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Molecular Advances in Cancer Genetics 2.0

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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: closed (31 October 2022) | Viewed by 31201

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Prof. Dr. Paola Ghiorzo

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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, Collections and Topics in MDPI journals

Dr. William Bruno

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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, Collections and Topics 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 second version of the Topical Collection, 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
Dr. William Bruno
Guest Editors

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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

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Published Papers (10 papers)

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Research

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17 pages, 4751 KiB

Open AccessArticle

Effect of LDHA Inhibition on TNF-α-Induced Cell Migration in Esophageal Cancers

by Agata Forkasiewicz, Wojciech Stach, Jaroslaw Wierzbicki, Kamilla Stach, Renata Tabola, Anita Hryniewicz-Jankowska and Katarzyna Augoff

Int. J. Mol. Sci. 2022, 23(24), 16062; https://doi.org/10.3390/ijms232416062 - 16 Dec 2022

Cited by 9 | Viewed by 2386

Abstract

Cell migration is an essential part of the complex and multistep process that is the development of cancer, a disease that is the second most common cause of death in humans. An important factor promoting the migration of cancer cells is TNF-α, a pro-inflammatory cytokine that, among its many biological functions, also plays a major role in mediating the expression of MMP9, one of the key regulators of cancer cell migration. It is also known that TNF-α is able to induce the Warburg effect in some cells by increasing glucose uptake and enhancing the expression and activity of lactate dehydrogenase subunit A (LDHA). Therefore, the aim of the present study was to investigate the interrelationship between the TNF-α-induced promigratory activity of cancer cells and their glucose metabolism status, using esophageal cancer cells as an example. By inhibiting LDHA activity with sodium oxamate (SO, also known as aminooxoacetic acid sodium salt or oxamic acid sodium salt) or siRNA-mediated gene silencing, we found using wound healing assay and gelatin zymography that LDHA downregulation impairs TNF-α-dependent tumor cell migration and significantly reduces TNF-α-induced MMP9 expression. These effects were associated with disturbances in the activation of the ERK1/2 signaling pathway, as we observed by Western blotting. We also reveal that in esophageal cancer cells, SO effectively reduces the production of lactic acid, which, as we have shown, synergizes the stimulating effect of TNF-α on MMP9 expression. In conclusion, our findings identified LDHA as a regulator of TNF-α-induced cell migration in esophageal cancer cells by the ERK1/2 signaling pathway, suggesting that LDHA inhibitors that limit the migration of cancer cells caused by the inflammatory process may be considered as an adjunct to standard therapy in esophageal cancer patients. Full article

(This article belongs to the Special Issue Molecular Advances in Cancer Genetics 2.0)

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13 pages, 6188 KiB

Open AccessArticle

Ataxia-Telangiectasia Mutated Loss of Heterozygosity in Melanoma

by Lorenza Pastorino, Bruna Dalmasso, Eleonora Allavena, Irene Vanni, Filippo Ugolini, Gianna Baroni, Michela Croce, Antonio Guadagno, Francesco Cabiddu, Virginia Andreotti, William Bruno, Gabriele Zoppoli, Lorenzo Ferrando, Enrica Teresa Tanda, Francesco Spagnolo, Chiara Menin, Rosaria Gangemi, Daniela Massi and Paola Ghiorzo

Int. J. Mol. Sci. 2022, 23(24), 16027; https://doi.org/10.3390/ijms232416027 - 16 Dec 2022

Cited by 4 | Viewed by 1864

Abstract

ATM germline pathogenic variants were recently found enriched in high-risk melanoma patients. However, ATM loss of heterozygosity (LOH) has never been investigated in melanoma and, therefore, a causal association with melanoma development has not been established yet. The purpose of this study was to functionally characterize 13 germline ATM variants found in high-risk melanoma patients—and classified by in silico tools as pathogenic, uncertain significance, or benign—using multiple assays evaluating ATM/pATM expression and/or LOH in melanoma tissues and cell lines. We assessed ATM status by Immunohistochemistry (IHC), Western Blot, Whole-Exome Sequencing/Copy Number Variation analysis, and RNA sequencing, supported by Sanger sequencing and microsatellite analyses. For most variants, IHC results matched those obtained with in silico classification and LOH analysis. Two pathogenic variants (p.Ser1135_Lys1192del and p.Ser1993ArgfsTer23) showed LOH and complete loss of ATM activation in melanoma. Two variants of unknown significance (p.Asn358Ile and p.Asn796His) showed reduced expression and LOH, suggestive of a deleterious effect. This study, showing a classic two-hit scenario in a well-known tumor suppressor gene, supports the inclusion of melanoma in the ATM-related cancer spectrum. Full article

(This article belongs to the Special Issue Molecular Advances in Cancer Genetics 2.0)

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23 pages, 38063 KiB

Open AccessArticle

Upregulated Apelin Signaling in Pancreatic Cancer Activates Oncogenic Signaling Pathways to Promote Tumor Development

by Carline Chaves-Almagro, Johanna Auriau, Alizée Dortignac, Pascal Clerc, Hubert Lulka, Simon Deleruyelle, Fabrice Projetti, Jessica Nakhlé, Audrey Frances, Judit Berta, Véronique Gigoux, Daniel Fourmy, Marlène Dufresne, Anne Gomez-Brouchet, Julie Guillermet-Guibert, Pierre Cordelier, Bernard Knibiehler, Ralf Jockers, Philippe Valet, Yves Audigier and Bernard Masri Show full author list Hide full author list

Int. J. Mol. Sci. 2022, 23(18), 10600; https://doi.org/10.3390/ijms231810600 - 13 Sep 2022

Cited by 8 | Viewed by 2628

Abstract

Despite decades of effort in understanding pancreatic ductal adenocarcinoma (PDAC), there is still a lack of innovative targeted therapies for this devastating disease. Herein, we report the expression of apelin and its receptor, APJ, in human pancreatic adenocarcinoma and its protumoral function. Apelin and APJ protein expression in tumor tissues from patients with PDAC and their spatiotemporal pattern of expression in engineered mouse models of PDAC were investigated by immunohistochemistry. Apelin signaling function in tumor cells was characterized in pancreatic tumor cell lines by Western blot as well as proliferation, migration assays and in murine orthotopic xenograft experiments. In premalignant lesions, apelin was expressed in epithelial lesions whereas APJ was found in isolated cells tightly attached to premalignant lesions. However, in the invasive stage, apelin and APJ were co-expressed by tumor cells. In human tumor cells, apelin induced a long-lasting activation of PI3K/Akt, upregulated β-catenin and the oncogenes c-myc and cyclin D1 and promoted proliferation, migration and glucose uptake. Apelin receptor blockades reduced cancer cell proliferation along with a reduction in pancreatic tumor burden. These findings identify the apelin signaling pathway as a new actor for PDAC development and a novel therapeutic target for this incurable disease. Full article

(This article belongs to the Special Issue Molecular Advances in Cancer Genetics 2.0)

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Review

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15 pages, 2478 KiB

Open AccessReview

HER2 Amplification Level Predicts Pathological Complete Response in the Neoadjuvant Setting of HER2-Overexpressing Breast Cancer: A Meta-Analysis and Systematic Review

by Burak Gonullu, Eurydice Angeli, Frédéric Pamoukdjian and Guilhem Bousquet

Int. J. Mol. Sci. 2023, 24(4), 3590; https://doi.org/10.3390/ijms24043590 - 10 Feb 2023

Cited by 4 | Viewed by 2344

Abstract

Anti-HER2 therapies have dramatically improved the prognosis of human epidermal growth factor receptor 2 (HER2)-overexpressing cancers. However, the correlation between the HER2 copy number and the response rate to anti-HER2 remains unclear. Here, following the PRISMA method, we performed a meta-analysis in the neoadjuvant setting in breast cancer to study the association between the HER2 amplification level and the pathological complete response (pCR) to anti-HER2 therapies. Nine articles (four clinical trials, five observational studies) were retrieved after full-text screening, involving 11,238 women with locally advanced breast cancer in the neoadjuvant setting. The median HER2/CEP17 ratio cut-off value was 5.0 ± 5.0 (min-max = 1.0–14.0). For the overall population, the median pCR rate was 48% using the random effect model. The studies were categorized in quartiles as follows: ≤2 (Class 1); 2.1 to 5.0 (Class 2); 5.1 to 7.0 (Class 3); and >7.0 (Class 4). After grouping, the pCR rates were 33%, 49%, 57%, and 79%, respectively. When we excluded the study by Greenwell et al., which accounted for 90% of the patients, using the same quartiles, we still observed an increasing rate of pCR as the HER2/CEP17 ratio increased. This is the first meta-analysis demonstrating the relationship between the HER2 amplification level and the percentage of pCR in the neoadjuvant setting among women with HER2-overexpressing breast cancer, with potential therapeutic applications. Full article

(This article belongs to the Special Issue Molecular Advances in Cancer Genetics 2.0)

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19 pages, 685 KiB

Open AccessReview

Genomics and Epigenomics in the Molecular Biology of Melanoma—A Prerequisite for Biomarkers Studies

by Daniela Luminita Zob, Iolanda Augustin, Lavinia Caba, Monica-Cristina Panzaru, Setalia Popa, Alina Delia Popa, Laura Florea and Eusebiu Vlad Gorduza

Int. J. Mol. Sci. 2023, 24(1), 716; https://doi.org/10.3390/ijms24010716 - 31 Dec 2022

Cited by 8 | Viewed by 2361

Abstract

Melanoma is a common and aggressive tumor originating from melanocytes. The increasing incidence of cutaneous melanoma in recent last decades highlights the need for predictive biomarkers studies. Melanoma development is a complex process, involving the interplay of genetic, epigenetic, and environmental factors. Genetic aberrations include BRAF, NRAS, NF1, MAP2K1/MAP2K2, KIT, GNAQ, GNA11, CDKN2A, TERT mutations, and translocations of kinases. Epigenetic alterations involve microRNAs, non-coding RNAs, histones modifications, and abnormal DNA methylations. Genetic aberrations and epigenetic marks are important as biomarkers for the diagnosis, prognosis, and prediction of disease recurrence, and for therapeutic targets. This review summarizes our current knowledge of the genomic and epigenetic changes in melanoma and discusses the latest scientific information. Full article

(This article belongs to the Special Issue Molecular Advances in Cancer Genetics 2.0)

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11 pages, 2592 KiB

Open AccessReview

Association of BRAF^V600E Mutation with the Aggressive Behavior of Papillary Thyroid Microcarcinoma: A Meta-Analysis of 33 Studies

by Abdallah S. Attia, Mohammad Hussein, Peter P. Issa, Ahmad Elnahla, Ashraf Farhoud, Brandon M. Magazine, Mohanad R. Youssef, Mohamed Aboueisha, Mohamed Shama, Eman Toraih and Emad Kandil

Int. J. Mol. Sci. 2022, 23(24), 15626; https://doi.org/10.3390/ijms232415626 - 9 Dec 2022

Cited by 20 | Viewed by 2401

Abstract

An association between the BRAF^V600E mutation and the clinicopathological progression of papillary thyroid microcarcinoma (PTMC) has been suggested. We aimed to summarize the relevant literature and determine the predictive value of BRAF^V600E mutation in predicting clinical outcomes and risk stratification in patients with PTMC. A systematic search using PubMed, Cochrane, and Embase up to February 2020 was performed. A total of 33 studies met the inclusion criteria, resulting in a pool of 8838 patients, of whom 5043 (57.1%) patients were positive for BRAF^V600E mutation. Tumors with positive BRAF^V600E mutation had a higher tendency for multifocality (RR = 1.09, 95%CI = 1.03–1.16), extrathyroidal extension (RR = 1.79, 95%CI = 1.37–2.32), and lymph node metastasis (RR = 1.43, 95%CI = 1.19–1.71). Patients with BRAF^V600E mutation were at increased risk of disease recurrence (RR = 1.90, 95%CI = 1.43–2.53). PTMC in patients positive for the BRAF^V600E mutation is more aggressive than wild-type BRAF PTMC. Since BRAF-mutated PTMC is generally more resistant to radioiodine treatment, patients with BRAF^V600E-mutated PTMC may require earlier management, such as a minimally invasive ablative intervention. Conservative management by active surveillance may be suitable for patients with wild-type BRAF^V600E PTMC. Full article

(This article belongs to the Special Issue Molecular Advances in Cancer Genetics 2.0)

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19 pages, 1346 KiB

Open AccessReview

Laser Capture Microdissection: A Gear for Pancreatic Cancer Research

by Bhavana Hemantha Rao, Pavel Souček and Viktor Hlaváč

Int. J. Mol. Sci. 2022, 23(23), 14566; https://doi.org/10.3390/ijms232314566 - 23 Nov 2022

Cited by 7 | Viewed by 3349

Abstract

The advancement in molecular techniques has been attributed to the quality and significance of cancer research. Pancreatic cancer (PC) is one of the rare cancers with aggressive behavior and a high mortality rate. The asymptomatic nature of the disease until its advanced stage has resulted in late diagnosis as well as poor prognosis. The heterogeneous character of PC has complicated cancer development and progression studies. The analysis of bulk tissues of the disease was insufficient to understand the disease, hence, the introduction of the single-cell separating technique aided researchers to decipher more about the specific cell population of tumors. This review gives an overview of the Laser Capture Microdissection (LCM) technique, one of the single-cell separation methods used in PC research. Full article

(This article belongs to the Special Issue Molecular Advances in Cancer Genetics 2.0)

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30 pages, 1610 KiB

Open AccessReview

Molecular Management of High-Grade Serous Ovarian Carcinoma

by Paula Punzón-Jiménez, Victor Lago, Santiago Domingo, Carlos Simón and Aymara Mas

Int. J. Mol. Sci. 2022, 23(22), 13777; https://doi.org/10.3390/ijms232213777 - 9 Nov 2022

Cited by 9 | Viewed by 6536

Abstract

High-grade serous ovarian carcinoma (HGSOC) represents the most common form of epithelial ovarian carcinoma. The absence of specific symptoms leads to late-stage diagnosis, making HGSOC one of the gynecological cancers with the worst prognosis. The cellular origin of HGSOC and the role of reproductive hormones, genetic traits (such as alterations in P53 and DNA-repair mechanisms), chromosomal instability, or dysregulation of crucial signaling pathways have been considered when evaluating prognosis and response to therapy in HGSOC patients. However, the detection of HGSOC is still based on traditional methods such as carbohydrate antigen 125 (CA125) detection and ultrasound, and the combined use of these methods has yet to support significant reductions in overall mortality rates. The current paradigm for HGSOC management has moved towards early diagnosis via the non-invasive detection of molecular markers through liquid biopsies. This review presents an integrated view of the relevant cellular and molecular aspects involved in the etiopathogenesis of HGSOC and brings together studies that consider new horizons for the possible early detection of this gynecological cancer. Full article

(This article belongs to the Special Issue Molecular Advances in Cancer Genetics 2.0)

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26 pages, 797 KiB

Open AccessReview

Beyond BRCA: The Emerging Significance of DNA Damage Response and Personalized Treatment in Pancreatic and Prostate Cancer Patients

by Bruna Dalmasso, Alberto Puccini, Fabio Catalano, Roberto Borea, Maria Laura Iaia, William Bruno, Giuseppe Fornarini, Stefania Sciallero, Sara Elena Rebuzzi and Paola Ghiorzo

Int. J. Mol. Sci. 2022, 23(9), 4709; https://doi.org/10.3390/ijms23094709 - 24 Apr 2022

Cited by 16 | Viewed by 3769

Abstract

The BRCA1/2 germline and/or somatic pathogenic variants (PVs) are key players in the hereditary predisposition and therapeutic response for breast, ovarian and, more recently, pancreatic and prostate cancers. Aberrations in other genes involved in homologous recombination and DNA damage response (DDR) pathways are being investigated as promising targets in ongoing clinical trials. However, DDR genes are not routinely tested worldwide. Due to heterogeneity in cohort selection and dissimilar sequencing approaches across studies, neither the burden of PVs in DDR genes nor the prevalence of PVs in genes in common among pancreatic and prostate cancer can be easily quantified. We aim to contextualize these genes, altered in both pancreatic and prostate cancers, in the DDR process, to summarize their hereditary and somatic burden in different studies and harness their deficiency for cancer treatments in the context of currently ongoing clinical trials. We conclude that the inclusion of DDR genes, other than BRCA1/2, shared by both cancers considerably increases the detection rate of potentially actionable variants, which are triplicated in pancreatic and almost doubled in prostate cancer. Thus, DDR alterations are suitable targets for drug development and to improve the outcome in both pancreatic and prostate cancer patients. Importantly, this will increase the detection of germline pathogenic variants, thereby patient referral to genetic counseling. Full article

(This article belongs to the Special Issue Molecular Advances in Cancer Genetics 2.0)

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Other

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12 pages, 1038 KiB

Open AccessCase Report

Increased Co-Occurrence of Pathogenic Variants in Hereditary Breast and Ovarian Cancer and Lynch Syndromes: A Consequence of Multigene Panel Genetic Testing?

by Mar Infante, Mónica Arranz-Ledo, Enrique Lastra, Luis Enrique Abella, Raquel Ferreira, Marta Orozco, Lara Hernández, Noemí Martínez and Mercedes Durán

Int. J. Mol. Sci. 2022, 23(19), 11499; https://doi.org/10.3390/ijms231911499 - 29 Sep 2022

Cited by 7 | Viewed by 2371

Abstract

The probability of carrying two pathogenic variants (PVs) in dominant cancer-predisposing genes for hereditary breast and ovarian cancer and lynch syndromes in the same patient is uncommon, except in populations where founder effects exist. Two breast cancer women that are double heterozygotes (DH) for both BRCA1/BRCA2, one ovarian cancer case DH for BRCA1/RAD51C, and another breast and colorectal cancer who is DH for BRCA2/PMS2 were identified in our cohort. Ages at diagnosis and severity of disease in BRCA1/BRCA2 DH resembled BRCA1 single-carrier features. Similarly, the co-existence of the BRCA2 and PMS2 mutations prompted the development of breast and colorectal cancer in the same patient. The first BRCA1/BRCA2 DH was identified by HA-based and Sanger sequencing (1 of 623 families with BRCA PVs). However, this ratio has increased up to 2.9% (1 DH carrier vs. 103 single PV carriers) since using a custom 35-cancer gene on-demand panel. The type of cancer developed in each DH patient was consistent with the independently inherited condition, and the clinical outcome was no worse than in patients with single BRCA1 mutations. Therefore, the clinical impact, especially in patients with two hereditary syndromes, lies in genetic counseling tailor-made for each family based on the clinical guidelines for each syndrome. The number of DH is expected to be increased in the future as a result of next generation sequencing routines. Full article

(This article belongs to the Special Issue Molecular Advances in Cancer Genetics 2.0)

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