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Genomics and Molecular Regulation in Cancer Pathogenesis
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Genomics and Molecular Regulation in Cancer Pathogenesis

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 January 2023) | Viewed by 11508

Special Issue Editors

Dr. Xiaoqun Dong

E-Mail Website
Guest Editor
The Liver Research Center, Division of Gastroenterology, Rhode Island Hospital/Lifespan, Department of Medicine, The Warren Alpert Medical School of Brown University, Providence, RI 02903, USA
Interests: cancer immunology and immune therapy; molecular mechanisms of cancer development and metastasis; cancer diagnosis and prognosis
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Ioana Berindan-Neagoe

E-Mail Website
Guest Editor
Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 400015 Cluj-Napoca, Romania
Interests: microRNAs; biomarkers; apoptosis; cancer profiling; immunology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues, 

This Special Issue is the continuation of our 2022 Special Issue, “Genomics and Molecular Regulation in Cancer Pathogenesis ” (https://www.mdpi.com/journal/ijms/special_issues/cancer_pathogenesis).

A Special Issue on the hot topic " Molecular Regulation and Mechanism in Cancer Pathogenesis" is being prepared for the journal IJMS. The idea moves from the basis that (genetic and epigenetic) molecular mechanism is essential for better understanding of cancer development and progression. A complex network of oncogenes, tumour suppressor genes and related molecules cooperate to initiate and promote cancer development and progression (especially multi-drug resistance, relapse/recurrence, local invasion and distant metastasis). The network is regulated in response to selective pressure under stress and treatment. Identification and validation of molecular biomarkers and targets have been explored over the years using different and complementary tools from in vivo, ex vivo to in vitro systems, as well as in silico methodologies. A few validated biomarkers and therapeutic targets have boosted extensive investigations of cancer molecular and cellular mechanisms.

Original manuscripts and reviews dealing with specific and/or systematic aspects of cancer histopathology, biology as well as genetics/epigenetics are very welcome from outstanding experts of the topic.

Dr. Xiaoqun Dong
Prof. Dr. Ioana Berindan-Neagoe
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. 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.

Published Papers (5 papers)

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Research

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27 pages, 3580 KiB  
Article
Systemic Alterations of Cancer Cells and Their Boost by Polyploidization: Unicellular Attractor (UCA) Model
by Alexander E. Vinogradov and Olga V. Anatskaya
Int. J. Mol. Sci. 2023, 24(7), 6196; https://doi.org/10.3390/ijms24076196 - 24 Mar 2023
Cited by 5 | Viewed by 1945
Abstract
Using meta-analyses, we introduce a unicellular attractor (UCA) model integrating essential features of the ‘atavistic reversal’, ‘cancer attractor’, ‘somatic mutation’, ‘genome chaos’, and ‘tissue organization field’ theories. The ‘atavistic reversal’ theory is taken as a keystone. We propose a possible mechanism of this [...] Read more.
Using meta-analyses, we introduce a unicellular attractor (UCA) model integrating essential features of the ‘atavistic reversal’, ‘cancer attractor’, ‘somatic mutation’, ‘genome chaos’, and ‘tissue organization field’ theories. The ‘atavistic reversal’ theory is taken as a keystone. We propose a possible mechanism of this reversal, its refinement called ‘gradual atavism’, and evidence for the ‘serial atavism’ model. We showed the gradual core-to-periphery evolutionary growth of the human interactome resulting in the higher protein interaction density and global interactome centrality in the UC center. In addition, we revealed that UC genes are more actively expressed even in normal cells. The modeling of random walk along protein interaction trajectories demonstrated that random alterations in cellular networks, caused by genetic and epigenetic changes, can result in a further gradual activation of the UC center. These changes can be induced and accelerated by cellular stress that additionally activates UC genes (especially during cell proliferation), because the genes involved in cellular stress response and cell cycle are mostly of UC origin. The functional enrichment analysis showed that cancer cells demonstrate the hyperactivation of energetics and the suppression of multicellular genes involved in communication with the extracellular environment (especially immune surveillance). Collectively, these events can unleash selfish cell behavior aimed at survival at all means. All these changes are boosted by polyploidization. The UCA model may facilitate an understanding of oncogenesis and promote the development of therapeutic strategies. Full article
(This article belongs to the Special Issue Genomics and Molecular Regulation in Cancer Pathogenesis)
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13 pages, 1429 KiB  
Article
A Comprehensive Biomarker Analysis of Microsatellite Unstable/Mismatch Repair Deficient Colorectal Cancer Cohort Treated with Immunotherapy
by Elena Élez, Núria Mulet-Margalef, Miriam Sanso, Fiorella Ruiz-Pace, Francesco M. Mancuso, Raquel Comas, Javier Ros, Guillem Argilés, Giulia Martini, Enrique Sanz-Garcia, Iosune Baraibar, Francesc Salvà, Alba Noguerido, Jose Luis Cuadra-Urteaga, Roberta Fasani, Ariadna Garcia, Jose Jimenez, Susana Aguilar, Stefania Landolfi, Javier Hernández-Losa, Irene Braña, Paolo Nuciforo, Rodrigo Dienstmann, Josep Tabernero, Ramon Salazar and Ana Vivancosadd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2023, 24(1), 118; https://doi.org/10.3390/ijms24010118 - 21 Dec 2022
Cited by 3 | Viewed by 2212
Abstract
The search for immunotherapy biomarkers in Microsatellite Instability High/Deficient Mismatch Repair system (MSI-H/dMMR) metastatic colorectal cancer (mCRC) is an unmet need. Sixteen patients with mCRC and MSI-H/dMMR (determined by either immunohistochemistry or polymerase chain reaction) treated with PD-1/PD-L1 inhibitors at our institution were [...] Read more.
The search for immunotherapy biomarkers in Microsatellite Instability High/Deficient Mismatch Repair system (MSI-H/dMMR) metastatic colorectal cancer (mCRC) is an unmet need. Sixteen patients with mCRC and MSI-H/dMMR (determined by either immunohistochemistry or polymerase chain reaction) treated with PD-1/PD-L1 inhibitors at our institution were included. According to whether the progression-free survival with PD-1/PD-L1 inhibitors was longer than 6 months or shorter, patients were clustered into the IT-responder group (n: 9 patients) or IT-resistant group (n: 7 patients), respectively. In order to evaluate determinants of benefit with PD-1/PD-L1 inhibitors, we performed multimodal analysis including genomics (through NGS panel tumour-only with 431 genes) and the immune microenvironment (using CD3, CD8, FOXP3 and PD-L1 antibodies). The following mutations were more frequent in IT-resistant compared with IT-responder groups: B2M (4/7 versus 2/9), CTNNB1 (2/7 versus 0/9), and biallelic PTEN (3/7 versus 1/9). Biallelic ARID1A mutations were found exclusively in the IT-responder group (4/9 patients). Tumour mutational burden did not correlate with immunotherapy benefit, neither the rate of indels in homopolymeric regions. Of note, biallelic ARID1A mutated tumours had the highest immune infiltration and PD-L1 scores, contrary to tumours with CTNNB1 mutation. Immune microenvironment analysis showed higher densities of different T cell subpopulations and PD-L1 expression in IT-responders. Misdiagnosis of MSI-H/dMMR inferred by discordances between immunohistochemistry and polymerase chain reaction was only found in the IT-resistant population (3/7 patients). Biallelic ARID1A mutations and Wnt signalling activation through CTNNB1 mutation were associated with high and low T cell immune infiltrates, respectively, and deserve special attention as determinants of response to PD-1/PD-L1 inhibitors. The non-MSI-H phenotype in dMMR is associated with poor benefit to immunotherapy. Our results suggest that mechanisms of resistance to immunotherapy are multi-factorial. Full article
(This article belongs to the Special Issue Genomics and Molecular Regulation in Cancer Pathogenesis)
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10 pages, 1018 KiB  
Article
Characteristics of BRCA2 Mutated Prostate Cancer at Presentation
by Hyunho Han, Cheol Keun Park, Nam Hoon Cho, Jongsoo Lee, Won Sik Jang, Won Sik Ham, Young Deuk Choi and Kang Su Cho
Int. J. Mol. Sci. 2022, 23(21), 13426; https://doi.org/10.3390/ijms232113426 - 03 Nov 2022
Cited by 5 | Viewed by 1979
Abstract
Genetic alterations of DNA repair genes, particularly BRCA2 in patients with prostate cancer, are associated with aggressive behavior of the disease. It has reached consensus that somatic and germline tests are necessary when treating advanced prostate cancer patients. Yet, it is unclear whether [...] Read more.
Genetic alterations of DNA repair genes, particularly BRCA2 in patients with prostate cancer, are associated with aggressive behavior of the disease. It has reached consensus that somatic and germline tests are necessary when treating advanced prostate cancer patients. Yet, it is unclear whether the mutations are associated with any presenting clinical features. We assessed the incidences and characteristics of BRCA2 mutated cancers by targeted sequencing in 126 sets of advanced prostate cancer tissue sequencing data. At the time of diagnosis, cT3/4, N1 and M1 stages were 107 (85%), 54 (43%) and 35 (28%) samples, respectively. BRCA2 alterations of clinical significance by AMP/ASCO/CAP criteria were found in 19 of 126 samples (15.1%). The BRCA2 mutated cancer did not differ in the distributions of TNM stage, Gleason grade group or histological subtype compared to BRCA2 wild-type cancers. Yet, they had higher tumor mutation burden, and higher frequency of ATM and BRCA1 mutations (44% vs. 10%, p = 0.002 and 21% vs. 4%, p = 0.018, respectively). Of the metastatic subgroup (M1, n = 34), mean PSA was significantly lower in BRCA2 mutated cancers than wild-type (p = 0.018). In the non-metastatic subgroup (M0, n = 64), PSA was not significantly different (p = 0.425). A similar trend was noted in multiple metastatic prostate cancer public datasets. We conclude that BRCA2 mutated metastatic prostate cancers may present in an advanced stage with relatively low PSA. Full article
(This article belongs to the Special Issue Genomics and Molecular Regulation in Cancer Pathogenesis)
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16 pages, 1859 KiB  
Article
The Inhibitory Response to PI3K/AKT Pathway Inhibitors MK-2206 and Buparlisib Is Related to Genetic Differences in Pancreatic Ductal Adenocarcinoma Cell Lines
by Yixuan Ma, Sina Sender, Anett Sekora, Weibo Kong, Peter Bauer, Najim Ameziane, Ruslan Al-Ali, Susann Krake, Mandy Radefeldt, Frank Ulrich Weiss, Markus M. Lerch, Alisha Parveen, Dietmar Zechner, Christian Junghanss and Hugo Murua Escobar
Int. J. Mol. Sci. 2022, 23(8), 4295; https://doi.org/10.3390/ijms23084295 - 13 Apr 2022
Cited by 6 | Viewed by 2035
Abstract
The aberrant activation of the phosphoinositide 3-kinase (PI3K)/ protein kinase B (AKT) pathway is common in pancreatic ductal adenocarcinomas (PDAC). The application of inhibitors against PI3K and AKT has been considered as a therapeutic option. We investigated PDAC cell lines exposed to increasing [...] Read more.
The aberrant activation of the phosphoinositide 3-kinase (PI3K)/ protein kinase B (AKT) pathway is common in pancreatic ductal adenocarcinomas (PDAC). The application of inhibitors against PI3K and AKT has been considered as a therapeutic option. We investigated PDAC cell lines exposed to increasing concentrations of MK-2206 (an AKT1/2/3 inhibitor) and Buparlisib (a pan-PI3K inhibitor). Cell proliferation, metabolic activity, biomass, and apoptosis/necrosis were evaluated. Further, whole-exome sequencing (WES) and RNA sequencing (RNA-seq) were performed to analyze the recurrent aberrations and expression profiles of the inhibitor target genes and the genes frequently mutated in PDAC (Kirsten rat sarcoma virus (KRAS), Tumor protein p53 (TP53)). MK-2206 and Buparlisib demonstrated pronounced cytotoxic effects and limited cell-line-specific effects in cell death induction. WES revealed two sequence variants within the direct target genes (PIK3CA c.1143C > G in Colo357 and PIK3CD c.2480C > G in Capan-1), but a direct link to the Buparlisib response was not observed. RNA-seq demonstrated that the expression level of the inhibitor target genes did not affect the efficacy of the corresponding inhibitors. Moreover, increased resistance to MK-2206 was observed in the analyzed cell lines carrying a KRAS variant. Further, increased resistance to both inhibitors was observed in SU.86.86 carrying two TP53 missense variants. Additionally, the presence of the PIK3CA c.1143C > G in KRAS-variant-carrying cell lines was observed to correlate with increased sensitivity to Buparlisib. In conclusion, the present study reveals the distinct antitumor effects of PI3K/AKT pathway inhibitors against PDAC cell lines. Aberrations in specific target genes, as well as KRAS and TP53, individually or together, affect the efficacy of the two PI3K/AKT pathway inhibitors. Full article
(This article belongs to the Special Issue Genomics and Molecular Regulation in Cancer Pathogenesis)
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Review

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25 pages, 1252 KiB  
Review
The Implications of Noncoding RNAs in the Evolution and Progression of Nonalcoholic Fatty Liver Disease (NAFLD)-Related HCC
by Ioana Rusu, Radu Pirlog, Paul Chiroi, Andreea Nutu, Vlad Radu Puia, Alin Cornel Fetti, Daniel Radu Rusu, Ioana Berindan-Neagoe and Nadim Al Hajjar
Int. J. Mol. Sci. 2022, 23(20), 12370; https://doi.org/10.3390/ijms232012370 - 15 Oct 2022
Cited by 6 | Viewed by 2407
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver pathology worldwide. Meanwhile, liver cancer represents the sixth most common malignancy, with hepatocellular carcinoma (HCC) as the primary, most prevalent subtype. Due to the rising incidence of metabolic disorders, NAFLD has become one [...] Read more.
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver pathology worldwide. Meanwhile, liver cancer represents the sixth most common malignancy, with hepatocellular carcinoma (HCC) as the primary, most prevalent subtype. Due to the rising incidence of metabolic disorders, NAFLD has become one of the main contributing factors to HCC development. However, although NAFLD might account for about a fourth of HCC cases, there is currently a significant gap in HCC surveillance protocols regarding noncirrhotic NAFLD patients, so the majority of NAFLD-related HCC cases were diagnosed in late stages when survival chances are minimal. However, in the past decade, the focus in cancer genomics has shifted towards the noncoding part of the genome, especially on the microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), which have proved to be involved in the regulation of several malignant processes. This review aims to summarize the current knowledge regarding some of the main dysregulated, noncoding RNAs (ncRNAs) and their implications for NAFLD and HCC development. A central focus of the review is on miRNA and lncRNAs that can influence the progression of NAFLD towards HCC and how they can be used as potential screening tools and future therapeutic targets. Full article
(This article belongs to the Special Issue Genomics and Molecular Regulation in Cancer Pathogenesis)
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