Discovery of new therapeutic targets in ovarian cancer through identifying significantly non-mutated genes
![Thumbnail](/bitstream/handle/10576/47775/s12967-022-03440-5.pdf.jpg?sequence=3&isAllowed=y)
عرض / فتح
التاريخ
2022المؤلف
Al-Farsi, HalemaAl-Azwani, Iman
Malek, Joel A.
Chouchane, Lotfi
Rafii, Arash
Halabi, Najeeb M.
...show more authors ...show less authors
البيانات الوصفية
عرض كامل للتسجيلةالملخص
Background: Mutated and non-mutated genes interact to drive cancer growth and metastasis. While research has focused on understanding the impact of mutated genes on cancer biology, understanding non-mutated genes that are essential to tumor development could lead to new therapeutic strategies. The recent advent of high-throughput whole genome sequencing being applied to many different samples has made it possible to calculate if genes are significantly non-mutated in a specific cancer patient cohort. Methods: We carried out random mutagenesis simulations of the human genome approximating the regions sequenced in the publicly available Cancer Growth Atlas Project for ovarian cancer (TCGA-OV). Simulated mutations were compared to the observed mutations in the TCGA-OV cohort and genes with the largest deviations from simulation were identified. Pathway analysis was performed on the non-mutated genes to better understand their biological function. We then compared gene expression, methylation and copy number distributions of non-mutated and mutated genes in cell lines and patient data from the TCGA-OV project. To directly test if non-mutated genes can affect cell proliferation, we carried out proof-of-concept RNAi silencing experiments of a panel of nine selected non-mutated genes in three ovarian cancer cell lines and one primary ovarian epithelial cell line. Results: We identified a set of genes that were mutated less than expected (non-mutated genes) and mutated more than expected (mutated genes). Pathway analysis revealed that non-mutated genes interact in cancer associated pathways. We found that non-mutated genes are expressed significantly more than mutated genes while also having lower methylation and higher copy number states indicating that they could be functionally important. RNAi silencing of the panel of non-mutated genes resulted in a greater significant reduction of cell viability in the cancer cell lines than in the non-cancer cell line. Finally, as a test case, silencing ANKLE2, a significantly non-mutated gene, affected the morphology, reduced migration, and increased the chemotherapeutic response of SKOV3 cells. Conclusion: We show that we can identify significantly non-mutated genes in a large ovarian cancer cohort that are well-expressed in patient and cell line data and whose RNAi-induced silencing reduces viability in three ovarian cancer cell lines. Targeting non-mutated genes that are important for tumor growth and metastasis is a promising approach to expand cancer therapeutic options.
المجموعات
- أبحاث الطب [1382 items ]
وثائق ذات صلة
عرض الوثائق المتصلة بواسطة: العنوان، المؤلف، المنشئ والموضوع.
-
Understanding the structure-function relationship of HPRT1 missense mutations in association with Lesch-Nyhan disease and HPRT1-related gout by in silico mutational analysis.
Agrahari, Ashish Kumar; Krishna Priya, M; Praveen Kumar, Medapalli; Tayubi, Iftikhar Aslam; Siva, R; Prabhu Christopher, B; George Priya Doss, C; Zayed, Hatem... more authors ... less authors ( Elsevier , 2019 , Article)The nucleotide salvage pathway is used to recycle degraded nucleotides (purines and pyrimidines); one of the enzymes that helps to recycle purines is hypoxanthine guanine phosphoribosyl transferase 1 (HGPRT1). Therefore, ... -
A computational approach for investigating the mutational landscape of RAC-alpha serine/threonine-protein kinase (AKT1) and screening inhibitors against the oncogenic E17K mutation causing breast cancer.
Thirumal Kumar, D; Jain, Nikita; Evangeline, Judith; Kamaraj, Balu; Siva, R; Zayed, Hatem; George Priya Doss, C... more authors ... less authors ( Elsevier , 2019 , Article)Breast cancer (BC) is the most commonly diagnosed cancer among females worldwide, and among the BC-associated mutations in various proteins, mutations in the RAC-alpha serine/threonine-protein kinase (AKT1) remain the most ... -
The Spectrum of Mutations of Homocystinuria in the MENA Region
Al-Sadeq, Duaa W.; Nasrallah, Gheyath K. ( MDPI , 2020 , Article Review)Homocystinuria is an inborn error of metabolism due to the deficiency in cystathionine beta-synthase (CBS) enzyme activity. It leads to the elevation of both homocysteine and methionine levels in the blood and urine. ...