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In Silico Pathway Analysis Based on Chromosomal Instability in Breast

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In Silico Pathway Analysis Based on Chromosomal Instability in Breast Kour et al. BMC Med Genomics (2020) 13:168 https://doi.org/10.1186/s12920-020-00811-z RESEARCH ARTICLE Open Access In silico pathway analysis based on chromosomal instability in breast cancer patients Akeen Kour1, Vasudha Sambyal1* , Kamlesh Guleria1, Neeti Rajan Singh2, Manjit Singh Uppal2, Mridu Manjari3 and Meena Sudan4 Abstract Background: Complex genomic changes that arise in tumors are a consequence of chromosomal instability. In tumor cells genomic aberrations disrupt core signaling pathways involving various genes, thus delineating of signal- ing pathways can help understand the pathogenesis of cancer. The bioinformatics tools can further help in identifying networks of interactions between the genes to get a greater biological context of all genes afected by chromosomal instability. Methods: Karyotypic analyses was done in 150 clinically confrmed breast cancer patients and 150 age and gender matched healthy controls after 72 h Peripheral lymphocyte culturing and GTG-banding. Reactome database from Cytoscape software version 3.7.1 was used to perform in-silico analysis (functional interaction and gene enrichment). Results: Frequency of chromosomal aberrations (structural and numerical) was found to be signifcantly higher in patients as compared to controls. The genes harbored by chromosomal regions showing increased aberration frequency in patients were further analyzed in-silico. Pathway analysis on a set of genes that were not linked together revealed that genes HDAC3, NCOA1, NLRC4, COL1A1, RARA, WWTR1, and BRCA1 were enriched in the RNA Polymerase II Transcription pathway which is involved in recruitment, initiation, elongation and dissociation during transcription. Conclusion: The current study employs the information inferred from chromosomal instability analysis in a non- target tissue for determining the genes and the pathways associated with breast cancer. These results can be further extrapolated by performing either mutation analysis in the genes/pathways deduced or expression analysis which can pinpoint the relevant functional impact of chromosomal instability. Keywords: Chromosomal instability, Breast cancer, Pathway analysis Background indicate errors in DNA repair, mitotic segregation and Complex genomic changes that arise in tumors are a cell cycle checkpoints [2, 3] and may cause (N)-CIN. consequence of Chromosomal Instability (CIN), which Structural rearrangements emerge by anomalous DNA leads to numerical [(N)-CIN] as well as structural chro- repair pathways that cause abnormalities in both homol- mosomal instability [(S)-CIN] [1]. Te increased levels ogous and non-homologous end-joining of double- of aneuploidy and structural complexity in these tumors stranded DNA [4, 5]. (S)-CIN may also appear through telomere-mediated events, where decisively short telom- eres get identifed as DNA breaks capable of recombining *Correspondence: [email protected] 1 Human Cytogenetics Laboratory, Department of Human Genetics, Guru (either homologously or nonhomologously) when DNA- Nanak Dev University, Amritsar, Punjab, India repair pathways get compromised and leads to activation Full list of author information is available at the end of the article of telomerase [6]. Te mechanism leading to aneuploidy © The Author(s) 2020. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Kour et al. BMC Med Genomics (2020) 13:168 Page 2 of 13 is distinct from structural changes and aneuploidy arises informative “linker” genes so as to get a greater biological by disruptions in cell cycle checkpoints and errors in context of all genes afected by chromosomal instability. mitotic segregation [2, 7]. Tis can help to stratify breast cancer patients for choos- CIN is clinically important as it is associated with ing optimal treatments and therapies. poor outcome in patients with cancers of lung, breast Karyotyping aids in efcient single cell screening and and colon [8–10] leading to loss or gain of chromosome identifes important genomic aberrations in normal or segments, deletions, translocations, and DNA amplifca- diseased samples [41]. A copy number alteration (CNA) tions [11]. Various studies have reported the correlation is represented by any alteration in banding pattern [42]. between chromosomal aberration and tumor grade and Tis has been indicated by studies which have reported prognosis [8, 12]. Cytogenetic studies in cancer cells have a relation between chromosomal anomalies in peripheral recognized the complexity of genomic rearrangements in blood lymphocytes (PBLs) and risk prediction in cancers cancer cells [13] and have reported recurrent abnormali- [43–46]. Blood-test screening is considered a non-inva- ties in a broad range of tumors [14, 15]. sive, cost efective technique [41]. Also, genetic aberra- A link between aneuploidy and/or CIN and poor clini- tions in a non-target tissue like PBLs may display related cal outcome has been identifed by several studies [16]. events in target tissue [47]. Cancer cells can be targeted based on the whole chromo- Te present study therefore aimed to identify chromo- some instability (W-CIN) phenotype they carry. National somal anomalies in PBLs of breast cancer patients to: a) cancer Institute (NCI), USA screened compounds hav- identify the recurring aberrant chromosomal lesions ing anticancer activity by examining the data-rich drug and chromosomal loci that are frequently involved in discovery panel of NCI-60 cancer cell lines and enlisted breast cancer; b) determine the genes harboured by these potential agents with anticancer activity which targeted regions, and to delineate the biological pathway which is chromosomally unstable and aneuploid cancer cells [17– enriched by them by bioinformatic tools. 19]. NCI also provided a confrmation of the possibility of discovering potential anticancer agents based on the link Methods between their activity and the karyotypic state. An asso- In the present study 150 patients with confrmed malig- ciation between aneuploidy and chromosomal instability nant breast cancer were included. Te patients were with distinctive clinical and histopathological features clinically investigated at Sri Guru Ram Das Institute of and poor prognosis has also been reported in various Medical Sciences and Research, Vallah, Amritsar, Pun- cancers [20–22]. Tus, the need to target CIN with new jab, India. Tis study was conducted after approval by the combinatorial strategies has been suggested [23]. institutional ethical committee of Guru Nanak Dev Uni- Data from large scale genome wide projects have versity, Amritsar, Punjab, India. Patients with confrmed unveiled common core signaling pathways which lead malignant breast cancer without any history of any other to the development of various cancers [24–28]. Studies cancer were included in the study whereas patients hav- to delineate pathways involved in pathogenesis of can- ing received any kind of therapy (chemotherapy, hormone cers like colon and glioblastoma multiforme [29], have therapy, radiotherapy or surgery) or blood transfusion, provided characterization of the genes involved in the prior to sampling were excluded from the study. After pathogenesis of the disease, thus making it signifcant to informed consent relevant information including age, focus on pathways which involve various genes [30, 31]. gender, occupation, personal history, habitat, habits and Genomic aberrations disrupt signaling cascades or path- disease history were recorded in pre-designed question- ways in tumor cells thereby causing the tumor to prolif- naire. Te blood samples of 150 patients and 150 sex and erate or dediferentiate uncontrollably [32]. For instance, gender matched healthy controls (with no family history deletion in any of the components of TGFβ pathway of cancer) were collected in a heparinized vial. Peripheral paves way for some of the breast cancers [33–37]. Tera- Lymphocyte Culturing was performed by standard 72 h peutic targeting of pathways that are directly involved in culture method using phytohemagglutinin as mitogen. initiation of CIN has also gained clinical interest [20, 38]. GTG banding was performed and karyotyping was done Pathways-based analysis has gained much importance in following ISCN 2016 [48]. Chromosomal anomalies were the past decade as it is able to, frstly identify the actual assessed in 50–100 metaphases for each subject. genes associated with the phenotype and demarcates Te genes (Table 4) present on the chromosomes them from other false positive hits [39] and secondly involved
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