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Application of Large-Scale Genome Data in Identifying Clinically Actionable Targets...
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Application of Large-Scale Genome Data in Identifying Clinically Actionable Targets in Cancer

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: 15 June 2026 | Viewed by 3312

Special Issue Editor

Dr. Arezou A. Ghazani

E-Mail Website
Guest Editor
Harvard Medical School, 25 Shattuck St, Boston, MA 02115, USA
Interests: precision oncology; clinical genomics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Large-scale data analysis has contributed tremendously to precision oncology. Genome data analysis has enabled the identification of signature tumor profiles in selective cancers. Many of these targets (e.g., tumor burden or MSI) have therapeutic or diagnostic applications. Separately, large-scale data analysis in constitutional cancer has enabled the identification of alterations related to cancer risk and familial cancer.

This Special Issue provides a platform for studies that utilize large-scale genome data to investigate clinically actionable targets in tumors (i.e., somatic) or germline (i.e., constitutional) cancer. We welcome manuscripts that include large data analysis to present novel methods to identify validated clinical targets in the genome, novel actional variants in selected cancer types (somatic or inherited cancer), functional analysis of genomics and genome targets, analysis of multi-omics data, cancer cohort analysis, variant pattern recognition analysis, and applications of machine learning and AI in identifying actional clinical targets.

Dr. Arezou A. Ghazani
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • genome
  • cancers
  • oncology

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Published Papers (3 papers)

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Research

19 pages, 1655 KB  
Article
Gene Expression in Muscle-Invasive and Non-Muscle-Invasive Bladder Cancer Cells Exposed to Hypoxia
by Rekaya Shabbir, Conrado G. Quiles, Brian Lane, Leo Zeef, Peter J. Hoskin, Ananya Choudhury, Catharine M. L. West and Tim A. D. Smith
Cancers 2025, 17(16), 2624; https://doi.org/10.3390/cancers17162624 - 11 Aug 2025
Viewed by 712
Abstract
Introduction: Hypoxic cancers are radioresistant, but biomarkers based on expression of multiple genes can identify patients who will benefit from hypoxia modification. Most studies identifying relevant genes exposed cells in culture to 1% oxygen, which activates hypoxia-inducible factor (HIF). However, oxygen concentrations in [...] Read more.
Introduction: Hypoxic cancers are radioresistant, but biomarkers based on expression of multiple genes can identify patients who will benefit from hypoxia modification. Most studies identifying relevant genes exposed cells in culture to 1% oxygen, which activates hypoxia-inducible factor (HIF). However, oxygen concentrations in hypoxic tumours are heterogeneous ranging from <0.1%. As lower oxygen levels would likely affect transcriptional responses, we aimed to investigate how gene selection at different oxygen levels affects the genes identified and their prognostic capability. Methods: Four MIBC (J82, T24, UMUC3, HT1376) and two non-MIBC (RT4, RT112) bladder cancer cell lines were exposed to varying oxygen levels (20%, 1%, 0.2% and 0.1% O2) for 24 h and were then harvested and frozen. RNA was extracted and transcriptomes analysed using Clariom S microarrays. Differences in gene expression were investigated. Prognostic and predictive significance of a published 24-gene signature was compared with one generated from genes identified at lower oxygen levels. Results: The number of upregulated genes increased with decreasing O2 level. The number of biological pathways involved also increased. Differences between cell lines dominated those due to hypoxia. Some genes were commonly upregulated in MIBC and NMIBC cells and others increased exclusively in either MIBC or NMIBC cells. The median expression of a published 24-gene bladder cancer hypoxia-associated signature increased with decreasing oxygen levels. Seventy-seven genes were upregulated in at least three cell lines by exposure to 0.1% O2. The median expression of the 77 genes was of borderline prognostic significance in the bladder cancer cohort in the TCGA (The Cancer Genome Atlas). Five of the seventy-seven genes upregulated by hypoxia were present in the twenty-four-gene bladder hypoxia signature. The median expression of the 5 genes demonstrated identical prognostication to the 24-gene signature but failed to predict benefit from hypoxia modification. Conclusions: The number of genes upregulated by exposure of bladder cancer cells to hypoxia increases as O2 level is decreased from 1% to 0.2% to 0.1%. Differential upregulation of gene expression by MIBC and NMIBC cells and the associated biological pathways may be useful in understanding the genetics of bladder cancer invasiveness. Based on a search of the literature, this is the first study that assessed the expression of genes in bladder cancer using three hypoxic concentration levels to identify biomarkers for disease progression and prognosis among differentially expressed bladder cancer genes. Full article
(This article belongs to the Special Issue Application of Large-Scale Genome Data in Identifying Clinically Actionable Targets in Cancer)
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23 pages, 2905 KB  
Article
Advancing the Landscape of Clinical Actionability in Von Hippel–Lindau Syndrome: An Evidence-Based Framework from the INT2GRATE Oncology Consortium
by Diane R. Koeller, McKenzie Walker, Busra Unal, Anu Chittenden, Alison Schwartz Levine, Connor P. Hayes, Paul C. Oramasionwu, Monica D. Manam, Ryan M. Buehler, Israel Gomy, Wilson Araujo Silva, Jr., Jordan Lerner-Ellis, Selina Casalino, Radhika Mahajan, Nicholas Watkins, Nihat Bugra Agaoglu, Danielle K. Manning, Justine A. Barletta, Jason L. Hornick, Neal I. Lindeman, Lynette M. Sholl, Huma Q. Rana, Judy E. Garber and Arezou A. Ghazaniadd Show full author list remove Hide full author list
Cancers 2025, 17(13), 2173; https://doi.org/10.3390/cancers17132173 - 27 Jun 2025
Viewed by 610
Abstract
Background/Objectives: An accurate evaluation of variant actionability is essential in cancer management. In Von Hippel–Lindau Syndrome (VHL), the interpretation of the germline variants is confounded by the presence of non-syndromic component tumors, such as clear cell renal cell carcinoma (ccRCC), hemangioblastoma, pheochromocytoma, and [...] Read more.
Background/Objectives: An accurate evaluation of variant actionability is essential in cancer management. In Von Hippel–Lindau Syndrome (VHL), the interpretation of the germline variants is confounded by the presence of non-syndromic component tumors, such as clear cell renal cell carcinoma (ccRCC), hemangioblastoma, pheochromocytoma, and neuroendocrine tumors. These tumors frequently occur sporadically, without any association with VHL syndrome. The presence of these tumors in a patient with a germline VHL variant could lead to inaccurate attribution of these tumors to the germline variant and VHL syndrome. In our previous INT2GRATE (INTegrated INTerpretation of GeRmline And Tumor gEnomes) programs, we demonstrated that integrating tumor-derived and germline evidence offers a comprehensive approach for the accurate assessment of the germline variants in cancer syndromes. Methods/Results: Here, we present a novel INT2GRATE variant evidence framework (VEF) for evaluating the clinical actionability of the germline variants in VHL syndrome, offering an integrated approach that incorporates both constitutional and tumor data. We analyzed 2672 variants in the VHL gene and their associated tumors and clinical evidence to effectively distinguish between constitutional, sporadic, VHL differentials, and VHL allelic genetic conditions. The germline INT2GRATE variants, along with their comprehensive associated evidence, were made accessible in the first open-access INT2GRATE Variant data Portal. Conclusions: This novel and integrated approach to variant assessment and data sharing in hereditary cancer syndromes is essential in the clinical evaluation of genomic variants, advancing precision oncology, and improving patient care. Full article
(This article belongs to the Special Issue Application of Large-Scale Genome Data in Identifying Clinically Actionable Targets in Cancer)
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16 pages, 3890 KB  
Article
A TaqMan-Based qRT-PCR Assay for Accurate Evaluation of the Oncogenic TrkAIII Splice Variant in Tumor cDNAs
by Maddalena Sbaffone, Antonietta Rosella Farina, Ilaria Martelli, Eugenio Pontieri, Stefano Guadagni, Andrew Reay Mackay, Lucia Cappabianca and Veronica Zelli
Cancers 2025, 17(3), 471; https://doi.org/10.3390/cancers17030471 - 30 Jan 2025
Viewed by 1512
Abstract
Background: Alternative NTRK1/TrkA splicing resulting in TrkAIII expression, originally discovered in advanced-stage metastatic neuroblastomas, is also pronounced in prostate, medullary thyroid, glioblastoma multiforme, MCPyV-positive Merkel cell, cutaneous malignant melanoma, and pituitary neuroendocrine tumor subsets. In tumor models, TrkAIII exhibits actionable oncogenic activity equivalent [...] Read more.
Background: Alternative NTRK1/TrkA splicing resulting in TrkAIII expression, originally discovered in advanced-stage metastatic neuroblastomas, is also pronounced in prostate, medullary thyroid, glioblastoma multiforme, MCPyV-positive Merkel cell, cutaneous malignant melanoma, and pituitary neuroendocrine tumor subsets. In tumor models, TrkAIII exhibits actionable oncogenic activity equivalent to the TrkT3-fused oncogene, and in tumor cell lines, alternative TrkAIII splicing is promoted by hypoxia, nutrient deprivation, endoplasmic reticulum stress, and SV40 large T antigen, implicating tumor microenvironmental conditions and oncogenic polyoma viruses in tumor-associated TrkAIII expression. Collectively, these observations characterize TrkAIII as a potentially frequent, actionable oncogenic alternative to TrkA gene fusion in different tumor types. Currently, therapeutic approval for efficacious Trk inhibitors is restricted to Trk-fused gene positive tumors and not for tumors potentially driven by TrkAIII. Methods: With the therapeutically relevant aim of improving the identification of tumors potentially driven by TrkAIII, we have developed a TaqMan-based qRT-PCR assay for evaluating TrkAIII expression in tumor cDNAs. Results: This assay, validated using gel-purified fs-TrkA and TrkAIII cDNAs alone and in complex cDNA mixtures, employs primers and probes designed from fs-TrkA and TrkAIII sequences, with specificity provided by a TaqMan probe spanning the TrkAIII exon 5–8 splice junction. It is highly efficient, reproducible, and specific and can detect as few as 10 TrkAIII copies in complex RNAs extracted from either fresh or FFPE tumor tissues. Conclusions: Inclusion of this assay into precision oncology algorithms, when paired with fs-TrkA qRT-PCR and TrkA immune histochemistry, will make it easier to identify patients with therapy-resistant, advanced-stage metastatic Trk-fused gene-negative tumors potentially driven by TrkAIII, for whom approval of third-line effective Trk inhibitors could be extended. Full article
(This article belongs to the Special Issue Application of Large-Scale Genome Data in Identifying Clinically Actionable Targets in Cancer)
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