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Special Issue "Molecular Genetics of Pancreatic Cancer and Translational Challenges"

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: 31 January 2023 | Viewed by 6380

Special Issue Editors

Prof. Dr. Lorenza Pastorino
E-Mail Website
Guest Editor
Genetics of Rare Cancers, Department of Internal Medicine and Medical Specialties, University of Genoa, 16132 Genova, Italy
Interests: melanoma; rare hereditary cancer syndrome; gene expression; functional analysis of mutations
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, Collections and Topics in MDPI journals
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, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues, 

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies in industrialized countries and is predicted to become the second leading cause of cancer death by 2030.

Therefore, PDAC represents a challenge both in terms of early detection and treatment.

Many advancements have been made recently regarding the genetics of PDAC thanks to the current methodologies in the field of molecular genetics and genomics. These methods have the potential to improve our knowledge of the molecular mechanisms of the disease and to provide drug developers with new therapy targets. Despite these advancements, more research in needed.

An exhaustive comprehension of neoplastic initiation and progression events may require a broad approach, integrating concurrent events in cancer progression or susceptibility (genetics, epigenetics, RNA interference and noncodingRNA, transcriptomics).

Basic research studies on animal models, cell cultures, organoids, and liquid biopsy can also help elucidate mechanisms of tumorigenesis which are difficult to unravel with in vivo studies due to the frequently late diagnosis of PDAC or the scarce availability of appropriate biological samples.

In this Special Issue, we warmly welcome reviews, original research articles, or short communications about any novel findings that can elucidate the development of the PDAC  through molecular genetics, at different levels, and their potential actionability,  from inheritance to biomarkers to novel therapeutic targets.

Prof. Dr. Lorenza Pastorino
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 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 2400 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

  • molecular genetics
  • genetic susceptibility
  • animal models
  • mechanisms of tumorigenesis
  • transcriptomic profiles
  • RNA interference
  • noncoding RNA
  • biomarkers
  • liquid biopsy
  • novel therapeutic targets

Published Papers (7 papers)

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Research

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Article
Inhibition of KRAS, MEK and PI3K Demonstrate Synergistic Anti-Tumor Effects in Pancreatic Ductal Adenocarcinoma Cell Lines
Cancers 2022, 14(18), 4467; https://doi.org/10.3390/cancers14184467 - 14 Sep 2022
Viewed by 930
Abstract
Kirsten rat sarcoma virus (KRAS) mutations are widespread in pancreatic ductal adenocarcinoma (PDAC) and contribute significantly to tumor initiation, progression, tumor relapse/resistance, and prognosis of patients. Although inhibitors against KRAS mutations have been developed, this therapeutic approach is not routinely used [...] Read more.
Kirsten rat sarcoma virus (KRAS) mutations are widespread in pancreatic ductal adenocarcinoma (PDAC) and contribute significantly to tumor initiation, progression, tumor relapse/resistance, and prognosis of patients. Although inhibitors against KRAS mutations have been developed, this therapeutic approach is not routinely used in PDAC patients. We investigated the anti-tumor efficacy of two KRAS inhibitors BI-3406 (KRAS::SOS1 inhibitor) and sotorasib (KRAS G12C inhibitor) alone or in combination with MEK1/2 inhibitor trametinib and/or PI3K inhibitor buparlisib in seven PDAC cell lines. Whole transcriptomic analysis of combined inhibition and control groups were comparatively analyzed to explore the corresponding mechanisms of inhibitor combination. Both KRAS inhibitors and corresponding combinations exhibited cytotoxicity against specific PDAC cell lines. BI-3406 enhance the efficacy of trametinib and buparlisib in BXPC-3, ASPC-1 and MIA PACA-2, but not in CAPAN-1, while sotorasib enhances the efficacy of trametinib and buparlisib only in MIA PACA-2. The whole transcriptomic analysis demonstrates that the two triple-inhibitor combinations exert antitumor effects by affecting related cell functions, such as affecting the immune system, cell adhesion, cell migration, and cytokine binding. As well as directly involved in RAF/MEK/ERK pathway and PI3K/AKT pathway affect cell survival. Our current study confirmed inhibition of KRAS and its downstream pathways as a potential novel therapy for PDAC and provides fundamental data for in vivo evaluations. Full article
(This article belongs to the Special Issue Molecular Genetics of Pancreatic Cancer and Translational Challenges)
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Article
Clinical Significance of Germline Pathogenic Variants among 51 Cancer Predisposition Genes in an Unselected Cohort of Italian Pancreatic Cancer Patients
Cancers 2022, 14(18), 4447; https://doi.org/10.3390/cancers14184447 - 13 Sep 2022
Cited by 1 | Viewed by 701
Abstract
Multigene germline panel testing is recommended for Pancreatic Cancer (PC) patients; however, for non-BRCA1/2 genes, the clinical utility is unclear. A comprehensive multi-gene assessment in unselected Italian PC patients is missing. We evaluated the prevalence and impact of Pathogenic Variants (PV) in [...] Read more.
Multigene germline panel testing is recommended for Pancreatic Cancer (PC) patients; however, for non-BRCA1/2 genes, the clinical utility is unclear. A comprehensive multi-gene assessment in unselected Italian PC patients is missing. We evaluated the prevalence and impact of Pathogenic Variants (PV) in 51 PC susceptibility genes in a real-world series of 422 Italian PC patients unselected for Family History (FH), compared the clinical characteristics and conducted survival analyses. 17% of patients had PVs (70/422), mainly in BRCA1/2 (4.5%, all <70 y), CDKN2A (4.5%, all >50 y), ATM (2.1%). PV carriers were younger (64 vs. 67; p = 0.02) and had more frequent personal/FH of PC, melanoma and breast/ovarian cancer (all p < 0.05). The Overall Survival (OS) was longer in patients carrying PVs (HR 0.78; p = 0.090), comprising ATM carriers (HR 0.33; p = 0.054). In the oxaliplatin-treated subset, PV carriers showed better control of the disease, although this was not statistically significant (67% vs. 56%). CDKN2A, BRCA2 and ATM were the most frequently altered genes. ATM PVs were positively associated with OS in 41% of PV carriers, 60% of whom carried CDKN2A,BRCA2 or ATM PVs, had negative FH and would have been missed by traditional referral. Thus, CDKN2A and ATM should be added to BRCA1/2 testing regardless of FH. Full article
(This article belongs to the Special Issue Molecular Genetics of Pancreatic Cancer and Translational Challenges)
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Article
A Genome-First Approach to Estimate Prevalence of Germline Pathogenic Variants and Risk of Pancreatic Cancer in Select Cancer Susceptibility Genes
Cancers 2022, 14(13), 3257; https://doi.org/10.3390/cancers14133257 - 02 Jul 2022
Cited by 2 | Viewed by 1196
Abstract
Patients with germline pathogenic variants (GPV) in cancer predisposition genes are at increased risk of pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer. The genes most frequently found to harbor GPV in unselected PDAC cases are ATM, BRCA1, BRCA2 [...] Read more.
Patients with germline pathogenic variants (GPV) in cancer predisposition genes are at increased risk of pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer. The genes most frequently found to harbor GPV in unselected PDAC cases are ATM, BRCA1, BRCA2, CDKN2A, CHEK2, and PALB2. However, GPV prevalence and gene-specific associations have not been extensively studied in the general population. To further explore these associations, we analyzed genomic and phenotypic data obtained from the UK Biobank (UKB) and Geisinger MyCode Community Health Initiative (GHS) cohorts comprising 200,600 and 175,449 participants, respectively. We estimated the frequency and calculated relative risks (RRs) of heterozygotes in both cohorts and a subset of individuals with PDAC. The combined frequency of heterozygous carriers of GPV in the general population ranged from 1.22% for CHEK2 to 0.05% for CDKN2A. The frequency of GPV in PDAC cases varied from 2.38% (ATM) to 0.19% (BRCA1 and CDKN2A). The RRs of PDAC were elevated for all genes except for BRCA1 and varied widely by gene from high (ATM) to low (CHEK2, BRCA2). This work expands our understanding of the frequencies of GPV heterozygous carriers and associations between PDAC and GPV in several important PDAC susceptibility genes. Full article
(This article belongs to the Special Issue Molecular Genetics of Pancreatic Cancer and Translational Challenges)
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Article
Oncogenic KRAS-Induced Protein Signature in the Tumor Secretome Identifies Laminin-C2 and Pentraxin-3 as Useful Biomarkers for the Early Diagnosis of Pancreatic Cancer
Cancers 2022, 14(11), 2653; https://doi.org/10.3390/cancers14112653 - 27 May 2022
Viewed by 1184
Abstract
KRAS mutations characterize pancreatic cell transformation from the earliest stages of carcinogenesis, and are present in >95% of pancreatic ductal adenocarcinoma (PDAC) cases. In search of novel biomarkers for the early diagnosis of PDAC, we identified the proteins secreted by the normal human [...] Read more.
KRAS mutations characterize pancreatic cell transformation from the earliest stages of carcinogenesis, and are present in >95% of pancreatic ductal adenocarcinoma (PDAC) cases. In search of novel biomarkers for the early diagnosis of PDAC, we identified the proteins secreted by the normal human pancreatic cell line (HPDE) recently transformed by inducing the overexpression of the KRASG12V oncogene. We report a proteomic signature of KRAS-induced secreted proteins, which was confirmed in surgical tumor samples from resected PDAC patients. The putative diagnostic performance of three candidates, Laminin-C2 (LAMC2), Tenascin-C (TNC) and Pentraxin-3 (PTX3), was investigated by ELISA quantification in two cohorts of PDAC patients (n = 200) eligible for surgery. Circulating levels of LAMC2, TNC and PTX3 were significantly higher in PDAC patients compared to the healthy individuals (p < 0.0001). The Receiver Operating Characteristics (ROC) curve showed good sensitivity (1) and specificity (0.63 and 0.85) for LAMC2 and PTX3, respectively, but not for TNC, and patients with high levels of LAMC2 had significantly shorter overall survival (p = 0.0007). High levels of LAMC2 and PTX3 were detected at early stages (I–IIB) and in CA19-9-low PDAC patients. In conclusion, pancreatic tumors release LAMC2 and PTX3, which can be quantified in the systemic circulation, and may be useful in selecting patients for further diagnostic imaging. Full article
(This article belongs to the Special Issue Molecular Genetics of Pancreatic Cancer and Translational Challenges)
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Review

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Review
Epithelial to Mesenchymal Transition as Mechanism of Progression of Pancreatic Cancer: From Mice to Men
Cancers 2022, 14(23), 5797; https://doi.org/10.3390/cancers14235797 - 24 Nov 2022
Viewed by 296
Abstract
Owed to its aggressive yet subtle nature, pancreatic cancer remains unnoticed till an advanced stage so that in most cases the diagnosis is made when the cancer has already spread to other organs with deadly efficiency. The progression from primary tumor to metastasis [...] Read more.
Owed to its aggressive yet subtle nature, pancreatic cancer remains unnoticed till an advanced stage so that in most cases the diagnosis is made when the cancer has already spread to other organs with deadly efficiency. The progression from primary tumor to metastasis involves an intricate cascade of events comprising the pleiotropic process of epithelial to mesenchymal transition (EMT) facilitating cancer spread. The elucidation of this pivotal phenotypic change in cancer cell morphology, initially heretic, moved from basic studies dissecting the progression of pancreatic cancer in animal models to move towards human disease, although no clinical translation of the concept emerged yet. Despite this transition, a full-blown mesenchymal phenotype may not be accomplished; rather, the plasticity of the program and its dependency on heterotopic signals implies a series of fluctuating modifications of cancer cells encompassing mesenchymal and epithelial features. Despite the evidence supporting the activation of EMT and MET during cancer progression, our understanding of the relationship between tumor microenvironment and EMT is not yet mature for a clinical application. In this review, we attempt to resume the knowledge on EMT and pancreatic cancer, aiming to include the EMT among the hallmarks of cancer that could potentially modify our clinical thinking with the purpose of filling the gap between the results pursued in basic research by animal models and those achieved in translational research by surrogate biomarkers, as well as their application for prognostic and predictive purposes. Full article
(This article belongs to the Special Issue Molecular Genetics of Pancreatic Cancer and Translational Challenges)
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Review
Exploring the Biology of Cancer-Associated Fibroblasts in Pancreatic Cancer
Cancers 2022, 14(21), 5302; https://doi.org/10.3390/cancers14215302 - 28 Oct 2022
Viewed by 527
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy characterised by a stubbornly low 5-year survival which is essentially unchanged in the past 5 decades. Despite recent advances in chemotherapy and surgical outcomes, progress continues to lag behind that of other cancers. The PDAC [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy characterised by a stubbornly low 5-year survival which is essentially unchanged in the past 5 decades. Despite recent advances in chemotherapy and surgical outcomes, progress continues to lag behind that of other cancers. The PDAC microenvironment is characterised by a dense, fibrotic stroma of which cancer-associated fibroblasts (CAFs) are key players. CAFs and fibrosis were initially thought to be uniformly tumour-promoting, however this doctrine is now being challenged by a wealth of evidence demonstrating CAF phenotypic and functional heterogeneity. Recent technological advances have allowed for the molecular profiling of the PDAC tumour microenvironment at exceptional detail, and these technologies are being leveraged at pace to improve our understanding of this previously elusive cell population. In this review we discuss CAF heterogeneity and recent developments in CAF biology. We explore the complex relationship between CAFs and other cell types within the PDAC microenvironment. We discuss the potential for therapeutic targeting of CAFs, and we finally provide an overview of future directions for the field and the possibility of improving outcomes for patients with this devastating disease. Full article
(This article belongs to the Special Issue Molecular Genetics of Pancreatic Cancer and Translational Challenges)
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Review
Targeting KRAS in PDAC: A New Way to Cure It?
Cancers 2022, 14(20), 4982; https://doi.org/10.3390/cancers14204982 - 11 Oct 2022
Viewed by 852
Abstract
Pancreatic cancer is one of the most intractable malignant tumors worldwide, and is known for its refractory nature and poor prognosis. The fatality rate of pancreatic cancer can reach over 90%. In pancreatic ductal carcinoma (PDAC), the most common subtype of pancreatic cancer, [...] Read more.
Pancreatic cancer is one of the most intractable malignant tumors worldwide, and is known for its refractory nature and poor prognosis. The fatality rate of pancreatic cancer can reach over 90%. In pancreatic ductal carcinoma (PDAC), the most common subtype of pancreatic cancer, KRAS is the most predominant mutated gene (more than 80%). In recent decades, KRAS proteins have maintained the reputation of being “undruggable” due to their special molecular structures and biological characteristics, making therapy targeting downstream genes challenging. Fortunately, the heavy rampart formed by KRAS has been broken down in recent years by the advent of KRASG12C inhibitors; the covalent inhibitors bond to the switch-II pocket of the KRASG12C protein. The KRASG12C inhibitor sotorasib has been received by the FDA for the treatment of patients suffering from KRASG12C-driven cancers. Meanwhile, researchers have paid close attention to the development of inhibitors for other KRAS mutations. Due to the high incidence of PDAC, developing KRASG12D/V inhibitors has become the focus of attention. Here, we review the clinical status of PDAC and recent research progress in targeting KRASG12D/V and discuss the potential applications. Full article
(This article belongs to the Special Issue Molecular Genetics of Pancreatic Cancer and Translational Challenges)
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