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Cancer Genomics: Interpreting the Changing Landscape in Cancer Diagnosis and Treatment

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Causes, Screening and Diagnosis".

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 19395

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Special Issue Editors

Dr. Maria Paola Paronetto

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Guest Editor

Department of Movement, Human and Health Sciences, University of Rome “Foro Italico”, Rome, Italy
Interests: alternative splicing; RNA metabolism; cancer genomics; RNA binding proteins; ewing sarcoma
Special Issues, Collections and Topics in MDPI journals

Dr. Claudia Ghigna

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Guest Editor

Institute of Molecular Genetics Luigi Luca Cavalli-Sforza, National Research Council, 27100 Pavia, Italy
Interests: alternative splicing; cancer; angiogenesis; vascular development; RNA binding proteins
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The expanding knowledge and comprehension of human genetics are transforming the path and direction of research and medical approaches to cancer diagnosis and treatment.

Recent high-throughput sequencing technologies are gradually reshaping our understanding of cancer origin and complexity, providing more reliable information on tumor progression, metastases, and survival. Genome sequencing is now yielding insightful information about genetic mutations that trigger or contribute to cancer development and how cancer evolves in response to treatments. In this way, cancer-genome profiling is now providing an important tool for the assessment of molecular cancer subtypes and the most appropriate therapeutic options for patients in routine clinical practice. Deciphering the temporal series of events leading to cancer is essential for a comprehensive understanding of tumorigenesis, and for identifying the earliest markers in tumor development, ensuring faster diagnosis and treatment, as well as improving the capability to predict disease progression.

This Special Issue will cover key cancer genetics concepts and cutting-edge clinical applications.

Prof. Dr. Maria Paola Paronetto
Dr. Claudia Ghigna
Guest Editors

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 short 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

Genomic profiling
Cancer trademarks
Mutational signatures
Cancer therapeutics
Post-transcriptional alterations in human cancers

Published Papers (7 papers)

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Research

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16 pages, 3021 KiB

Open AccessArticle

DNA Damage Regulates the Functions of the RNA Binding Protein Sam68 through ATM-Dependent Phosphorylation

by Venturina Stagni, Silvia Orecchia, Luca Mignini, Sara Beji, Ambra Antonioni, Cinzia Caggiano, Daniela Barilà, Pamela Bielli and Claudio Sette

Cancers 2022, 14(16), 3847; https://doi.org/10.3390/cancers14163847 - 9 Aug 2022

Cited by 5 | Viewed by 2105

Abstract

Cancer cells frequently exhibit dysregulation of the DNA damage response (DDR), genomic instability, and altered RNA metabolism. Recent genome-wide studies have strongly suggested an interaction between the pathways involved in the cellular response to DDR and in the regulation of RNA metabolism, but the molecular mechanism(s) involved in this crosstalk are largely unknown. Herein, we found that activation of the DDR kinase ATM promotes its interaction with Sam68, leading to phosphorylation of this multifunctional RNA binding protein (RBP) on three residues: threonine 61, serine 388 and serine 390. Moreover, we demonstrate that ATM-dependent phosphorylation of threonine 61 promotes the function of Sam68 in the DDR pathway and enhances its RNA processing activity. Importantly, ATM-mediated phosphorylation of Sam68 in prostate cancer cells modulates alternative polyadenylation of transcripts that are targets of Sam68, supporting the notion that the ATM–Sam68 axis exerts a multifaceted role in the response to DNA damage. Thus, our work validates Sam68 as an ATM kinase substrate and uncovers an unexpected bidirectional interplay between ATM and Sam68, which couples the DDR pathway to modulation of RNA metabolism in response to genotoxic stress. Full article

(This article belongs to the Special Issue Cancer Genomics: Interpreting the Changing Landscape in Cancer Diagnosis and Treatment)

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11 pages, 457 KiB

Open AccessArticle

Novel Germline Mutations in a Cohort of Men with Familial Prostate Cancer

by Romy Mondschein, Damien Bolton, David Clouston, James Dowty, Liam Kavanagh, Declan Murphy, Prudence Scott, Renea A. Taylor and Heather Thorne

Cancers 2022, 14(15), 3623; https://doi.org/10.3390/cancers14153623 - 26 Jul 2022

Cited by 1 | Viewed by 1986

Abstract

Background: Germline mutations in BRCA2 are associated with aggressive prostate cancer. Additional information regarding the clinical phenotype of germline pathogenic variants in other prostate cancer predisposition genes is required. Clinical testing has been limited by evidence, further restricting knowledge of variants that contribute to prostate cancer development. Objective: Prostate cancer patients who were first- and second-degree relatives from multi-case prostate cancer families underwent a gene panel screen to identify novel (non-BRCA) germline pathogenic variants in cancer predisposition genes and define clinical phenotypes associated with each gene. Methods: The germline genomic DNA (gDNA) of 94 index cases with verified prostate cancer from families with a minimum of two verified prostate cancer cases was screened with an 84-cancer-gene panel. Families were recruited for multi-case breast/ovarian cancer (n = 66), or multi-case prostate cancer (n = 28). Prostate cancer characteristics associated with each gene were compared with prostate cancer cases of confirmed non-mutation carriers (BRCAX), also from multi-case prostate cancer families (n = 111), and with data from the Prostate Cancer Outcomes Registry (PCOR). Results: Ninety-four prostate cancer index cases underwent gene panel testing; twenty-two index cases (22/94; 23%) were found to carry a class 4–5 (C4/5) variant. Six of twenty-two (27%) variants were not clinically notifiable, and seven of twenty-two (31.8%) variants were in BRCA1/2 genes. Nine of twenty-two (40.9%) index cases had variants identified in ATM (n = 4), CHEK2 (n = 2) and HOXB13G84 (n = 3); gDNA for all relatives of these nine cases was screened for the corresponding familial variant. The final cohort comprised 15 confirmed germline mutation carriers with prostate cancer (ATM n = 9, CHEK2 n = 2, HOXB13G84 n = 4). ATM and CHEK2-associated cancers were D’Amico intermediate or high risk, comparable to our previously published BRCA2 and BRCAX prostate cancer cohort. HOXB13G84 carriers demonstrated low- to intermediate-risk prostate cancer. In the BRCAX cohort, 53.2% of subjects demonstrated high-risk disease compared with 25% of the PCOR cohort. Conclusions:ATM and CHEK2 germline mutation carriers and the BRCAX (confirmed non-mutation carriers) cohort demonstrated high risk disease compared with the general population. Targeted genetic testing will help identify men at greater risk of prostate-cancer-specific mortality. Data correlating rare variants with clinical phenotype and familial predisposition will strengthen the clinical validity and utility of these results and establish these variants as significant in prostate cancer detection and management. Full article

(This article belongs to the Special Issue Cancer Genomics: Interpreting the Changing Landscape in Cancer Diagnosis and Treatment)

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13 pages, 1466 KiB

Open AccessArticle

SRSF6 Regulates the Alternative Splicing of the Apoptotic Fas Gene by Targeting a Novel RNA Sequence

by Namjeong Choi, Ha Na Jang, Jagyeong Oh, Jiyeon Ha, Hyungbin Park, Xuexiu Zheng, Sunjae Lee and Haihong Shen

Cancers 2022, 14(8), 1990; https://doi.org/10.3390/cancers14081990 - 14 Apr 2022

Cited by 6 | Viewed by 2497

Abstract

Alternative splicing (AS) is a procedure during gene expression that allows the production of multiple mRNAs from a single gene, leading to a larger number of proteins with various functions. The alternative splicing (AS) of Fas (Apo-1/CD95) pre-mRNA can generate membrane-bound or soluble isoforms with pro-apoptotic and anti-apoptotic functions. SRSF6, a member of the Serine/Arginine-rich protein family, plays essential roles in both constitutive and alternative splicing. Here, we identified SRSF6 as an important regulatory protein in Fas AS. The cassette exon inclusion of Fas was decreased by SRSF6-targeting shRNA treatment, but increased by SRSF6 overexpression. The deletion and substitution mutagenesis of the Fas minigene demonstrated that the UGCCAA sequence in the cassette exon of the Fas gene causes the functional disruption of SRSF6, indicating that these sequences are essential for SRSF6 function in Fas splicing. In addition, biotin-labeled RNA-pulldown and immunoblotting analysis showed that SRSF6 interacted with these RNA sequences. Mutagenesis in the splice-site strength alteration demonstrated that the 5′ splice-site, but not the 3′ splice-site, was required for the SRSF6 regulation of Fas pre-mRNA. In addition, a large-scale RNA-seq analysis using GTEX and TCGA indicated that while SRSF6 expression was correlated with Fas expression in normal tissues, the correlation was disrupted in tumors. Furthermore, high SRSF6 expression was linked to the high expression of pro-apoptotic and immune activation genes. Therefore, we identified a novel RNA target with 5′ splice-site dependence of SRSF6 in Fas pre-mRNA splicing, and a correlation between SRSF6 and Fas expression. Full article

(This article belongs to the Special Issue Cancer Genomics: Interpreting the Changing Landscape in Cancer Diagnosis and Treatment)

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36 pages, 8839 KiB

Open AccessArticle

High Grade of Amplification of Six Regions on Chromosome 2p in a Neuroblastoma Patient with Very Poor Outcome: The Putative New Oncogene TSSC1

by Marzia Ognibene, Loredana Amoroso, Fraia Melchionda, Davide Cangelosi, Federico Zara, Stefano Parodi and Annalisa Pezzolo

Cancers 2021, 13(22), 5792; https://doi.org/10.3390/cancers13225792 - 18 Nov 2021

Cited by 1 | Viewed by 1867

Abstract

We observed a case of high-risk neuroblastoma (NB) carried by a 28-month-old girl, displaying metastatic disease and a rapid decline of clinical conditions. By array-CGH analysis of the tumor tissue and of the metastatic bone marrow aspirate cells, we found a high-grade amplification of six regions besides MYCN on bands 2p25.3–p24.3. The genes involved in these amplifications were MYT1L, TSSC1, CMPK2, RSAD2, RNF144A, GREB1, NTSR2, LPIN1, NBAS, and the two intergenic non-protein coding RNAs LOC730811 and LOC339788. We investigated if these DNA co-amplifications may have an effect on enhancing tumor aggressiveness. We evaluated the association between the high expression of the amplified genes and NB patient’s outcome using the integration of gene expression data of 786 NB samples profiled with different public platforms from patients with at least five-year follow-up. NB patients with high expression of the TSSC1 gene were associated with a reduced survival rate. Immunofluorescence staining on primary tumor tissues confirmed that the TSSC1 protein expression was high in the relapsed or dead stage 4 cases, but it was generally low in NB patients in complete remission. TSSC1 appears as a putative new oncogene in NB. Full article

(This article belongs to the Special Issue Cancer Genomics: Interpreting the Changing Landscape in Cancer Diagnosis and Treatment)

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Review

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20 pages, 1688 KiB

Open AccessReview

Somatic Mutations in Core Spliceosome Components Promote Tumorigenesis and Generate an Exploitable Vulnerability in Human Cancer

by Claudio Sette and Maria Paola Paronetto

Cancers 2022, 14(7), 1827; https://doi.org/10.3390/cancers14071827 - 4 Apr 2022

Cited by 8 | Viewed by 2907

Abstract

Alternative pre-mRNA processing enables the production of distinct mRNA and protein isoforms from a single gene, thus greatly expanding the coding potential of eukaryotic genomes and fine-tuning gene expression programs. Splicing is carried out by the spliceosome, a complex molecular machinery which assembles step-wise on mRNA precursors in the nucleus of eukaryotic cells. In the last decade, exome sequencing technologies have allowed the identification of point mutations in genes encoding splicing factors as a recurrent hallmark of human cancers, with higher incidence in hematological malignancies. These mutations lead to production of splicing factors that reduce the fidelity of the splicing process and yield splicing variants that are often advantageous for cancer cells. However, at the same time, these mutations increase the sensitivity of transformed cells to splicing inhibitors, thus offering a therapeutic opportunity for novel targeted strategies. Herein, we review the recent literature documenting cancer-associated mutations in components of the early spliceosome complex and discuss novel therapeutic strategies based on small-molecule spliceosome inhibitors that exhibit strong anti-tumor effects, particularly against cancer cells harboring mutations in spliceosomal components. Full article

(This article belongs to the Special Issue Cancer Genomics: Interpreting the Changing Landscape in Cancer Diagnosis and Treatment)

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26 pages, 3675 KiB

Open AccessEditor’s ChoiceReview

Clinical Significance and Regulation of ERK5 Expression and Function in Cancer

by Matilde Monti, Jacopo Celli, Francesco Missale, Francesca Cersosimo, Mariapia Russo, Elisa Belloni, Anna Di Matteo, Silvia Lonardi, William Vermi, Claudia Ghigna and Emanuele Giurisato

Cancers 2022, 14(2), 348; https://doi.org/10.3390/cancers14020348 - 11 Jan 2022

Cited by 14 | Viewed by 4202

Abstract

Extracellular signal-regulated kinase 5 (ERK5) is a unique kinase among MAPKs family members, given its large structure characterized by the presence of a unique C-terminal domain. Despite increasing data demonstrating the relevance of the ERK5 pathway in the growth, survival, and differentiation of normal cells, ERK5 has recently attracted the attention of several research groups given its relevance in inflammatory disorders and cancer. Accumulating evidence reported its role in tumor initiation and progression. In this review, we explore the gene expression profile of ERK5 among cancers correlated with its clinical impact, as well as the prognostic value of ERK5 and pERK5 expression levels in tumors. We also summarize the importance of ERK5 in the maintenance of a cancer stem-like phenotype and explore the major known contributions of ERK5 in the tumor-associated microenvironment. Moreover, although several questions are still open concerning ERK5 molecular regulation, different ERK5 isoforms derived from the alternative splicing process are also described, highlighting the potential clinical relevance of targeting ERK5 pathways. Full article

(This article belongs to the Special Issue Cancer Genomics: Interpreting the Changing Landscape in Cancer Diagnosis and Treatment)

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16 pages, 2027 KiB

Open AccessFeature PaperReview

Recurrent Spliceosome Mutations in Cancer: Mechanisms and Consequences of Aberrant Splice Site Selection

by Carlos A. Niño, Rossella Scotto di Perrotolo and Simona Polo

Cancers 2022, 14(2), 281; https://doi.org/10.3390/cancers14020281 - 7 Jan 2022

Cited by 2 | Viewed by 2626

Abstract

Splicing alterations have been widely documented in tumors where the proliferation and dissemination of cancer cells is supported by the expression of aberrant isoform variants. Splicing is catalyzed by the spliceosome, a ribonucleoprotein complex that orchestrates the complex process of intron removal and exon ligation. In recent years, recurrent hotspot mutations in the spliceosome components U1 snRNA, SF3B1, and U2AF1 have been identified across different tumor types. Such mutations in principle are highly detrimental for cells as all three spliceosome components are crucial for accurate splice site selection: the U1 snRNA is essential for 5′ splice site recognition, and SF3B1 and U2AF1 are important for 3′ splice site selection. Nonetheless, they appear to be selected to promote specific types of cancers. Here, we review the current molecular understanding of these mutations in cancer, focusing on how they influence splice site selection and impact on cancer development. Full article

(This article belongs to the Special Issue Cancer Genomics: Interpreting the Changing Landscape in Cancer Diagnosis and Treatment)

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