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Cancers
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Inside Cancer Genomics: From Structure to Therapy
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Inside Cancer Genomics: From Structure to Therapy

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

Deadline for manuscript submissions: closed (15 May 2022) | Viewed by 41636

Special Issue Editor

Dr. Vincenza Barresi

E-Mail Website
Guest Editor
Department of Biomedical and Biotechnological Sciences, Section of Medical Biochemistry, University of Catania, 95123 Catania, Italy
Interests: genomics; transcriptomics; cancer; molecular biomarkers; cancer driver genes; proteases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cancer initiation, growth, and progression are sustained by point mutations, focal genomic errors, and, last but not least, broad chromosomal copy number alterations. In recent years, our extensive knowledge of DNA mutations in cancer genomes has inspired a vast range of targeted therapies. These mutations can hit protein-coding genes and noncoding regions and, via heterogeneous mechanisms, are crucial in tumorigenesis. However, it is significant that almost all solid tumors are characterized by a high percentage of aneuploidy (50–80% depending on the specific tumor), and its impact on cancer driver genes and gene networks is poorly known. The context seems to include both single mutation-single pathogenic gene and single alteration–multiple candidate pathogenic genes affecting DNA and RNA molecules.

This Special Issue will focus on the role and contribution of focal and broad alterations in cancer genomics in order to ameliorate cancer diagnosis and prognosis and to design new precision therapies.

Dr. Vincenza Barresi
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 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

  • cancer aneuploidy
  • gene copy number abnormalities
  • DNA mutations
  • DNA and RNA editing
  • transcriptomics
  • biochemical pathways
  • gene-dosage effect
  • nucleic acid-based therapeutics
  • transcriptional therapy

Published Papers (14 papers)

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Editorial

Jump to: Research, Review

6 pages, 225 KiB  
Editorial
The Crucial Findings Derived from the Special Issue “Inside Cancer Genomics: From Structure to Therapy”
by Vincenza Barresi
Cancers 2023, 15(13), 3488; https://doi.org/10.3390/cancers15133488 - 4 Jul 2023
Viewed by 773
Abstract
Cancer initiation, growth, and progression are sustained by multiple types of genetic alterations, ranging in size from single point mutations, focal genomic errors to broad chromosomal copy number alterations, gains, and losses [...] Full article
(This article belongs to the Special Issue Inside Cancer Genomics: From Structure to Therapy)

Research

Jump to: Editorial, Review

19 pages, 2992 KiB  
Article
CSMD1 Shows Complex Patterns of Somatic Copy Number Alterations and Expressions of mRNAs and Target Micro RNAs in Esophageal Squamous Cell Carcinoma
by Nan Hu, Chaoyu Wang, Tongwu Zhang, Hua Su, Huaitian Liu, Howard H. Yang, Carol Giffen, Ying Hu, Philip R. Taylor and Alisa M. Goldstein
Cancers 2022, 14(20), 5001; https://doi.org/10.3390/cancers14205001 - 13 Oct 2022
Cited by 2 | Viewed by 1408
Abstract
Background: Human Cub and Sushi Multiple Domains 1 (CSMD1) is a novel candidate tumor-suppressor gene that codes for multiple domains, including complement regulatory and adhesion proteins, and has recently been shown to have alterations in multiple cancers. We investigated CSMD1 in esophageal squamous [...] Read more.
Background: Human Cub and Sushi Multiple Domains 1 (CSMD1) is a novel candidate tumor-suppressor gene that codes for multiple domains, including complement regulatory and adhesion proteins, and has recently been shown to have alterations in multiple cancers. We investigated CSMD1 in esophageal squamous cell carcinoma (ESCC) by performing an integrated analysis on somatic copy number alterations (CNAs), including copy-number gain or loss, allelic imbalance (AI), loss of heterozygosity (LOH), and the expressions of mRNA and its target miRNAs on specimens from the same patients with ESCC. Results: (i) Two-thirds of ESCC patients had all three types of alterations studied—somatic DNA alterations in 70%, and abnormal expressions of CSMD1 RNA in 69% and in target miRNAs in 66%; patterns among these alterations were complex. (ii) In total, 97% of 888 CSMD1 SNPs studied showed somatic DNA alterations, with most located near exons 4–11, 24–25, 39–40, 55–56, and 69–70. (iii) In total, 68% of SNPs with a CNA were correlated with expression of CSMD1. (iv) A total of 33 correlations between non-coding SNPs and expression of CSMD1 target miRs were found. Conclusions: Our results indicate that the CSMD1 gene may play a role in ESCC through complex patterns of DNA alterations and RNA and miRNA expressions. Alterations in some somatic SNPs in non-coding regions of CSMD1 appear to influence expression of this gene and its target miRNAs. Full article
(This article belongs to the Special Issue Inside Cancer Genomics: From Structure to Therapy)
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17 pages, 3048 KiB  
Article
Multi-Omic Analysis of Two Common P53 Mutations: Proteins Regulated by Mutated P53 as Potential Targets for Immunotherapy
by Jayakumar Vadakekolathu, David J. Boocock, Kirti Pandey, Barbara-ann Guinn, Antoine Legrand, Amanda K. Miles, Clare Coveney, Rochelle Ayala, Anthony W. Purcell and Stephanie E. McArdle
Cancers 2022, 14(16), 3975; https://doi.org/10.3390/cancers14163975 - 17 Aug 2022
Cited by 3 | Viewed by 2140
Abstract
The p53 protein is mutated in more than 50% of human cancers. Mutated p53 proteins not only lose their normal function but often acquire novel oncogenic functions, a phenomenon termed mutant p53 gain-of-function. Mutant p53 has been shown to affect the transcription of [...] Read more.
The p53 protein is mutated in more than 50% of human cancers. Mutated p53 proteins not only lose their normal function but often acquire novel oncogenic functions, a phenomenon termed mutant p53 gain-of-function. Mutant p53 has been shown to affect the transcription of a range of genes, as well as protein–protein interactions with transcription factors and other effectors; however, no one has intensively investigated and identified these proteins, or their MHC presented epitopes, from the viewpoint of their ability to act as targets for immunotherapeutic interventions. We investigated the molecular changes that occurred after the TP53 null osteosarcoma cells, SaOS-2, were transfected with one of two conformational p53-mutants, either R175H or R273H. We then examined the phenotypic and functional changes using macroscopic observations, proliferation, gene expression and proteomics alongside immunopeptidome profiling of peptide antigen presentation in the context of major histocompatibility complex (MHC) class I molecules. We identified several candidate proteins in both TP53 mutant cell lines with differential expression when compared to the TP53 null vector control, SaOS-V. Quantitative SWATH proteomics combined with immune-peptidome analysis of the class-I eluted peptides identified several epitopes presented on pMHC and in silico analysis shortlisted which antigens were expressed in a range of cancerous but not adjacent healthy tissues. Out of all the candidates, KLC1 and TOP2A showed high levels of expression in every tumor type examined. From these proteins, three A2 and four pan HLA-A epitopes were identified in both R175H and R273H from TOP2A. We have now provided a short list of future immunotherapy targets for the treatment of cancers harboring mutated TP53. Full article
(This article belongs to the Special Issue Inside Cancer Genomics: From Structure to Therapy)
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17 pages, 1726 KiB  
Article
Genetic Polymorphisms Associated with Vincristine Pharmacokinetics and Vincristine-Induced Peripheral Neuropathy in Pediatric Oncology Patients
by Mirjam E. van de Velde, Aniek Uittenboogaard, Wenjian Yang, Erik Bonten, Cheng Cheng, Deqing Pei, Marleen H. van den Berg, Inge M. van der Sluis, Cor van den Bos, Floor C. H. Abbink, Marry M. van den Heuvel-Eibrink, Heidi Segers, Christophe Chantrain, Jutte van der Werff ten Bosch, Leen Willems, William E. Evans and Gertjan J. L. Kaspers
Cancers 2022, 14(14), 3510; https://doi.org/10.3390/cancers14143510 - 19 Jul 2022
Cited by 7 | Viewed by 1968
Abstract
Vincristine (VCR) is an important component of curative chemotherapy for many childhood cancers. Its main side effect is VCR-induced peripheral neuropathy (VIPN), a dose limiting toxicity. Some children are more susceptible to VIPN, which is at least partially dependent on genetic factors and [...] Read more.
Vincristine (VCR) is an important component of curative chemotherapy for many childhood cancers. Its main side effect is VCR-induced peripheral neuropathy (VIPN), a dose limiting toxicity. Some children are more susceptible to VIPN, which is at least partially dependent on genetic factors and pharmacokinetics (PK). In this study, we identify and replicate genetic variants associated with VCR PK and VIPN. Patient samples from a randomized clinical trial studying the effect of administration duration of VCR on VIPN in 90 patients were used. PK sampling was conducted on between one and five occasions at multiple time points. A linear two-compartment model with first-order elimination was used, and targeted next-generation DNA sequencing was performed. Genotype–trait associations were analyzed using mixed-effect models or logistic regression analysis for repeated measures, or Poisson regression analysis in which the highest VIPN score per patient was included. Nine single-nucleotide polymorphisms (SNPs) in seven genes (NDRG1, GARS, FIG4, FGD4, SEPTIN9, CEP72, and ETAA1) were associated with VIPN. Furthermore, three SNPs in three genes (MTNR1B, RAB7A and SNU13) were associated with PK of VCR. In conclusion, PK of VCR and VIPN are influenced by SNPs; upfront identification of those that lead to an altered susceptibility to VIPN or VCR exposure could help individualize VCR treatment. Full article
(This article belongs to the Special Issue Inside Cancer Genomics: From Structure to Therapy)
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18 pages, 3366 KiB  
Article
KIT Mutations Correlate with Higher Galectin Levels and Brain Metastasis in Breast and Non-Small Cell Lung Cancer
by Avery T. Funkhouser, Alexander M. Strigenz, Bailey B. Blair, Andrew P. Miller, Jonah C. Shealy, Joseph A. Ewing, Julie C. Martin, Christopher R. Funk, William J. Edenfield and Anna V. Blenda
Cancers 2022, 14(11), 2781; https://doi.org/10.3390/cancers14112781 - 3 Jun 2022
Cited by 12 | Viewed by 3409
Abstract
To investigate a potential role for galectins as biomarkers that enable diagnosis or prognostication of breast or non-small cell lung cancer, the serum levels of galectins -1, -3, -7, -8, and -9 of cancer patients determined by ELISA assays were compared to the [...] Read more.
To investigate a potential role for galectins as biomarkers that enable diagnosis or prognostication of breast or non-small cell lung cancer, the serum levels of galectins -1, -3, -7, -8, and -9 of cancer patients determined by ELISA assays were compared to the mutation status of 50 known cancer-critical genes, which were determined using multiplex PCR in tumors of the same patients. Mutations in the KIT proto-oncogene, which codes for the c-Kit protein, a receptor tyrosine kinase, correlated with higher levels of galectins -1, -3, -8, and -9 in breast cancer patients and galectin-1 in non-small cell lung cancer patients. Mutations in the KIT gene were more likely found in brain metastases from both of these primary cancers. The most common KIT mutation in our panel was p.M541L, a missense mutation in the transmembrane domain of the c-Kit protein. These results demonstrate an association between KIT oncogenic signaling and elevated serum galectins in patients with metastatic disease. Changes in protein trafficking and the glycocalyx composition of cancer cells may explain the observed alterations in galectin expression. This study can be useful for the targeted selection of receptor tyrosine kinase and galectin inhibitor anti-cancer treatments. Full article
(This article belongs to the Special Issue Inside Cancer Genomics: From Structure to Therapy)
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Graphical abstract

11 pages, 1245 KiB  
Article
BRCA 1/2 Germline Mutation Predicts the Treatment Response of FOLFIRINOX with Pancreatic Ductal Adenocarcinoma in Korean Patients
by Ji Hoon Park, Jung Hyun Jo, Sung Ill Jang, Moon Jae Chung, Jeong Youp Park, Seungmin Bang, Seung Woo Park, Si Young Song, Hee Seung Lee and Jae Hee Cho
Cancers 2022, 14(1), 236; https://doi.org/10.3390/cancers14010236 - 4 Jan 2022
Cited by 7 | Viewed by 2426
Abstract
We evaluated the proportion of BRCA 1/2 germline mutations in Korean patients with sporadic pancreatic ductal adenocarcinoma (PDAC) and its effect on the chemotherapeutic response of FOLFIRINOX. This retrospective study included patients who were treated at two tertiary hospitals between 2012 [...] Read more.
We evaluated the proportion of BRCA 1/2 germline mutations in Korean patients with sporadic pancreatic ductal adenocarcinoma (PDAC) and its effect on the chemotherapeutic response of FOLFIRINOX. This retrospective study included patients who were treated at two tertiary hospitals between 2012 and 2020, were pathologically confirmed to have PDAC, and had undergone targeted next-generation sequencing-based germline genetic testing. Sixty-six patients were included in the study (24 men; median age 57.5 years). In the germline test, BRCA 1/2 pathogenic mutations were found in nine patients (9/66, 13%, BRCA 1, n = 3; BRCA 2, n = 5; and BRCA 1/2, n = 1). There was no significant difference in the baseline characteristics according to BRCA mutation positivity. Among patients who underwent FOLFIRINOX chemotherapy, patients with a BRCA 1/2 mutation showed a higher overall response rate than those without a BRCA 1/2 mutation (71.4% vs. 13.9%, p = 0.004). Patients with a germline BRCA 1/2 mutation showed longer progression-free survival than those without a BRCA 1/2 mutation, without a significant time difference (18 months vs. 10 months, p = 0.297). Patients with a BRCA 1/2 mutation in the germline blood test had a higher response rate to FOLFIRINOX chemotherapy in PDAC. The high proportion of BRCA 1/2 germline mutations and response rate supports the need for germline testing in order to predict better treatment response. Full article
(This article belongs to the Special Issue Inside Cancer Genomics: From Structure to Therapy)
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13 pages, 2316 KiB  
Article
A Transgenic Model Reveals the Role of Klotho in Pancreatic Cancer Development and Paves the Way for New Klotho-Based Therapy
by Tammi Arbel Rubinstein, Inbal Reuveni, Arkadi Hesin, Anat Klein-Goldberg, Hannes Olauson, Tobias E. Larsson, Carmela R. Abraham, Ella Zeldich, Assumpció Bosch, Miguel Chillón, Kenneth Samuel Hollander, Ayelet Shabtay-Orbach, Gilad W. Vainer, Ido Wolf and Tami Rubinek
Cancers 2021, 13(24), 6297; https://doi.org/10.3390/cancers13246297 - 15 Dec 2021
Cited by 10 | Viewed by 3068
Abstract
Klotho is an anti-aging transmembrane protein, which can be shed and can function as a hormone. Accumulating data indicate that klotho is a tumor suppressor in a wide array of malignancies, and designate the subdomain KL1 as the active region of the protein [...] Read more.
Klotho is an anti-aging transmembrane protein, which can be shed and can function as a hormone. Accumulating data indicate that klotho is a tumor suppressor in a wide array of malignancies, and designate the subdomain KL1 as the active region of the protein towards this activity. We aimed to study the role of klotho as a tumor suppressor in pancreatic ductal adenocarcinoma (PDAC). Bioinformatics analyses of The Cancer Genome Atlas (TCGA) datasets revealed a correlation between the survival of PDAC patients, levels of klotho expression, and DNA methylation, and demonstrated a unique hypermethylation pattern of klotho in pancreatic tumors. The in vivo effects of klotho and KL1 were examined using three mouse models. Employing a novel genetic model, combining pancreatic klotho knockdown with a mutation in Kras, the lack of klotho contributed to PDAC generation and decreased mousece survival. In a xenograft model, administration of viral particles carrying sKL, a spliced klotho isoform containing the KL1 domain, inhibited pancreatic tumors. Lastly, treatment with soluble sKL prolonged survival of Pdx1-Cre; KrasG12D/+;Trp53R172H/+ (KPC) mice, a model known to recapitulate human PDAC. In conclusion, this study provides evidence that klotho is a tumor suppressor in PDAC. Furthermore, these data suggest that the levels of klotho expression and DNA methylation could have prognostic value in PDAC patients, and that administration of exogenous sKL may serve as a novel therapeutic strategy to treat PDAC. Full article
(This article belongs to the Special Issue Inside Cancer Genomics: From Structure to Therapy)
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19 pages, 2395 KiB  
Article
BC-Monitor: Towards a Routinely Accessible Circulating Tumor DNA-Based Tool for Real-Time Monitoring Breast Cancer Progression and Treatment Effectiveness
by Katalin Priskin, Sára Pólya, Lajos Pintér, Gábor Jaksa, Bernadett Csányi, Márton Zsolt Enyedi, Eszter Sági-Zsigmond, Farkas Sükösd, Orsolya Oláh-Németh, Gyöngyi Kelemen, Alíz Nikolényi, Gabriella Uhercsák, Dóra Sántha, Ágnes Dobi, Éva Szilágyi, Erzsébet Valicsek, László Tordai, Rozália Tóth, Zsuzsanna Kahán and Lajos Haracska
Cancers 2021, 13(14), 3489; https://doi.org/10.3390/cancers13143489 - 12 Jul 2021
Cited by 3 | Viewed by 2591
Abstract
Circulating tumor DNA (ctDNA) is increasingly employed in the screening, follow-up, and monitoring of the continuously evolving tumor; however, most ctDNA assays validated for clinical use cannot maintain the right balance between sensitivity, coverage, sample requirements, time, and cost. Here, we report our [...] Read more.
Circulating tumor DNA (ctDNA) is increasingly employed in the screening, follow-up, and monitoring of the continuously evolving tumor; however, most ctDNA assays validated for clinical use cannot maintain the right balance between sensitivity, coverage, sample requirements, time, and cost. Here, we report our BC-monitor, a simple, well-balanced ctDNA diagnostic approach using a gene panel significant in breast cancer and an optimized multiplex PCR-based NGS protocol capable of identifying allele variant frequencies below 1% in cell-free plasma DNA. We monitored a cohort of 45 breast cancer patients prospectively enrolled into our study receiving neoadjuvant chemotherapy or endocrine therapy or palliative therapy for metastatic diseases. Their tumor mutation status was examined in the archived tumor samples and plasma samples collected before and continuously during therapy. Traceable mutations of the used 38-plex NGS assay were found in approximately two-thirds of the patients. Importantly, we detected new pathogenic variants in follow-up plasma samples that were not detected in the primary tumor and baseline plasma samples. We proved that the BC-monitor can pre-indicate disease progression four–six months earlier than conventional methods. Our study highlights the need for well-designed ctDNA monitoring during treatment and follow-up, integrated into a real-time treatment assessment, which could provide information on the active tumor DNA released into the blood. Full article
(This article belongs to the Special Issue Inside Cancer Genomics: From Structure to Therapy)
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16 pages, 1422 KiB  
Article
Prognostic Significance of BIRC5/Survivin in Breast Cancer: Results from Three Independent Cohorts
by Nina Oparina, Malin C. Erlandsson, Anna Fäldt Beding, Toshima Parris, Khalil Helou, Per Karlsson, Zakaria Einbeigi and Maria I. Bokarewa
Cancers 2021, 13(9), 2209; https://doi.org/10.3390/cancers13092209 - 4 May 2021
Cited by 27 | Viewed by 3121
Abstract
Breast cancer (BC) histological and molecular classifications significantly improved the treatment strategy and prognosis. Inhibitor of apoptosis BIRC5/survivin is often overexpressed in cancers, however, indications of its importance in BC are inconsistent. We integrate BIRC5 protein and mRNA measures with clinical associates and [...] Read more.
Breast cancer (BC) histological and molecular classifications significantly improved the treatment strategy and prognosis. Inhibitor of apoptosis BIRC5/survivin is often overexpressed in cancers, however, indications of its importance in BC are inconsistent. We integrate BIRC5 protein and mRNA measures with clinical associates and long-term outcome in three independent cohorts Protein levels of BIRC5 were measured in primary lysates of 845 patients of the West Swedish BC cohort (VGR-BC) and linked to 5- and 27-years survival. The results were externally validated in transcriptomic data from METABRIC and SCAN-B cohorts. Survival analysis showed that high levels of BIRC5 were consistently associated with a poor probability of 5-year overall survival. High BIRC5 in VGR-BC contributed negatively to the disease-specific survival at 5 and 27 years. Subsets with different status by ER (estrogen receptor) expression and presence of nodal metastasis supported independent association of high BIRC5 with poor prognosis in all cohorts. In METABRIC and SCAN-B cohorts, high levels of BIRC5 mRNA were associated with the basal-like and luminal B molecular BC subtypes and with increasing histologic grade. BIRC5 is a sensitive survival marker that acts independent of ER and nodal status, and its levels need to be considered when making treatment decisions. Full article
(This article belongs to the Special Issue Inside Cancer Genomics: From Structure to Therapy)
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34 pages, 6017 KiB  
Article
Aberrations of Chromosomes 1 and 16 in Breast Cancer: A Framework for Cooperation of Transcriptionally Dysregulated Genes
by Anna Provvidenza Privitera, Vincenza Barresi and Daniele Filippo Condorelli
Cancers 2021, 13(7), 1585; https://doi.org/10.3390/cancers13071585 - 30 Mar 2021
Cited by 9 | Viewed by 4183
Abstract
Derivative chromosome der(1;16), isochromosome 1q, and deleted 16q—producing arm-level 1q-gain and/or 16q-loss—are recurrent cytogenetic abnormalities in breast cancer, but their exact role in determining the malignant phenotype is still largely unknown. We exploited The Cancer Genome Atlas (TCGA) data to generate and analyze [...] Read more.
Derivative chromosome der(1;16), isochromosome 1q, and deleted 16q—producing arm-level 1q-gain and/or 16q-loss—are recurrent cytogenetic abnormalities in breast cancer, but their exact role in determining the malignant phenotype is still largely unknown. We exploited The Cancer Genome Atlas (TCGA) data to generate and analyze groups of breast invasive carcinomas, called 1,16-chromogroups, that are characterized by a pattern of arm-level somatic copy number aberrations congruent with known cytogenetic aberrations of chromosome 1 and 16. Substantial differences were found among 1,16-chromogroups in terms of other chromosomal aberrations, aneuploidy scores, transcriptomic data, single-point mutations, histotypes, and molecular subtypes. Breast cancers with a co-occurrence of 1q-gain and 16q-loss can be distinguished in a “low aneuploidy score” group, congruent to der(1;16), and a “high aneuploidy score” group, congruent to the co-occurrence of isochromosome 1q and deleted 16q. Another three groups are formed by cancers showing separately 1q-gain or 16q-loss or no aberrations of 1q and 16q. Transcriptome comparisons among the 1,16-chromogroups, integrated with functional pathway analysis, suggested the cooperation of overexpressed 1q genes and underexpressed 16q genes in the genesis of both ductal and lobular carcinomas, thus highlighting the putative role of genes encoding gamma-secretase subunits (APH1A, PSEN2, and NCSTN) and Wnt enhanceosome components (BCL9 and PYGO2) in 1q, and the glycoprotein E-cadherin (CDH1), the E3 ubiquitin-protein ligase WWP2, the deubiquitinating enzyme CYLD, and the transcription factor CBFB in 16q. The analysis of 1,16-chromogroups is a strategy with far-reaching implications for the selection of cancer cell models and novel experimental therapies. Full article
(This article belongs to the Special Issue Inside Cancer Genomics: From Structure to Therapy)
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17 pages, 1076 KiB  
Article
Detection of Rare Germline Variants in the Genomes of Patients with B-Cell Neoplasms
by Adrián Mosquera Orgueira, Miguel Cid López, Andrés Peleteiro Raíndo, José Ángel Díaz Arias, Beatriz Antelo Rodríguez, Laura Bao Pérez, Natalia Alonso Vence, Ángeles Bendaña López, Aitor Abuin Blanco, Paula Melero Valentín, Roi Ferreiro Ferro, Carlos Aliste Santos, Máximo Francisco Fraga Rodríguez, Marta Sonia González Pérez, Manuel Mateo Pérez Encinas and José Luis Bello López
Cancers 2021, 13(6), 1340; https://doi.org/10.3390/cancers13061340 - 16 Mar 2021
Cited by 11 | Viewed by 3069
Abstract
There is growing evidence indicating the implication of germline variation in cancer predisposition and prognostication. Here, we describe an analysis of likely disruptive rare variants across the genomes of 726 patients with B-cell lymphoid neoplasms. We discovered a significant enrichment for two genes [...] Read more.
There is growing evidence indicating the implication of germline variation in cancer predisposition and prognostication. Here, we describe an analysis of likely disruptive rare variants across the genomes of 726 patients with B-cell lymphoid neoplasms. We discovered a significant enrichment for two genes in rare dysfunctional variants, both of which participate in the regulation of oxidative stress pathways (CHMP6 and GSTA4). Additionally, we detected 1675 likely disrupting variants in genes associated with cancer, of which 44.75% were novel events and 7.88% were protein-truncating variants. Among these, the most frequently affected genes were ATM, BIRC6, CLTCL1A, and TSC2. Homozygous or germline double-hit variants were detected in 28 cases, and coexisting somatic events were observed in 17 patients, some of which affected key lymphoma drivers such as ATM, KMT2D, and MYC. Finally, we observed that variants in six different genes were independently associated with shorter survival in CLL. Our study results support an important role for rare germline variation in the pathogenesis and prognosis of B-cell lymphoid neoplasms. Full article
(This article belongs to the Special Issue Inside Cancer Genomics: From Structure to Therapy)
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Review

Jump to: Editorial, Research

20 pages, 2025 KiB  
Review
The Clinical and Molecular Features in the VHL Renal Cancers; Close or Distant Relatives with Sporadic Clear Cell Renal Cell Carcinoma?
by Alessandra Cinque, Roberto Minnei, Matteo Floris and Francesco Trevisani
Cancers 2022, 14(21), 5352; https://doi.org/10.3390/cancers14215352 - 30 Oct 2022
Cited by 2 | Viewed by 4659
Abstract
Von Hippel-Lindau (VHL) disease is an autosomal dominant inherited cancer syndrome caused by germline mutations in the VHL tumor suppressor gene, characterized by the susceptibility to a wide array of benign and malign neoplasms, including clear-cell renal cell carcinoma. Moreover, VHL somatic inactivation [...] Read more.
Von Hippel-Lindau (VHL) disease is an autosomal dominant inherited cancer syndrome caused by germline mutations in the VHL tumor suppressor gene, characterized by the susceptibility to a wide array of benign and malign neoplasms, including clear-cell renal cell carcinoma. Moreover, VHL somatic inactivation is a crucial molecular event also in sporadic ccRCCs tumorigenesis. While systemic biomarkers in the VHL syndrome do not currently play a role in clinical practice, a new promising class of predictive biomarkers, microRNAs, has been increasingly studied. Lots of pan-genomic studies have deeply investigated the possible biological role of microRNAs in the development and progression of sporadic ccRCC; however, few studies have investigated the miRNA profile in VHL patients. Our review summarize all the new insights related to clinical and molecular features in VHL renal cancers, with a particular focus on the overlap with sporadic ccRCC. Full article
(This article belongs to the Special Issue Inside Cancer Genomics: From Structure to Therapy)
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24 pages, 2481 KiB  
Review
Methyladenosine Modification in RNAs: From Regulatory Roles to Therapeutic Implications in Cancer
by Xiaolin Qu, Yongqiu Zhang, Xianzheng Sang, Ding Ren, Hong Zhao and Stephen T. C. Wong
Cancers 2022, 14(13), 3195; https://doi.org/10.3390/cancers14133195 - 29 Jun 2022
Cited by 8 | Viewed by 2898
Abstract
Methyladenosine modifications are the most abundant RNA modifications, including N6-methyladenosine (m6A), N1-methyladenosine (m1A), and 2’-O-methyladenosine (m6Am). As reversible epigenetic modifications, methyladenosine modifications in eukaryotic RNAs are not invariable. Drastic alterations of m6A are [...] Read more.
Methyladenosine modifications are the most abundant RNA modifications, including N6-methyladenosine (m6A), N1-methyladenosine (m1A), and 2’-O-methyladenosine (m6Am). As reversible epigenetic modifications, methyladenosine modifications in eukaryotic RNAs are not invariable. Drastic alterations of m6A are found in a variety of diseases, including cancers. Dynamic changes of m6A modification induced by abnormal methyltransferase, demethylases, and readers can regulate cancer progression via interfering with the splicing, localization, translation, and stability of mRNAs. Meanwhile, m6A, m1A, and m6Am modifications also exert regulatory effects on noncoding RNAs in cancer progression. In this paper, we reviewed recent findings concerning the underlying biomechanism of methyladenosine modifications in oncogenesis and metastasis and discussed the therapeutic potential of methyladenosine modifications in cancer treatments. Full article
(This article belongs to the Special Issue Inside Cancer Genomics: From Structure to Therapy)
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25 pages, 1882 KiB  
Review
A Review of the Current Impact of Inhibitors of Apoptosis Proteins and Their Repression in Cancer
by Pierina Cetraro, Julio Plaza-Diaz, Alex MacKenzie and Francisco Abadía-Molina
Cancers 2022, 14(7), 1671; https://doi.org/10.3390/cancers14071671 - 25 Mar 2022
Cited by 34 | Viewed by 4055
Abstract
The Inhibitor of Apoptosis (IAP) family possesses the ability to inhibit programmed cell death through different mechanisms; additionally, some of its members have emerged as important regulators of the immune response. Both direct and indirect activity on caspases or the modulation of survival [...] Read more.
The Inhibitor of Apoptosis (IAP) family possesses the ability to inhibit programmed cell death through different mechanisms; additionally, some of its members have emerged as important regulators of the immune response. Both direct and indirect activity on caspases or the modulation of survival pathways, such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), have been implicated in mediating its effects. As a result, abnormal expression of inhibitor apoptosis proteins (IAPs) can lead to dysregulated apoptosis promoting the development of different pathologies. In several cancer types IAPs are overexpressed, while their natural antagonist, the second mitochondrial-derived activator of caspases (Smac), appears to be downregulated, potentially contributing to the acquisition of resistance to traditional therapy. Recently developed Smac mimetics counteract IAP activity and show promise in the re-sensitization to apoptosis in cancer cells. Given the modest impact of Smac mimetics when used as a monotherapy, pairing of these compounds with other treatment modalities is increasingly being explored. Modulation of molecules such as tumor necrosis factor-α (TNF-α) present in the tumor microenvironment have been suggested to contribute to putative therapeutic efficacy of IAP inhibition, although published results do not show this consistently underlining the complex interaction between IAPs and cancer. Full article
(This article belongs to the Special Issue Inside Cancer Genomics: From Structure to Therapy)
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