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Special Issue "Molecular Advances in Cancer Genetics"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: 15 January 2022.

Special Issue Editors

Prof. Dr. Paola Ghiorzo
E-Mail Website1 Website2
Guest Editor
Genetics of Rare Cancers, Department of Internal Medicine and Medical Specialties, University of Genoa, 16132 Genoa, Italy
Interests: cancer genetics and genomics; molecular genetics; functional analysis; melanoma; pancreatic cancer; cancerogenesis; gene regulation; regulatory variants; hereditary cancers; somatic mutations
Special Issues and Collections in MDPI journals
Prof. Dr. William Bruno
E-Mail Website
Guest Editor
Genetics of Rare Cancers, Department of Internal Medicine and Medical Specialties, University of Genoa, 16132 Genova, Italy
Interests: rare cancers; hereditary cancers; genetic testing; molecular genetics; tumor heterogeneity; gene expression; functional genomics; genomic variations
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

Recent advances in methodological approaches to the study of cancer genetics and genomics, which have resulted in increased detection of pathogenic variants and variants of unknown significance (VUS), have led to a paradigm shift in cancer susceptibility testing and revealed a  substantial number of germline variants across a range of tumors, with a combination of germline testing and tumor mutation assessment helping to discern the clinical relevance of VUS and guide therapeutic implications.  Therefore, hereditary predisposition and translation cancer genomics focused on therapeutic implications, previously considered separate, now meet and provide us with the opportunity to extend our identification of actionable germline and somatic variants in hereditary, rare, and common cancers, but also to improve our understanding of the genetic and molecular bases of cancer.

In this Special Issue, we welcome reviews, original research articles, and short communications that focus on or are relevant to the evolution of methodological approaches to the study of cancer genetics and genomics, the molecular bases of cancer, hereditary cancer syndromes, tumor mutational assessment and interpretation of genomic variants, or potential therapeutic implications of hereditary predisposition.

Prof. Dr. Paola Ghiorzo
Prof. Dr. William Bruno
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 papers will be 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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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 genetics;
  • molecular mechanisms;
  • genetics of hereditary and rare cancers;
  • evolution of methodological approaches to the study of cancer genetics and genomics;
  • variant interpretation;
  • actionability of genomic findings in cancer;
  • somatic mutation testing.

Published Papers (8 papers)

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Research

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Article
Comprehensive Genomic and Transcriptomic Analysis of Three Synchronous Primary Tumours and a Recurrence from a Head and Neck Cancer Patient
Int. J. Mol. Sci. 2021, 22(14), 7583; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147583 - 15 Jul 2021
Viewed by 605
Abstract
Synchronous primary malignancies occur in a small proportion of head and neck squamous cell carcinoma (HNSCC) patients. Here, we analysed three synchronous primaries and a recurrence from one patient by comparing the genomic and transcriptomic profiles among the tumour samples and determining the [...] Read more.
Synchronous primary malignancies occur in a small proportion of head and neck squamous cell carcinoma (HNSCC) patients. Here, we analysed three synchronous primaries and a recurrence from one patient by comparing the genomic and transcriptomic profiles among the tumour samples and determining the recurrence origin. We found remarkable levels of heterogeneity among the primary tumours, and through the patterns of shared mutations, we traced the origin of the recurrence. Interestingly, the patient carried germline variants that might have predisposed him to carcinogenesis, together with a history of alcohol and tobacco consumption. The mutational signature analysis confirmed the impact of alcohol exposure, with Signature 16 present in all tumour samples. Characterisation of immune cell infiltration highlighted an immunosuppressive environment in all samples, which exceeded the potential activity of T cells. Studies such as the one described here have important clinical value and contribute to personalised treatment decisions for patients with synchronous primaries and matched recurrences. Full article
(This article belongs to the Special Issue Molecular Advances in Cancer Genetics)
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Article
Detecting Variants in the NBN Gene While Testing for Hereditary Breast Cancer: What to Do Next?
Int. J. Mol. Sci. 2021, 22(11), 5832; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115832 - 29 May 2021
Viewed by 870
Abstract
The NBN gene has been included in breast cancer (BC) multigene panels based on early studies suggesting an increased BC risk for carriers, though not confirmed by recent research. To evaluate the impact of NBN analysis, we assessed the results of NBN sequencing [...] Read more.
The NBN gene has been included in breast cancer (BC) multigene panels based on early studies suggesting an increased BC risk for carriers, though not confirmed by recent research. To evaluate the impact of NBN analysis, we assessed the results of NBN sequencing in 116 BRCA-negative BC patients and reviewed the literature. Three patients (2.6%) carried potentially relevant variants: two, apparently unrelated, carried the frameshift variant c.156_157delTT and another one the c.628G>T variant. The latter was subsequently found in 4/1390 (0.3%) BC cases and 8/1580 (0.5%) controls in an independent sample, which, together with in silico predictions, provided evidence against its pathogenicity. Conversely, the rare c.156_157delTT variant was absent in the case-control set; moreover, a 50% reduction of NBN expression was demonstrated in one carrier. However, in one family it failed to co-segregate with BC, while the other carrier was found to harbor also a probably pathogenic TP53 variant that may explain her phenotype. Therefore, the c.156_157delTT, although functionally deleterious, was not supported as a cancer-predisposing defect. Pathogenic/likely pathogenic NBN variants were detected by multigene panels in 31/12314 (0.25%) patients included in 15 studies. The risk of misinterpretation of such findings is substantial and supports the exclusion of NBN from multigene panels. Full article
(This article belongs to the Special Issue Molecular Advances in Cancer Genetics)
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Article
The GNAQ T96S Mutation Affects Cell Signaling and Enhances the Oncogenic Properties of Hepatocellular Carcinoma
Int. J. Mol. Sci. 2021, 22(6), 3284; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22063284 - 23 Mar 2021
Viewed by 842
Abstract
Hepatocellular carcinoma (HCC), the most common malignant tumor in the liver, grows and metastasizes rapidly. Despite advances in treatment modalities, the five-year survival rate of HCC remains less than 30%. We sought genetic mutations that may affect the oncogenic properties of HCC, using [...] Read more.
Hepatocellular carcinoma (HCC), the most common malignant tumor in the liver, grows and metastasizes rapidly. Despite advances in treatment modalities, the five-year survival rate of HCC remains less than 30%. We sought genetic mutations that may affect the oncogenic properties of HCC, using The Cancer Genome Atlas (TCGA) data analysis. We found that the GNAQ T96S mutation (threonine 96 to serine alteration of the Gαq protein) was present in 12 out of 373 HCC patients (3.2%). To examine the effect of the GNAQ T96S mutation on HCC, we transfected the SK-Hep-1 cell line with the wild-type or the mutant GNAQ T96S expression vector. Transfection with the wild-type GNAQ expression vector enhanced anchorage-independent growth, migration, and the MAPK pathways in the SK-Hep-1 cells compared to control vector transfection. Moreover, cell proliferation, anchorage-independent growth, migration, and the MAPK pathways were further enhanced in the SK-Hep-1 cells transfected with the GNAQ T96S expression vector compared to the wild-type GNAQ-transfected cells. In silico structural analysis shows that the substitution of the GNAQ amino acid threonine 96 with a serine may destabilize the interaction between the regulator of G protein signaling (RGS) protein and GNAQ. This may reduce the inhibitory effect of RGS on GNAQ signaling, enhancing the GNAQ signaling pathway. Single nucleotide polymorphism (SNP) genotyping analysis for Korean HCC patients shows that the GNAQ T96S mutation was found in only one of the 456 patients (0.22%). Our data suggest that the GNAQ T96S hotspot mutation may play an oncogenic role in HCC by potentiating the GNAQ signal transduction pathway. Full article
(This article belongs to the Special Issue Molecular Advances in Cancer Genetics)
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Article
BRCA Methylation Testing Identifies a Subset of Ovarian Carcinomas without Germline Variants That Can Benefit from PARP Inhibitor
Int. J. Mol. Sci. 2020, 21(24), 9708; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21249708 - 19 Dec 2020
Cited by 2 | Viewed by 735
Abstract
Homologous Recombination Deficiency (HRD) is a frequent feature of high-grade epithelial ovarian carcinoma (EOC), associated with sensitivity to PARP-inhibitors (PARPi). The best characterized causes of HRD in EOCs are germline or somatic mutations in BRCA1 and BRCA2 genes. Although promoter methylation is a [...] Read more.
Homologous Recombination Deficiency (HRD) is a frequent feature of high-grade epithelial ovarian carcinoma (EOC), associated with sensitivity to PARP-inhibitors (PARPi). The best characterized causes of HRD in EOCs are germline or somatic mutations in BRCA1 and BRCA2 genes. Although promoter methylation is a well-known mechanism of gene transcriptional repression, few data have been published about BRCA gene methylation in EOCs. In this retrospective study, we quantitatively analyzed by pyrosequencing a selected series of 90 formalin-fixed (FFPE) primary EOCs without BRCA germline mutations. We identified 20/88 (22.7%) EOCs showing BRCA promoter methylation, including 17/88 (19.3%) in BRCA1 and 4/86 (4.6%) in BRCA2 promoters, one of which showing concomitant BRCA1 methylation. Mean methylation levels were 49.6% and 45.8% for BRCA1 and BRCA2, respectively, with methylation levels ≥50% in 10/20 methylated EOCs. Constitutive BRCA methylation was excluded by testing blood-derived DNA. In conclusion, pyrosequencing methylation analysis of BRCA genes is a robust, quantitative and sensitive assay applicable to FFPE samples. Remarkably, a considerable subset of germline BRCA-negative EOCs showed somatic methylation and, likely, HRD. A subpopulation of women with BRCA methylation, even without BRCA mutations, could potentially benefit from PARP-inhibitors; further clinical studies are needed to clarify the predictive role of somatic BRCA methylation of PARP-therapy response. Full article
(This article belongs to the Special Issue Molecular Advances in Cancer Genetics)
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Article
Genomic Analysis of Hematopoietic Stem Cell at the Single-Cell Level: Optimization of Cell Fixation and Whole Genome Amplification (WGA) Protocol
Int. J. Mol. Sci. 2020, 21(19), 7366; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197366 - 06 Oct 2020
Cited by 1 | Viewed by 1032
Abstract
Single-cell genomics has become the method of choice for the study of heterogeneous cell populations and represents an elective application in defining the architecture and clonal evolution in hematological neoplasms. Reconstructing the clonal evolution of a neoplastic population therefore represents the main way [...] Read more.
Single-cell genomics has become the method of choice for the study of heterogeneous cell populations and represents an elective application in defining the architecture and clonal evolution in hematological neoplasms. Reconstructing the clonal evolution of a neoplastic population therefore represents the main way to understand more deeply the pathogenesis of the neoplasm, but it is also a potential tool to understand the evolution of the tumor population with respect to its response to therapy. Pre-analytical phase for single-cell genomics analysis is crucial to obtain a cell population suitable for single-cell sorting, and whole genome amplification is required to obtain the necessary amount of DNA from a single cell in order to proceed with sequencing. Here, we evaluated the impact of different methods of cellular immunostaining, fixation and whole genome amplification on the efficiency and yield of single-cell sequencing. Full article
(This article belongs to the Special Issue Molecular Advances in Cancer Genetics)
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Review

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Review
Insights into Mechanisms of Tumorigenesis in Neuroendocrine Neoplasms
Int. J. Mol. Sci. 2021, 22(19), 10328; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221910328 - 25 Sep 2021
Viewed by 432
Abstract
Genomic studies have identified some of the most relevant genetic players in Neuroendocrine Neoplasm (NEN) tumorigenesis. However, we are still far from being able to draw a model that encompasses their heterogeneity, elucidates the different biological effects consequent to the identified molecular events, [...] Read more.
Genomic studies have identified some of the most relevant genetic players in Neuroendocrine Neoplasm (NEN) tumorigenesis. However, we are still far from being able to draw a model that encompasses their heterogeneity, elucidates the different biological effects consequent to the identified molecular events, or incorporates extensive knowledge of molecular biomarkers and therapeutic targets. Here, we reviewed recent insights in NEN tumorigenesis from selected basic research studies on animal models, highlighting novel players in the intergenic cooperation and peculiar mechanisms including splicing dysregulation, chromatin stability, or cell dedifferentiation. Furthermore, models of tumorigenesis based on composite interactions other than a linear progression of events are proposed, exemplified by the involvement in NEN tumorigenesis of genes regulating complex functions, such as MEN1 or DAXX. Although limited by interspecies differences, animal models have proved helpful for the more in-depth study of every facet of tumorigenesis, showing that the identification of driver mutations is only one of the many necessary steps and that other mechanisms are worth investigating. Full article
(This article belongs to the Special Issue Molecular Advances in Cancer Genetics)
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Review
Multi-Gene Testing Overview with a Clinical Perspective in Metastatic Triple-Negative Breast Cancer
Int. J. Mol. Sci. 2021, 22(13), 7154; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22137154 - 01 Jul 2021
Viewed by 1405
Abstract
Next-generation sequencing (NGS) is the technology of choice for the routine screening of tumor samples in clinical practice. In this setting, the targeted sequencing of a restricted number of clinically relevant genes represents the most practical option when looking for genetic variants associated [...] Read more.
Next-generation sequencing (NGS) is the technology of choice for the routine screening of tumor samples in clinical practice. In this setting, the targeted sequencing of a restricted number of clinically relevant genes represents the most practical option when looking for genetic variants associated with cancer, as well as for the choice of targeted treatments. In this review, we analyze available NGS platforms and clinical applications of multi-gene testing in breast cancer, with a focus on metastatic triple-negative breast cancer (mTNBC). We make an overview of the clinical utility of multi-gene testing in mTNBC, and then, as immunotherapy is emerging as a possible targeted therapy for mTNBC, we also briefly report on the results of the latest clinical trials involving immune checkpoint inhibitors (ICIs) and TNBC, where NGS could play a role for the potential predictive utility of homologous recombination repair deficiency (HRD) and tumor mutational burden (TMB). Full article
(This article belongs to the Special Issue Molecular Advances in Cancer Genetics)
Review
Genetic Markers in Lung Cancer Diagnosis: A Review
Int. J. Mol. Sci. 2020, 21(13), 4569; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134569 - 27 Jun 2020
Cited by 15 | Viewed by 3550
Abstract
Lung cancer is the most often diagnosed cancer in the world and the most frequent cause of cancer death. The prognosis for lung cancer is relatively poor and 75% of patients are diagnosed at its advanced stage. The currently used diagnostic tools are [...] Read more.
Lung cancer is the most often diagnosed cancer in the world and the most frequent cause of cancer death. The prognosis for lung cancer is relatively poor and 75% of patients are diagnosed at its advanced stage. The currently used diagnostic tools are not sensitive enough and do not enable diagnosis at the early stage of the disease. Therefore, searching for new methods of early and accurate diagnosis of lung cancer is crucial for its effective treatment. Lung cancer is the result of multistage carcinogenesis with gradually increasing genetic and epigenetic changes. Screening for the characteristic genetic markers could enable the diagnosis of lung cancer at its early stage. The aim of this review was the summarization of both the preclinical and clinical approaches in the genetic diagnostics of lung cancer. The advancement of molecular strategies and analytic platforms makes it possible to analyze the genome changes leading to cancer development—i.e., the potential biomarkers of lung cancer. In the reviewed studies, the diagnostic values of microsatellite changes, DNA hypermethylation, and p53 and KRAS gene mutations, as well as microRNAs expression, have been analyzed as potential genetic markers. It seems that microRNAs and their expression profiles have the greatest diagnostic potential value in lung cancer diagnosis, but their quantification requires standardization. Full article
(This article belongs to the Special Issue Molecular Advances in Cancer Genetics)
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