Proteogenomic Analysis of Pancreatic Cancer Subtypes

Kafita, Doris; Nkhoma, Panji; Zulu, Mildred; Sinkala, Musalula

doi:10.1101/2020.04.13.039834

Cited by 4 publications

(8 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These mutations are infrequent in cancers such as small cell carcinoma of the ovary (occurring in none of the 15 examined tumours), Ewing sarcoma (occurring in 3% of the 122 examined tumours) and myeloproliferative neoplasms (occurring in 5% of the 151 examined tumours). These exceptions reinforce the notion that there exist multiple MAPK pathway independent routes to oncogenesis [59][60][61][62][63] .…”

Section: Discussionsupporting

confidence: 77%

Integrated molecular characterisation of the MAPK pathways in human cancers reveals pharmacologically vulnerable mutations and gene dependencies

et al. 2021

Self Cite

View full text Add to dashboard Cite

The mitogen-activated protein kinase (MAPK) pathways are crucial regulators of the cellular processes that fuel the malignant transformation of normal cells. The molecular aberrations which lead to cancer involve mutations in, and transcription variations of, various MAPK pathway genes. Here, we examine the genome sequences of 40,848 patient-derived tumours representing 101 distinct human cancers to identify cancer-associated mutations in MAPK signalling pathway genes. We show that patients with tumours that have mutations within genes of the ERK-1/2 pathway, the p38 pathways, or multiple MAPK pathway modules, tend to have worse disease outcomes than patients with tumours that have no mutations within the MAPK pathways genes. Furthermore, by integrating information extracted from various large-scale molecular datasets, we expose the relationship between the fitness of cancer cells after CRISPR mediated gene knockout of MAPK pathway genes, and their dose-responses to MAPK pathway inhibitors. Besides providing new insights into MAPK pathways, we unearth vulnerabilities in specific pathway genes that are reflected in the re sponses of cancer cells to MAPK targeting drugs: a revelation with great potential for guiding the development of innovative therapies.

show abstract

Section: Discussionsupporting

confidence: 77%

Integrated molecular characterisation of the MAPK pathways in human cancers reveals pharmacologically vulnerable mutations and gene dependencies

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…MAPK1 (p = 4.82 × 10 −15 ), MAPK3 (p = 6.56 × 10 −14 ), MAPK8 (p = 1.71 × 10 −10 ), and MAPK14 (p = 2.68 × 10 −07 ; Figure 4c and Figure 5, also see Supplementary File 4). The MAPK pathway genes are altered in cervical cancers, and among other human cancers in which the MAPKs are the chief signal transduction proteins that regulate oncogenic behaviour such as cell proliferation, cell differentiation, cell survival, cancer metastasis, and resistance to drug therapy [36–40]. Accordingly, we suggest that the MAPK signalling pathways may present inflexion points for targeted therapies aimed at successfully treating HPV associated cervical cancer.…”

Section: Resultsmentioning

confidence: 89%

“…the top-ten predicted regulatory kinases ranked according to their combined statistical score based on the number of substrates they phosphorylate within a protein-protein interaction subnetwork. Shown along the columns of the plot are proteins which are the substrates for kinases along the rows.MAPK1 (p = 4.82 x 10 -15 ), MAPK3 (p = 6.56 x 10 -14 ), MAPK8 (p = 1.71 x 10 -10 ), and MAPK14 (p = 2.68 x 10 -07 ;Figure 4candFigure 5, also see Supplementary File 4).The MAPK pathway genes are altered in cervical cancers, and among other human cancers in which the MAPKs are the chief signal transduction proteins that regulate oncogenic behaviour such as cell proliferation, cell differentiation, cell survival, cancer metastasis, and resistance to drug therapy[36][37][38][39][40]. Accordingly, we suggest that the MAPK signalling pathways may present inflexion points for targeted therapies aimed at successfully treating HPV associated cervical cancer.…”

mentioning

confidence: 98%

A Systems Approach Identifies Key Regulators of HPV-Positive Cervical Cancer

Sinkala

Zulu

Nkhoma

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Cervical cancer has remained the most prevalent and lethal malignancy among women worldwide and accounted for over 250,000 deaths in 2019. Nearly ninety-five per cent of cervical cancer cases are associated with persistent infection with high-risk Human Papillomavirus (HPV), and seventy per cent of these are associated with viral integration in the host genome. HPV-infection imparts specific changes in the regulatory network of infected cancer cells that are of diagnostic, prognostic and therapeutic importance. Here, we conducted a systems-level analysis of the regulatory network changes, and the associated regulatory proteins thereof, in HPV-positive cervical cancer. We applied functional pathway analysis to show that HPV-positive cancers are characterised by perturbations of numerous cellular processes, predominantly in those linked to the cell cycle, mitosis, cytokine and immune cell signalling. Using computational predictions, we revealed that HPV-positive cervical cancers are regulated by transcription factors including, SOX2, E2F, NANOG, OCT4, and MYC, which control various processes such as the renewal of cancer stem cells, and the proliferation and differentiation of tumour cells. Through the analysis of upstream regulatory kinases, we identified the mitogen-activated protein kinases; among others, MAPK1, MAPK3 and MAPK8, and the cyclin-dependent kinases; among others, CDK1, CDK2 and CD4, as the key kinases that control the biological processes in HPV-positive cervical cancers. Taken together, we uncover a landscape of the key regulatory pathways and proteins in HPV-positive cervical cancers, all of which may provide attractive drug targets for future therapeutics.

show abstract

“…Data get by these large cancer profiling projects have guided the identification of frequently altered cancer genes and the cancer type-specific regulators. Additionally, large-scale drug response screening projects, such as the Genomics of Drug Sensitivity in Cancer (GDSC) project [ 16 ], have been valuable in providing well-characterised cancer cell lines as models of disease for both drug discovery and the evaluation of drug action dependencies of cancer cells [ 17 – 20 ].…”

Section: Introductionmentioning

confidence: 99%

High ELF4 expression in human cancers is associated with worse disease outcomes and increased resistance to anticancer drugs

et al. 2021

Self Cite

View full text Add to dashboard Cite

The malignant phenotype of tumour cells is fuelled by changes in the expression of various transcription factors, including some of the well-studied proteins such as p53 and Myc. Despite significant progress made, little is known about several other transcription factors, including ELF4, and how they help shape the oncogenic processes in cancer cells. To this end, we performed a bioinformatics analysis to facilitate a detailed understanding of how the expression variations of ELF4 in human cancers are related to disease outcomes and the cancer cell drug responses. Here, using ELF4 mRNA expression data of 9,350 samples from the Cancer Genome Atlas pan-cancer project, we identify two groups of patient’s tumours: those that expressed high ELF4 transcripts and those that expressed low ELF4 transcripts across 32 different human cancers. We uncover that patients segregated into these two groups are associated with different clinical outcomes. Further, we find that tumours that express high ELF4 mRNA levels tend to be of a higher-grade, afflict a significantly older patient population and have a significantly higher mutation burden. By analysing dose-response profiles to 397 anti-cancer drugs of 612 well-characterised human cancer cell lines, we discover that cell lines that expressed high ELF4 mRNA transcript are significantly less responsive to 129 anti-cancer drugs, and only significantly more response to three drugs: dasatinib, WH-4-023, and Ponatinib, all of which remarkably target the proto-oncogene tyrosine-protein kinase SRC and tyrosine-protein kinase ABL1. Collectively our analyses have shown that, across the 32 different human cancers, the patients afflicted with tumours that overexpress ELF4 tended to have a more aggressive disease that is also is more likely more refractory to most anti-cancer drugs, a finding upon which we could devise novel categorisation of patient tumours, treatment, and prognostic strategies.

show abstract

Proteogenomic Analysis of Pancreatic Cancer Subtypes

Cited by 4 publications

References 58 publications

Integrated molecular characterisation of the MAPK pathways in human cancers reveals pharmacologically vulnerable mutations and gene dependencies

Integrated molecular characterisation of the MAPK pathways in human cancers reveals pharmacologically vulnerable mutations and gene dependencies

A Systems Approach Identifies Key Regulators of HPV-Positive Cervical Cancer

High ELF4 expression in human cancers is associated with worse disease outcomes and increased resistance to anticancer drugs

Contact Info

Product

Resources

About