequencing: Relevance for Diagnosis and Treatment Strategies
Hamid Yaz1 ,
Akbar Ali2* ,
Rida Akhtar2
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1
Department of Botany and Microbiology, College of Science, King Saud University Riyadh, P.O. 2455, Riyadh 11451,
Saudi Arabia
2
Nishtar Medical University, Multan,
Pakistan
CP 2023, 5(3), 2586
Submitted: 12 June 2023 | Accepted: 21 August 2023 | Published: 29 August 2023
© 2023 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
Gastric cancer (GC) presents a significant global health dilemma, being the fifth most widespread cancer on a global scale and the third major contributor to cancer-related deaths. Given the intricacies of this malignancy, there is an urgent need for a thorough investigation into its molecular basis. In this study, we investigated the role of BRCA1 and BRCA2 mutations in Pakistani GC patients and their functional implications. Using Next-Generation Sequencing (NGS), we analyzed BRCA1/2 genes in a cohort of 31 Pakistani GC patients, revealing pathogenic mutations not previously documented in this context. Expression analyses of BRCA1 and BRCA2 genes at both mRNA and protein levels uncovered a consistent down-regulation in GC samples with pathogenic mutations. This down-regulation extends beyond the canonical role of BRCA1/2 in DNA repair, suggesting a broader impact on cellular processes. The clinical significance of these findings lies in the potential of these pathogenic mutations as biomarkers for GC diagnosis and treatment. Furthermore, our study explored potential drugs from the DrugBank database capable of up-regulating BRCA1/2 gene expression in GC treatment. Pathway analysis revealed the involvement of BRCA1/2 genes in diverse pathways, emphasizing their relevance in GC progression. Despite limitations, including a relatively small sample size, this study sheds light on the molecular intricacies of GC and offers promising avenues for further research and personalized therapeutic approaches. In conclusion, our study unveils the presence of pathogenic BRCA1 and BRCA2 mutations in Pakistani GC patients, shedding light on their potential as biomarkers and therapeutic targets. These findings offer promise for enhancing the management and treatment outcomes of this malignancy.
Keywords
Gastric cancer; BRCA1; BRCA2; Mutations; Next Generation Sequencing
Funding
This study did not receive any funding in any form.
Conflict of interest
The authors declare that they have no conflicts of interest.
References
- Schwarz RE. Current status of management of malignant disease: current management of gastric cancer. Journal of Gastrointestinal Surgery 2015; 19: 782-788.
- Berretta S, Berretta M, Fiorica F, Di Francia R, Magistri P, Bertola G, Fisichella R, Canzonieri V, Tarantino G and Di Benedetto F. Multimodal approach of advanced gastric cancer: based therapeutic algorithm. European review for medical and pharmacological sciences 2016; 20: 4018-4031.
- McLean MH and El-Omar EM. Genetics of gastric cancer. Nature reviews Gastroenterology & hepatology 2014; 11: 664-674.
- Dicken BJ, Bigam DL, Cass C, Mackey JR, Joy AA and Hamilton SM. Gastric adenocarcinoma: review and considerations for future directions. Annals of surgery 2005; 241: 27.
- Comen EA, Bowman RL and Kleppe M. Underlying causes and therapeutic targeting of the inflammatory tumor microenvironment. Frontiers in Cell and Developmental Biology 2018; 6: 56.
- Lu M and Zhan X. The crucial role of multiomic approach in cancer research and clinically relevant outcomes. EPMA Journal 2018; 9: 77-102.
- Cavanagh H and Rogers K. The role of BRCA1 and BRCA2 mutations in prostate, pancreatic and stomach cancers. Hereditary cancer in clinical practice 2015; 13: 1-7.
- Buckley KH, Niccum BA, Maxwell KN and Katona BW. Gastric cancer risk and pathogenesis in BRCA1 and BRCA2 carriers. Cancers 2022; 14: 5953.
- Tatematsu M, Tsukamoto T and Inada K. Stem cells and gastric cancer: role of gastric and intestinal mixed intestinal metaplasia. Cancer science 2003; 94: 135-141.
- Wang K, Yuen ST, Xu J, Lee SP, Yan HH, Shi ST, Siu HC, Deng S, Chu KM and Law S. Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer. Nature genetics 2014; 46: 573-582.
- Correa P. Gastric cancer: overview. Gastroenterology Clinics 2013; 42: 211-217.
- Van Cutsem E, Sagaert X, Topal B, Haustermans K and Prenen H. Gastric cancer. The Lancet 2016; 388: 2654-2664.
- Zhang Z-Z, Liu YJC, Yin X-L, Zhan P, Gu Y and Ni X-Z. Loss of BRCA1 expression leads to worse survival in patients with gastric carcinoma. World Journal of Gastroenterology: WJG 2013; 19: 1968.
- Semba S, Yokozaki H, Yasui W and Tahara E. Frequent microsatellite instability and loss of heterozygosity in the region including BRCA1 (17q21) in young patients with gastric cancer. International journal of oncology 1998; 12: 1245-1296.
- Blay P, Santamaría I, Pitiot AS, Luque M, Alvarado MG, Lastra A, Fernández Y, Paredes Á, Freije JM and Balbín M. Mutational analysis of BRCA1 and BRCA2 in hereditary breast and ovarian cancer families from Asturias (Northern Spain). BMC cancer 2013; 13: 1-10.
- Risch HA, McLaughlin JR, Cole DE, Rosen B, Bradley L, Fan I, Tang J, Li S, Zhang S and Shaw PA. Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: a kin–cohort study in Ontario, Canada. Journal Of The National Cancer Institute 2006; 98: 1694-1706.
- Iarmarcovai G, Bonassi S, Botta A, Baan R and Orsiere T. Genetic polymorphisms and micronucleus formation: a review of the literature. Mutation Research/Reviews in Mutation Research 2008; 658: 215-233.
- Migliore L and Coppedè F. Genetic and environmental factors in cancer and neurodegenerative diseases. Mutation Research/Reviews in Mutation Research 2002; 512: 135-153.
- World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. J Am Coll Dent 2014; 81: 14-18.
- Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K and Rehm HL. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17: 405-424.
- Gudmundsson S, Singer-Berk M, Watts NA, Phu W, Goodrich JK, Solomonson M, Rehm HL, MacArthur DG and O'Donnell-Luria A. Variant interpretation using population databases: Lessons from gnomAD. Hum Mutat 2022; 43: 1012-1030.
- Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, Jacobsen A, Byrne CJ, Heuer ML, Larsson E, Antipin Y, Reva B, Goldberg AP, Sander C and Schultz N. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2012; 2: 401-404.
- Livak KJ and Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001; 25: 402-408.
- Zhou Y, Zhou B, Pache L, Chang M, Khodabakhshi AH, Tanaseichuk O, Benner C and Chanda SK. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun 2019; 10: 019-09234.
- Zheng L, Wang L, Ajani J and Xie K. Molecular basis of gastric cancer development and progression. Gastric cancer 2004; 7: 61-77.
- Smyth EC, Nilsson M, Grabsch HI, van Grieken NC and Lordick F. Gastric cancer. The Lancet 2020; 396: 635-648.
- Sekine M, Nagata H, Tsuji S, Hirai Y, Fujimoto S, Hatae M, Kobayashi I, Fujii T, Nagata I and Ushijima K. Mutational analysis of BRCA1 and BRCA2 and clinicopathologic analysis of ovarian cancer in 82 ovarian cancer families: two common founder mutations of BRCA1 in Japanese population. Clinical Cancer Research 2001; 7: 3144-3150.
- Suszynska M, Ratajska M and Kozlowski P. BRIP1, RAD51C, and RAD51D mutations are associated with high susceptibility to ovarian cancer: Mutation prevalence and precise risk estimates based on a pooled analysis of~ 30,000 cases. Journal of ovarian research 2020; 13: 1-11.
- Backwell L and Marsh JA. Diverse molecular mechanisms underlying pathogenic protein mutations: beyond the loss-of-function paradigm. Annual review of genomics and human genetics 2022; 23: 475-498.
- Ansari S, Gantuya B, Tuan VP and Yamaoka Y. Diffuse gastric cancer: a summary of analogous contributing factors for its molecular pathogenicity. International journal of molecular sciences 2018; 19: 2424.
- Nathansen J, Meyer F, Müller L, Schmitz M, Borgmann K and Dubrovska A. Beyond the double-strand breaks: the role of DNA repair proteins in cancer stem-cell regulation. Cancers 2021; 13: 4818.
- Fleury H, Carmona E, Morin VG, Meunier L, Masson J-Y, Tonin PN, Provencher D and Mes-Masson A-M. Cumulative defects in DNA repair pathways drive the PARP inhibitor response in high-grade serous epithelial ovarian cancer cell lines. Oncotarget 2017; 8: 40152.
- Rosen EM, Fan S, Pestell RG and Goldberg ID. BRCA1 gene in breast cancer. Journal of Cellular Physiology 2003; 196: 19-41.
- Vodicka P, Andera L, Opattova A and Vodickova L. The interactions of DNA repair, telomere homeostasis, and p53 mutational status in solid cancers: Risk, prognosis, and prediction. Cancers 2021; 13: 479.
- Leung W, Baxley RM, Moldovan G-L and Bielinsky A-K. Mechanisms of DNA damage tolerance: Post-translational regulation of PCNA. Genes 2018; 10: 10.
- Kovalchuk I. Roles of RAD18 in DNA replication and post-replication repair (PRR). In: editors. Genome Stability. Elsevier; 2021. p. 275-292.
- Vaziri C, Tateishi S, Mutter-Rottmayer E and Gao Y. Roles of RAD18 in DNA Replication and Postreplication Repair. In: editors. Genome Stability. Elsevier; 2016. p. 257-273.