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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 May 2022) | Viewed by 24182

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Prof. Dr. Philippos Patsalis

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Department of Basic and Clinical Science, University of Nicosia Medical School, 93 Agiou Nikolaou, 2408 Engomi, Nicosia, Cyprus
Interests: human genetics; molecular genetics; clinical genetics; laboratory services; molecular diagnostics; cancer genetics

Special Issue Information

Dear colleagues,

Cancer is a leading cause of death globally, affecting more than 14 million people each year. This disease is often characterized as an evolutionary process driven by accumulation of somatic mutations and clonal selection. Therefore, genetic profiling of cancer is essential to better our understanding of the molecular etiology of this disease. The advent of next generation sequencing has revolutionized the field of genomics and has shifted cancer diagnosis, moving from a histopathologically defined tumor towards a molecularly characterized disease. This paradigm shift has opened new avenues for early cancer detection and diagnosis, personalized treatment, and overall better clinical management leading to improved clinical outcomes for patients with cancer.

In this context, the goal of this Special Issue is to focus on recent advances in molecular oncology as well as the application of advanced genomic technologies that enable in-depth characterization of different cancer types and highlight their potential utility in clinical practice. We extend our invitation to scientists in the broad field of cancer genetics and molecular oncology to contribute to this Special Issue.

Prof. Dr. Philippos Patsalis
Guest Editor

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Keywords

molecular oncology
cancer genetics
next generation sequencing
genomics
methylomics
transcriptomics
tumor profiling
personalized treatment

Published Papers (9 papers)

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Research

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12 pages, 909 KiB

Open AccessArticle

Investigation of Clinically Significant Molecular Aberrations in Patients with Prostate Cancer: Implications for Personalized Treatment, Prognosis and Genetic Testing

by Elena Fountzilas, Maria Kouspou, Alexia Eliades, Kyriaki Papadopoulou, Evangelos Bournakis, Anna Goussia, Marinos Tsiatas, Achilleas Achilleos, Kyriakos Tsangaras, Gaetan Billioud, Charalambos Loizides, Christos Lemesios, Elena Kypri, Marios Ioannides, George Koumbaris, Sofia Levva, Ioannis Vakalopoulos, Athanasios Paliouras, Stavroula Pervana, Filippos Koinis, Redi Bumci, Athina Christopoulou, Soultana Meditskou, Amanda Psyrri, Ioannis Boukovinas, Anastasios Visvikis, Vasilios Karavasilis, George K. Koukoulis, Athanasios Kotsakis, Dimitrios Giannakis, George Fountzilas and Philippos C. Patsalis Show full author list Hide full author list

Int. J. Mol. Sci. 2023, 24(14), 11834; https://doi.org/10.3390/ijms241411834 - 23 Jul 2023

Viewed by 1522

Abstract

The data on tumor molecular profiling of European patients with prostate cancer is limited. Our aim was to evaluate the prevalence and prognostic and predictive values of gene alterations in unselected patients with prostate cancer. The presence of gene alterations was assessed in patients with histologically confirmed prostate cancer using the ForeSENTIA^® Prostate panel (Medicover Genetics), targeting 36 clinically relevant genes and microsatellite instability testing. The primary endpoint was the prevalence of gene alterations in homologous recombination repair (HRR) genes. Overall, 196 patients with prostate cancer were evaluated (median age 72.2 years, metastatic disease in 141 (71.9%) patients). Gene alterations were identified in 120 (61%) patients, while alteration in HRR genes were identified in 34 (17.3%) patients. The most commonly mutated HRR genes were ATM (17, 8.7%), BRCA2 (9, 4.6%) and BRCA1 (4, 2%). The presence of HRR gene alterations was not associated with advanced stage (p = 0.21), age at diagnosis (p = 0.28), Gleason score (p = 0.17) or overall survival (HR 0.72; 95% CI: 0.41–1.26; p = 0.251). We identified clinically relevant somatic gene alterations in European patients with prostate cancer. These molecular alterations have prognostic significance and therapeutic implications and/or may trigger genetic testing in selected patients. In the era of precision medicine, prospective research on the predictive role of these alterations for innovative treatments or their combinations is warranted. Full article

(This article belongs to the Special Issue Molecular Genetics of Cancer)

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8 pages, 1145 KiB

Open AccessCommunication

TFIIIC as a Potential Epigenetic Modulator of Histone Acetylation in Human Stem Cells

by Marco Vezzoli, Lara Isabel de Llobet Cucalon, Chiara Di Vona, Marco Morselli, Barbara Montanini, Susana de la Luna, Martin Teichmann, Giorgio Dieci and Roberto Ferrari

Int. J. Mol. Sci. 2023, 24(4), 3624; https://doi.org/10.3390/ijms24043624 - 11 Feb 2023

Cited by 2 | Viewed by 1625

Abstract

Regulation of histone acetylation dictates patterns of gene expression and hence cell identity. Due to their clinical relevance in cancer biology, understanding how human embryonic stem cells (hESCs) regulate their genomic patterns of histone acetylation is critical, but it remains largely to be investigated. Here, we provide evidence that acetylation of histone H3 lysine-18 (H3K18ac) and lysine-27 (H3K27ac) is only partially established by p300 in stem cells, while it represents the main histone acetyltransferase (HAT) for these marks in somatic cells. Our analysis reveals that whereas p300 marginally associated with H3K18ac and H3K27ac in hESCs, it largely overlapped with these histone marks upon differentiation. Interestingly, we show that H3K18ac is found at “stemness” genes enriched in RNA polymerase III transcription factor C (TFIIIC) in hESCs, whilst lacking p300. Moreover, TFIIIC was also found in the vicinity of genes involved in neuronal biology, although devoid of H3K18ac. Our data suggest a more complex pattern of HATs responsible for histone acetylations in hESCs than previously considered, suggesting a putative role for H3K18ac and TFIIIC in regulating “stemness” genes as well as genes associated with neuronal differentiation of hESCs. The results break ground for possible new paradigms for genome acetylation in hESCs that could lead to new avenues for therapeutic intervention in cancer and developmental diseases. Full article

(This article belongs to the Special Issue Molecular Genetics of Cancer)

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19 pages, 3819 KiB

Open AccessArticle

Sample-Specific Perturbation of Gene Interactions Identifies Pancreatic Cancer Subtypes

by Ran Wei, Huihui Zhang, Jianzhong Cao, Dailei Qin, Shengping Li and Wuguo Deng

Int. J. Mol. Sci. 2022, 23(9), 4792; https://doi.org/10.3390/ijms23094792 - 26 Apr 2022

Cited by 3 | Viewed by 2004

Abstract

Pancreatic cancer is a highly fatal disease and an increasing common cause of cancer mortality. Mounting evidence now indicates that molecular heterogeneity in pancreatic cancer significantly impacts its clinical features. However, the dynamic nature of gene expression pattern makes it difficult to rely solely on gene expression alterations to estimate disease status. By contrast, biological networks tend to be more stable over time under different situations. In this study, we used a gene interaction network from a new point of view to explore the subtypes of pancreatic cancer based on individual-specific edge perturbations calculated by relative gene expression value. Our study shows that pancreatic cancer patients from the TCGA database could be separated into four subtypes based on gene interaction perturbations at the individual level. The new network-based subtypes of pancreatic cancer exhibited substantial heterogeneity in many aspects, including prognosis, phenotypic traits, genetic mutations, the abundance of infiltrating immune cell, and predictive therapeutic efficacy (chemosensitivity and immunotherapy efficacy). The new network-based subtypes were closely related to previous reported molecular subtypes of pancreatic cancer. This work helps us to better understand the heterogeneity and mechanisms of pancreatic cancer from a network perspective. Full article

(This article belongs to the Special Issue Molecular Genetics of Cancer)

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20 pages, 2004 KiB

Open AccessArticle

Detection of Germline Variants in 450 Breast/Ovarian Cancer Families with a Multi-Gene Panel Including Coding and Regulatory Regions

by Chiara Guglielmi, Rosa Scarpitta, Gaetana Gambino, Eleonora Conti, Francesca Bellè, Mariella Tancredi, Tiziana Cervelli, Elisabetta Falaschi, Cinzia Cosini, Paolo Aretini, Caterina Congregati, Marco Marino, Margherita Patruno, Brunella Pilato, Francesca Spina, Luisa Balestrino, Elena Tenedini, Ileana Carnevali, Laura Cortesi, Enrico Tagliafico, Maria Grazia Tibiletti, Stefania Tommasi, Matteo Ghilli, Caterina Vivanet, Alvaro Galli and Maria Adelaide Caligo Show full author list Hide full author list

Int. J. Mol. Sci. 2021, 22(14), 7693; https://doi.org/10.3390/ijms22147693 - 19 Jul 2021

Cited by 5 | Viewed by 3049

Abstract

With the progress of sequencing technologies, an ever-increasing number of variants of unknown functional and clinical significance (VUS) have been identified in both coding and non-coding regions of the main Breast Cancer (BC) predisposition genes. The aim of this study is to identify a mutational profile of coding and intron-exon junction regions of 12 moderate penetrance genes (ATM, BRIP1, CDH1, CHEK2, NBN, PALB2, PTEN, RAD50, RAD51C, RAD51D, STK11, TP53) in a cohort of 450 Italian patients with Hereditary Breast/Ovarian Cancer Syndrome, wild type for germline mutation in BRCA1/2 genes. The analysis was extended to 5′UTR and 3′UTR of all the genes listed above and to the BRCA1 and BRCA2 known regulatory regions in a subset of 120 patients. The screening was performed through NGS target resequencing on the Illumina platform MiSeq. 8.7% of the patients analyzed is carriers of class 5/4 coding variants in the ATM (3.6%), BRIP1 (1.6%), CHEK2 (1.8%), PALB2 (0.7%), RAD51C (0.4%), RAD51D (0.4%), and TP53 (0.2%) genes, while variants of uncertain pathological significance (VUSs)/class 3 were identified in 9.1% of the samples. In intron-exon junctions and in regulatory regions, variants were detected respectively in 5.1% and in 32.5% of the cases analyzed. The average age of disease onset of 44.4 in non-coding variant carriers is absolutely similar to the average age of disease onset in coding variant carriers for each proband’s group with the same cancer type. Furthermore, there is not a statistically significant difference in the proportion of cases with a tumor onset under age of 40 between the two groups, but the presence of multiple non-coding variants in the same patient may affect the aggressiveness of the tumor and it is worth underlining that 25% of patients with an aggressive tumor are carriers of a PTEN 3′UTR-variant. This data provides initial information on how important it might be to extend mutational screening to the regulatory regions in clinical practice. Full article

(This article belongs to the Special Issue Molecular Genetics of Cancer)

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14 pages, 2951 KiB

Open AccessArticle

Insulin-Like Growth Factor 2 mRNA-Binding Protein 1 (IGF2BP1) Is a Prognostic Biomarker and Associated with Chemotherapy Responsiveness in Colorectal Cancer

by Hung-Ming Chen, Chun-Chi Lin, Wei-Shone Chen, Jeng-Kai Jiang, Shung-Haur Yang, Shih-Ching Chang, Ching-Liang Ho, Chung-Chi Yang, Shih-Ching Huang, Yee Chao, Tsai-Tsen Liao, Wei-Lun Hwang and Hao-Wei Teng

Int. J. Mol. Sci. 2021, 22(13), 6940; https://doi.org/10.3390/ijms22136940 - 28 Jun 2021

Cited by 18 | Viewed by 2767

Abstract

Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) is an RNA-binding protein and serves as a post-transcriptional fine-tuner regulating the expression of mRNA targets. However, the clinicopathological roles of IGF2BP1 in colorectal cancer (CRC) remains limited. Thus, we aimed to elucidate the clinical significance and biomarker potentials of IGF2BP1 in CRC. A total of 266 specimens from two sets of CRC patients were collected. IGF2BP1 expression was studied by immunohistochemical (IHC) staining. The Kaplan-Meier survival plot and a log-rank test were used for survival analysis. The Cox proportional hazards model was applied to determine the survival impact of IGF2BP1. Public datasets sets from The Cancer Genome Atlas (TCGA) and Human Cancer Metastasis Database (HCMDB), receiver operating characteristic (ROC) plotter, and two CRC cell lines, HCT-116 and DLD-1, were used for validating our findings. We showed that IGF2BP1 was overexpressed in tumor specimens compared to 13 paired normal parts by examining the immunoreactivity of IGF2BP1 (p = 0.045). The increased expression of IGF2BP1 in primary tumor parts was observed regardless of metastatic status (p < 0.001) in HCMDB analysis. IGF2BP1 expression was significantly associated with young age (59.6% vs. 46.7%, p-value = 0.043) and advanced stage (61.3% vs. 40.0%, p-value = 0.001). After controlling for confounding factors, IGF2BP1 remained an independent prognostic factor (HR = 1.705, p-value = 0.005). TCGA datasets analysis indicated that high IGF2BP1 expression showed a lower 5-year survival rate (58% vs. 65%) in CRC patients. The increased expression of IGF2BP1 in chemotherapy non-responder rectal cancer patients was observed using a ROC plotter. Overexpression of IGF2BP1 promoted the colony-forming capacity and 5-fluorouracil and etoposide resistance in CRC cells. Here, IGF2BP1 was an independent poor prognostic marker in CRC patients and contributed to aggressive phenotypes in CRC cell lines. Full article

(This article belongs to the Special Issue Molecular Genetics of Cancer)

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13 pages, 1406 KiB

Open AccessArticle

Promoter Methylation of PRKCB, ADAMTS12, and NAALAD2 Is Specific to Prostate Cancer and Predicts Biochemical Disease Recurrence

by Kristina Daniunaite, Arnas Bakavicius, Kristina Zukauskaite, Ieva Rauluseviciute, Juozas Rimantas Lazutka, Albertas Ulys, Feliksas Jankevicius and Sonata Jarmalaite

Int. J. Mol. Sci. 2021, 22(11), 6091; https://doi.org/10.3390/ijms22116091 - 5 Jun 2021

Cited by 11 | Viewed by 2675

Abstract

The molecular diversity of prostate cancer (PCa) has been demonstrated by recent genome-wide studies, proposing a significant number of different molecular markers. However, only a few of them have been transferred into clinical practice so far. The present study aimed to identify and validate novel DNA methylation biomarkers for PCa diagnosis and prognosis. Microarray-based methylome data of well-characterized cancerous and noncancerous prostate tissue (NPT) pairs was used for the initial screening. Ten protein-coding genes were selected for validation in a set of 151 PCa, 51 NPT, as well as 17 benign prostatic hyperplasia samples. The Prostate Cancer Dataset (PRAD) of The Cancer Genome Atlas (TCGA) was utilized for independent validation of our findings. Methylation frequencies of ADAMTS12, CCDC181, FILIP1L, NAALAD2, PRKCB, and ZMIZ1 were up to 91% in our study. PCa specific methylation of ADAMTS12, CCDC181, NAALAD2, and PRKCB was demonstrated by qualitative and quantitative means (all p < 0.05). In agreement with PRAD, promoter methylation of these four genes was associated with the transcript down-regulation in the Lithuanian cohort (all p < 0.05). Methylation of ADAMTS12, NAALAD2, and PRKCB was independently predictive for biochemical disease recurrence, while NAALAD2 and PRKCB increased the prognostic power of multivariate models (all p < 0.01). The present study identified methylation of ADAMTS12, NAALAD2, and PRKCB as novel diagnostic and prognostic PCa biomarkers that might guide treatment decisions in clinical practice. Full article

(This article belongs to the Special Issue Molecular Genetics of Cancer)

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Review

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25 pages, 885 KiB

Open AccessReview

Theranostic Interpolation of Genomic Instability in Breast Cancer

by Rabia Rasool, Inam Ullah, Bismillah Mubeen, Sultan Alshehri, Syed Sarim Imam, Mohammed M. Ghoneim, Sami I. Alzarea, Fahad A. Al-Abbasi, Bibi Nazia Murtaza, Imran Kazmi and Muhammad Shahid Nadeem

Int. J. Mol. Sci. 2022, 23(3), 1861; https://doi.org/10.3390/ijms23031861 - 7 Feb 2022

Cited by 8 | Viewed by 3409

Abstract

Breast cancer is a diverse disease caused by mutations in multiple genes accompanying epigenetic aberrations of hazardous genes and protein pathways, which distress tumor-suppressor genes and the expression of oncogenes. Alteration in any of the several physiological mechanisms such as cell cycle checkpoints, DNA repair machinery, mitotic checkpoints, and telomere maintenance results in genomic instability. Theranostic has the potential to foretell and estimate therapy response, contributing a valuable opportunity to modify the ongoing treatments and has developed new treatment strategies in a personalized manner. “Omics” technologies play a key role while studying genomic instability in breast cancer, and broadly include various aspects of proteomics, genomics, metabolomics, and tumor grading. Certain computational techniques have been designed to facilitate the early diagnosis of cancer and predict disease-specific therapies, which can produce many effective results. Several diverse tools are used to investigate genomic instability and underlying mechanisms. The current review aimed to explore the genomic landscape, tumor heterogeneity, and possible mechanisms of genomic instability involved in initiating breast cancer. We also discuss the implications of computational biology regarding mutational and pathway analyses, identification of prognostic markers, and the development of strategies for precision medicine. We also review different technologies required for the investigation of genomic instability in breast cancer cells, including recent therapeutic and preventive advances in breast cancer. Full article

(This article belongs to the Special Issue Molecular Genetics of Cancer)

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24 pages, 879 KiB

Open AccessReview

Epigenetic Biomarkers of Renal Cell Carcinoma for Liquid Biopsy Tests

by Raimonda Kubiliute and Sonata Jarmalaite

Int. J. Mol. Sci. 2021, 22(16), 8846; https://doi.org/10.3390/ijms22168846 - 17 Aug 2021

Cited by 17 | Viewed by 3636

Abstract

Renal cell carcinomas (RCC) account for 2–3% of the global cancer burden and are characterized by the highest mortality rate among all genitourinary cancers. However, excluding conventional imagining approaches, there are no reliable diagnostic and prognostic tools available for clinical use at present. Liquid biopsies, such as urine, serum, and plasma, contain a significant amount of tumor-derived nucleic acids, which may serve as non-invasive biomarkers that are particularly useful for early cancer detection, follow-up, and personalization of treatment. Changes in epigenetic phenomena, such as DNA methylation level, expression of microRNAs (miRNAs), and long noncoding RNAs (lncRNAs), are observed early during cancer development and are easily detectable in biofluids when morphological changes are still undetermined by conventional diagnostic tools. Here, we reviewed recent advances made in the development of liquid biopsy-derived DNA methylation-, miRNAs- and lncRNAs-based biomarkers for RCC, with an emphasis on the performance characteristics. In the last two decades, a mass of circulating epigenetic biomarkers of RCC were suggested, however, most of the studies done thus far analyzed biomarkers selected from the literature, used relatively miniature, local, and heterogeneous cohorts, and suffered from a lack of sufficient validations. In summary, for improved translation into the clinical setting, there is considerable demand for the validation of the existing pool of RCC biomarkers and the discovery of novel ones with better performance and clinical utility. Full article

(This article belongs to the Special Issue Molecular Genetics of Cancer)

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Other

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8 pages, 1334 KiB

Open AccessCase Report

A Pathogenic Variant Reclassified to the Pseudogene PMS2P1 in a Patient with Suspected Hereditary Cancer

by Veronica Fragoso-Ontiveros, Marcela Angelica De la Fuente-Hernandez, Vincent Gonzalez-Osnaya, Mario Gamez-Rosales, Maria Delia Perez-Montiel, David Isla-Ortiz, David Francisco Cantu-De Leon and Rosa Maria Alvarez-Gomez

Int. J. Mol. Sci. 2023, 24(2), 1398; https://doi.org/10.3390/ijms24021398 - 11 Jan 2023

Cited by 1 | Viewed by 2136

Abstract

The PMS2 gene is involved in DNA repair by the mismatch repair pathway. Deficiencies in this mechanism have been associated with Lynch Syndrome (LS), which is characterized by a high risk for colorectal, endometrial, ovarian, breast, and other cancers. Germinal pathogenic variants of PMS2 are associated with up to 5% of all cases of LS. The prevalence is overestimated for the existence of multiple homologous pseudogenes. We report the case of a 44-year-old woman diagnosed with breast cancer at 34 years without a relevant cancer family history. The presence of pathogenic variant NM_000535.7:c.1A > T, (p.Met1Leu) in PMS2 was determined by next-generation sequencing analysis with a panel of 322 cancer-associated genes and confirmed by capillary sequencing in the patient. The variant was determined in six family members (brothers, sisters, and a son) and seven non-cancerous unrelated individuals. Analysis of the amplified region showed high homology of PMS2 with five of its pseudogenes. We determined that the variant is associated with the PMS2P1 pseudogene following sequence alignment analysis. We propose considering the variant c.1A > T, (p.Met1Leu) in PMS2 for reclassification as not hereditary cancer-related, given the impact on the diagnosis and treatment of cancer patients and families carrying this variant. Full article

(This article belongs to the Special Issue Molecular Genetics of Cancer)

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