Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
7.4
5.2
Journals
Cancers
Special Issues
The Study of Cancer Susceptibility Genes
share announcement

The Study of Cancer Susceptibility Genes

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

Deadline for manuscript submissions: closed (30 September 2020) | Viewed by 59211

Special Issue Editors

Prof. Dr. Youri I. Pavlov

E-Mail Website
Guest Editor
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska, Omaha, NE, USA
Interests: mechanisms of maintenance of genomic stability during replication; repair; recombination; transcription and editing
Special Issues, Collections and Topics in MDPI journals
Dr. Igor Rogozin

E-Mail Website
Guest Editor
National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA
Interests: comparative studies of completely sequenced genomes; computational analysis of functional regions and signals in biological sequences; evolutionary analysis of sequences; theoretical analysis of mutagenesis
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Ashok S. Bhagwat

E-Mail Website
Guest Editor
1. Department of Chemistry, Wayne State University, Detroit, MI, USA
2. Immunology and Microbiology, Wayne State University, Detroit, MI, USA
Interests: somatic hypermutations; activation-induced deaminase; base-excision repair; uracils in DNA; APOBEC3s and innate immunity; APOBEC3s and cancer

Special Issue Information

Dear Colleagues,

The collection is the second edition of the previous one on "The Study of Cancer Susceptibility Genes" at https://0-www-mdpi-com.brum.beds.ac.uk/journal/cancers/special_issues/Susceptibility_Genes.

Cancer is a disease caused by heritable changes that include point mutations, chromosome rearrangements/copy number variation, and epigenetic reprogramming. Several sequential changes are required to produce tumor cells. Aberrant genome maintenance leads to increased mutation rates, fueling tumorigenesis and predisposing to cancer. The examples are genome alterations causing mismatch repair defects, lowering fidelity but increasing endurance of replicative DNA polymerases, and breaking precise control of intrinsic mutagenic factors: error-prone DNA polymerases or editing enzymes of the AID/APOBEC family. The analysis of tumor genomes allows identifying the origins of mutators. The type of factors causing increased cancer incidence influences therapeutic interventions’ outcomes.

Prof. Dr. Ashok S. Bhagwat
Dr. Youri I. Pavlov
Dr. Igor Rogozin
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 2900 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

  • cancer
  • metastasis
  • cancer susceptibility genes
  • cell signaling
  • DNA replication, repair and editing
  • hereditary cancer
  • sporadic cancer
  • stability of hereditary material

Published Papers (19 papers)

Download All Papers
Order results
Result details
Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:

Editorial

Jump to: Research, Review

3 pages, 194 KiB  
Editorial
The Study of Cancer Susceptibility Genes
by Youri I. Pavlov
Cancers 2021, 13(9), 2258; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13092258 - 08 May 2021
Cited by 1 | Viewed by 1301
Abstract
“…most complex, new direction for cancer medicine is to integrate our understanding of aberrant genes and pathways to explain the behavior of cancer as a whole, thereby renewing the cycle of knowledge, discovery and therapeutic intervention [...] Full article
(This article belongs to the Special Issue The Study of Cancer Susceptibility Genes)

Research

Jump to: Editorial, Review

16 pages, 779 KiB  
Article
Hereditary Diffuse Gastric Cancer: A Comparative Cohort Study According to Pathogenic Variant Status
by Tim Marwitz, Robert Hüneburg, Isabel Spier, Jan-Frederic Lau, Glen Kristiansen, Philipp Lingohr, Jörg C. Kalff, Stefan Aretz, Jacob Nattermann and Christian P. Strassburg
Cancers 2020, 12(12), 3726; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12123726 - 11 Dec 2020
Cited by 9 | Viewed by 2956
Abstract
Hereditary diffuse gastric cancer (HDGC) is an inherited cancer susceptibility syndrome characterized by an elevated risk for diffuse gastric cancer (DGC) and lobular breast cancer (LBC). Some patients fulfilling the clinical testing criteria harbor a pathogenic CDH1 or CTNNA1 germline variant. However, the [...] Read more.
Hereditary diffuse gastric cancer (HDGC) is an inherited cancer susceptibility syndrome characterized by an elevated risk for diffuse gastric cancer (DGC) and lobular breast cancer (LBC). Some patients fulfilling the clinical testing criteria harbor a pathogenic CDH1 or CTNNA1 germline variant. However, the underlying mechanism for around 80% of the patients with a family or personal history of DGC and LBC has so far not been elucidated. In this cohort study, patients meeting the 2015 HDGC clinical testing criteria were included, and subsequently, CDH1 sequencing was performed. Of the 207 patients (161 families) in this study, we detected 21 pathogenic or likely pathogenic CDH1 variants (PV) in 60 patients (28 families) and one CTNNA1 PV in two patients from one family. Sixty-eight percent (n = 141) of patients were female. The overall PV detection rate was 18% (29/161 families). Criterion 1 and 3 of the 2015 HDGC testing criteria yielded the highest detection rate of CDH1/CTNNA1 PVs (21% and 28%). PV carriers and patients without proven PV were compared. Risk of gastric cancer (GC) (38/62 61% vs. 102/140 73%) and age at diagnosis (40 ± 13 years vs. 44 ± 12 years) were similar between the two groups. However, GC was more advanced in gastrectomy specimens of patients without PV (81% vs. 26%). LBC prevalence in female carriers of a PV was 20% (n = 8/40). Clinical phenotypes differed strongly between families with the same PV. Emphasis should be on detecting more causative genes predisposing for HDGC and improve the management of patients without a proven pathogenic germline variant. Full article
(This article belongs to the Special Issue The Study of Cancer Susceptibility Genes)
►▼ Show Figures

Figure 1

15 pages, 631 KiB  
Article
SNP-SNP Interaction in Genes Encoding PD-1/PD-L1 Axis as a Potential Risk Factor for Clear Cell Renal Cell Carcinoma
by Marta Wagner, Krzysztof Tupikowski, Monika Jasek, Anna Tomkiewicz, Agata Witkowicz, Kuba Ptaszkowski, Pawel Karpinski, Romuald Zdrojowy, Agnieszka Halon and Lidia Karabon
Cancers 2020, 12(12), 3521; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12123521 - 26 Nov 2020
Cited by 8 | Viewed by 2269
Abstract
PD-1/PD-L1 axis plays an important role in maintaining homeostasis and prevention from autoimmunity; however, in the tumor microenvironment, PD-1/PD-L1 interaction is responsible for the evasion of immune surveillance by tumor cells. We therefore hypothesized that single nucleotide polymorphisms (SNPs) in genes encoding PD-1 [...] Read more.
PD-1/PD-L1 axis plays an important role in maintaining homeostasis and prevention from autoimmunity; however, in the tumor microenvironment, PD-1/PD-L1 interaction is responsible for the evasion of immune surveillance by tumor cells. We therefore hypothesized that single nucleotide polymorphisms (SNPs) in genes encoding PD-1 and PD-L1 molecules are associated with the development and outcome of renal cell carcinoma (RCC). Here we genotyped nine polymorphisms: five of PDCD1: rs36084323G>A, rs11568821G>A, rs2227981C>T, rs10204525G>A, rs7421861T>C and four of PD-L1: rs822335C>T, rs4143815G>C, rs4742098A>G, rs10815225G>C in 237 RCC patients (including 208 with clear cell RCC (ccRCC)) and 256 controls, with application of allelic discrimination method with use of TaqMan Assays. Interestingly, we found the SNP-SNP interaction between rs10815225 and rs7421861 polymorphisms associated with ccRCC risk. The rs7421861 TC genotype decreased the risk of ccRCC development compared to TT and CC genotypes in the group of rs10815225 GC + CC individuals (OR = 0.21, CI95% = 0.08; 0.54). While possessing of rs10815225 GC or CC genotype increased susceptibility to ccRCC when compared to rs10815225 GG genotype in individuals with rs7421861 TT or CC genotype (OR = 2.40, CI95% = 1.25; 4.61). In conclusion, genetic variants in PDCD1 and PD-L1 genes, especially taken together as SNP-SNP interactions, can be considered to be ccRCC risk factors. Full article
(This article belongs to the Special Issue The Study of Cancer Susceptibility Genes)
►▼ Show Figures

Figure 1

12 pages, 1751 KiB  
Article
Novel DNMT3A Germline Variant in a Patient with Multiple Paragangliomas and Papillary Thyroid Carcinoma
by Sara Mellid, Javier Coloma, Bruna Calsina, María Monteagudo, Juan M. Roldán-Romero, María Santos, Luis J. Leandro-García, Javier Lanillos, Ángel M. Martínez-Montes, Cristina Rodríguez-Antona, Cristina Montero-Conde, Joaquín Martínez-López, Rosa Ayala, Xavier Matias-Guiu, Mercedes Robledo and Alberto Cascón
Cancers 2020, 12(11), 3304; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12113304 - 09 Nov 2020
Cited by 4 | Viewed by 2527
Abstract
Over the past few years, next generation technologies have been applied to unravel the genetics of rare inherited diseases, facilitating the discovery of new susceptibility genes. We recently found germline DNMT3A gain-of-function variants in two patients with head and neck paragangliomas causing a [...] Read more.
Over the past few years, next generation technologies have been applied to unravel the genetics of rare inherited diseases, facilitating the discovery of new susceptibility genes. We recently found germline DNMT3A gain-of-function variants in two patients with head and neck paragangliomas causing a characteristic hypermethylated DNA profile. Here, whole-exome sequencing identifies a novel germline DNMT3A variant (p.Gly332Arg) in a patient with bilateral carotid paragangliomas, papillary thyroid carcinoma and idiopathic intellectual disability. The variant, located in the Pro-Trp-Trp-Pro (PWWP) domain of the protein involved in chromatin targeting, affects a residue mutated in papillary thyroid tumors and located between the two residues found mutated in microcephalic dwarfism patients. Structural modelling of the variant in the DNMT3A PWWP domain predicts that the interaction with H3K36me3 will be altered. An increased methylation of DNMT3A target genes, compatible with a gain-of-function effect of the alteration, was observed in saliva DNA from the proband and in one independent acute myeloid leukemia sample carrying the same p.Gly332Arg variant. Although further studies are needed to support a causal role of DNMT3A variants in paraganglioma, the description of a new DNMT3A alteration in a patient with multiple clinical features suggests a heterogeneous phenotypic spectrum related to DNMT3A germline variants. Full article
(This article belongs to the Special Issue The Study of Cancer Susceptibility Genes)
►▼ Show Figures

Figure 1

15 pages, 810 KiB  
Article
Association of Common Variants of TNFSF13 and TNFRSF13B Genes with CLL Risk and Clinical Picture, as Well as Expression of Their Products—APRIL and TACI Molecules
by Monika Jasek, Agnieszka Bojarska-Junak, Maciej Sobczyński, Marta Wagner, Sylwia Chocholska, Jacek Roliński, Dariusz Wołowiec and Lidia Karabon
Cancers 2020, 12(10), 2873; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12102873 - 06 Oct 2020
Cited by 4 | Viewed by 2102
Abstract
Interactions between APRIL (TNFSF13) and its receptor TACI (TNFRSF13B) are implicated in providing survival benefits for chronic lymphocytic leukaemia (CLL) cells. Here we explored the relationship between TNFSF13 and TNFRSF13B SNPs and expression of APRIL and TACI molecules and performed extended case-control study [...] Read more.
Interactions between APRIL (TNFSF13) and its receptor TACI (TNFRSF13B) are implicated in providing survival benefits for chronic lymphocytic leukaemia (CLL) cells. Here we explored the relationship between TNFSF13 and TNFRSF13B SNPs and expression of APRIL and TACI molecules and performed extended case-control study to evaluate earlier observations. Expression of APRIL and TACI was detected by FACS for 72 and 145 patients, respectively, and soluble APRIL was measured by ELISA in plasma of 122 patients. Genotypes were determined in 439 CLL patients and 477 control subjects with TaqMan Assays or restriction fragment length polymorphism (RFLP). The rs4968210GG genotype of TNFSF13 was associated with a lower percentage of CD19+APRIL+ cells in CLL patients when compared to (AA + GA) genotypes (p-value = 0.027). Homozygosity at rs11078355 TNFRSF13B was associated with higher CD19+ TACI+ cell percentage in CLL patients (p-value = 0.036). The analysis of extended groups of patients and healthy controls confirmed the association of TNFSF13 rs3803800AA genotype with a higher CLL risk (OR = 2.13; CI95% = 1.21; 3.75; p-value = 0.007), while the possession of TNFRSF13B rs4985726G allele (CG + GG) genotype was associated with lower risk of CLL (OR = 0.69; CI95% = 0.51; 0.95; p-value = 0.02). Genetic variants of TNFSF13 and TNFRSF13B may have an impact on APRIL and TACI expression and may be considered as possible CLL risk factors. Full article
(This article belongs to the Special Issue The Study of Cancer Susceptibility Genes)
►▼ Show Figures

Graphical abstract

11 pages, 742 KiB  
Article
Genetic Counseling for Hereditary Gastric and Pancreatic Cancer in High-Risk Gastrointestinal Cancer Clinics: An Effective Strategy
by Joan Llach, Lorena Moreno, Ariadna Sánchez, Cristina Herrera-Pariente, Teresa Ocaña, Miriam Cuatrecasas, Liseth Rivero-Sánchez, Rebeca Moreira, Mireia Díaz, Gerhard Jung, Maria Pellisé, Antoni Castells, Francesc Balaguer, Sabela Carballal and Leticia Moreira
Cancers 2020, 12(9), 2386; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12092386 - 23 Aug 2020
Cited by 10 | Viewed by 3065
Abstract
The identification of high-risk groups of gastric (GC) and pancreatic adenocarcinoma (PC) due to a hereditary basis could imply a benefit in the affected families by establishing personalized preventive strategies. We aimed at assessing the diagnostic yield of GC/PC hereditary syndromes in individuals [...] Read more.
The identification of high-risk groups of gastric (GC) and pancreatic adenocarcinoma (PC) due to a hereditary basis could imply a benefit in the affected families by establishing personalized preventive strategies. We aimed at assessing the diagnostic yield of GC/PC hereditary syndromes in individuals evaluated based on specific clinical criteria. In total, 77 unrelated individuals (45 from GC group/32 from PC group) were recruited: 51 (66.2%) cancer diagnosis ≤60 years, 3 (4%) with personal history of GC/PC and other cancer and 23 (29.8%) due to family history. Immunohistochemical analysis of DNA mismatch repair proteins was performed in 38 (49.3%) available tumors, being pathological in one (2%) GC. A genetic analysis was performed if clinical criteria of hereditary syndrome were fulfilled, identifying a mutation in 10/22 (45.5%) families [7/16 (43.7%) with GC and 3/6 (50%) with PC] and 19 (24.7%) fulfilled criteria of familial cancer. Diagnosis of cancer <40 years and personal history of other cancers were independent risk factors of a hereditary syndrome [OR:11.3 (95%IC 1.9–67); p = 0.007 and OR:17.4 (95% IC 2.5–119.9); p = 0.004; respectively]. The selection of patients based on clinical criteria leads to high diagnostic yield, detecting a causative germline mutation in almost half of the cases; therefore, both meticulous genetic counseling and use of multi-gen panels is crucial. Full article
(This article belongs to the Special Issue The Study of Cancer Susceptibility Genes)
►▼ Show Figures

Graphical abstract

18 pages, 961 KiB  
Article
Clinical and Molecular Assessment of Patients with Lynch Syndrome and Sarcomas Underpinning the Association with MSH2 Germline Pathogenic Variants
by Nathália de Angelis de Carvalho, Bianca Naomi Niitsuma, Vanessa Nascimento Kozak, Felipe D’almeida Costa, Mariana Petaccia de Macedo, Bruna Elisa Catin Kupper, Maria Letícia Gobo Silva, Maria Nirvana Formiga, Sahlua Miguel Volc, Samuel Aguiar Junior, Edenir Inez Palmero, José Cláudio Casali-da-Rocha, Dirce Maria Carraro and Giovana Tardin Torrezan
Cancers 2020, 12(7), 1848; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12071848 - 09 Jul 2020
Cited by 14 | Viewed by 2886
Abstract
Lynch syndrome (LS) is a hereditary cancer-predisposing syndrome associated most frequently with epithelial tumors, particularly colorectal (CRC) and endometrial carcinomas (EC). The aim of this study was to investigate the relationship between sarcomas and LS by performing clinical and molecular characterization of patients [...] Read more.
Lynch syndrome (LS) is a hereditary cancer-predisposing syndrome associated most frequently with epithelial tumors, particularly colorectal (CRC) and endometrial carcinomas (EC). The aim of this study was to investigate the relationship between sarcomas and LS by performing clinical and molecular characterization of patients presenting co-occurrence of sarcomas and tumors from the LS spectrum. We identified 27 patients diagnosed with CRC, EC, and other LS-associated tumors who had sarcomas in the same individuals or families. Germline genetic testing, mismatch repair (MMR) protein immunohistochemistry, microsatellite instability (MSI), and other molecular analyses were performed. Five LS patients presenting personal or family history of sarcomas were identified (3 MSH2 carriers and 2 MLH1), with 2 having Muir–Torre phenotypes. For two MSH2 carriers we confirmed the etiology of the sarcomas (one liposarcoma and two osteosarcomas) as LS-related, since the tumors were MSH2/MSH6-deficient, MSI-high, or presented a truncated MSH2 transcript. Additionally, we reviewed 43 previous reports of sarcomas in patients with LS, which revealed a high frequency (58%) of MSH2 alterations. In summary, sarcomas represent a rare clinical manifestation in patients with LS, especially in MSH2 carriers, and the analysis of tumor biological characteristics can be useful for definition of tumor etiology and novel therapeutic options. Full article
(This article belongs to the Special Issue The Study of Cancer Susceptibility Genes)
►▼ Show Figures

Figure 1

17 pages, 3374 KiB  
Article
TP53-Deficient Angiosarcoma Expression Profiling in Rat Model
by Urszula Smyczyńska, Damian Strzemecki, Anna M. Czarnecka, Wojciech Fendler, Michał Fiedorowicz, Marlena Wełniak-Kamińska, Magdalena Guzowska, Kamil Synoradzki, Łukasz Cheda, Zbigniew Rogulski and Paweł Grieb
Cancers 2020, 12(6), 1525; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12061525 - 10 Jun 2020
Cited by 4 | Viewed by 3390
Abstract
Sarcomas are a heterogeneous group of malignant tumors, that develop from mesenchymal cells. Sarcomas are tumors associated with poor prognosis and expected short overall survival. Efforts to improve treatment efficacy and treatment outcomes of advanced and metastatic sarcoma patients have not led to [...] Read more.
Sarcomas are a heterogeneous group of malignant tumors, that develop from mesenchymal cells. Sarcomas are tumors associated with poor prognosis and expected short overall survival. Efforts to improve treatment efficacy and treatment outcomes of advanced and metastatic sarcoma patients have not led to significant improvements in the last decades. In the Tp53C273X/C273X rat model we therefore aimed to characterize specific gene expression pattern of angiosarcomas with a loss of TP53 function. The presence of metabolically active tumors in several locations including the brain, head and neck, extremities and abdomen was confirmed by magnetic resonance imaging (MRI) and positron emission tomography (PET) examinations. Limb angiosarcoma tumors were selected for microarray expression analysis. The most upregulated pathways in angiosarcoma vs all other tissues were related to cell cycle with mitosis and meiosis, chromosome, nucleosome and telomere maintenance as well as DNA replication and recombination. The downregulated genes were responsible for metabolism, including respiratory chain electron transport, tricarboxylic acid (TCA) cycle, fatty acid metabolism and amino-acid catabolism. Our findings demonstrated that the type of developing sarcoma depends on genetic background, underscoring the importance of developing more malignancy susceptibility models in various strains and species to simulate the study of the diverse genetics of human sarcomas. Full article
(This article belongs to the Special Issue The Study of Cancer Susceptibility Genes)
►▼ Show Figures

Graphical abstract

16 pages, 3636 KiB  
Article
SPON2 Is Upregulated through Notch Signaling Pathway and Promotes Tumor Progression in Gastric Cancer
by Hyeon-Gu Kang, Won-Jin Kim, Myung-Giun Noh, Kyung-Hee Chun and Seok-Jun Kim
Cancers 2020, 12(6), 1439; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12061439 - 01 Jun 2020
Cited by 19 | Viewed by 3643
Abstract
Spondin-2 (SPON2) is involved in cancer progression and metastasis of many tumors; however, its role and underlying mechanism in gastric cancer are still obscure. In this study, we investigated the role of SPON2 and related signaling pathway in gastric cancer progression and metastasis. [...] Read more.
Spondin-2 (SPON2) is involved in cancer progression and metastasis of many tumors; however, its role and underlying mechanism in gastric cancer are still obscure. In this study, we investigated the role of SPON2 and related signaling pathway in gastric cancer progression and metastasis. SPON2 expression levels were found to be upregulated in gastric cancer cell lines and patient tissues compared to normal gastric epithelial cells and normal controls. Furthermore, SPON2 silencing was observed to decrease cell proliferation and motility and reduce tumor growth in xenograft mice. Conversely, SPON2 overexpression was found to increase cell proliferation and motility. Subsequently, we focused on regulatory mechanism of SPON2 in gastric cancer. cDNA microarray and in vitro study showed that Notch signaling is significantly correlated to SPON2 expression. Therefore, we confirmed how Notch signaling pathway regulate SPON2 expression using Notch signaling-related transcription factor interaction and reporter gene assay. Additionally, activation of Notch signaling was observed to increase cell proliferation, migration, and invasion through SPON2 expression. Our study demonstrated that Notch signaling-mediated SPON2 upregulation is associated with aggressive progression of gastric cancer. In conclusion, we suggest upregulated SPON2 via Notch signaling as a potential target gene to inhibit gastric cancer progression. Full article
(This article belongs to the Special Issue The Study of Cancer Susceptibility Genes)
►▼ Show Figures

Graphical abstract

9 pages, 1018 KiB  
Article
Genetic Analysis Reveals a Significant Contribution of CES1 to Prostate Cancer Progression in Taiwanese Men
by Chien-Chih Ke, Lih-Chyang Chen, Chia-Cheng Yu, Wei-Chung Cheng, Chao-Yuan Huang, Victor C. Lin, Te-Ling Lu, Shu-Pin Huang and Bo-Ying Bao
Cancers 2020, 12(5), 1346; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12051346 - 25 May 2020
Cited by 11 | Viewed by 2883
Abstract
The genes that influence prostate cancer progression remain largely unknown. Since the carboxylesterase gene family plays a crucial role in xenobiotic metabolism and lipid/cholesterol homeostasis, we hypothesize that genetic variants in carboxylesterase genes may influence clinical outcomes for prostate cancer patients. A total [...] Read more.
The genes that influence prostate cancer progression remain largely unknown. Since the carboxylesterase gene family plays a crucial role in xenobiotic metabolism and lipid/cholesterol homeostasis, we hypothesize that genetic variants in carboxylesterase genes may influence clinical outcomes for prostate cancer patients. A total of 478 (36 genotyped and 442 imputed) single nucleotide polymorphisms (SNPs) in five genes of the carboxylesterase family were assessed in terms of their associations with biochemical recurrence (BCR)-free survival in 643 Taiwanese patients with prostate cancer who underwent radical prostatectomy. The strongest association signal was shown in CES1 (P = 9.64 × 10−4 for genotyped SNP rs8192935 and P = 8.96 × 10−5 for imputed SNP rs8192950). After multiple test correction and adjustment for clinical covariates, CES1 rs8192935 (P = 9.67 × 10−4) and rs8192950 (P = 9.34 × 10−5) remained significant. These SNPs were correlated with CES1 expression levels, which in turn were associated with prostate cancer aggressiveness. Furthermore, our meta-analysis, including eight studies, indicated that a high CES1 expression predicted better outcomes among prostate cancer patients (hazard ratio 0.82, 95% confidence interval 0.70–0.97, P = 0.02). In conclusion, our findings suggest that CES1 rs8192935 and rs8192950 are associated with BCR and that CES1 plays a tumor suppressive role in prostate cancer. Full article
(This article belongs to the Special Issue The Study of Cancer Susceptibility Genes)
►▼ Show Figures

Figure 1

36 pages, 3282 KiB  
Article
Risk of Alzheimer’s Disease in Cancer Patients: Analysis of Mortality Data from the US SEER Population-Based Registries
by Roman Mezencev and Yury O. Chernoff
Cancers 2020, 12(4), 796; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12040796 - 26 Mar 2020
Cited by 14 | Viewed by 3848
Abstract
Previous studies have reported an inverse association between cancer and Alzheimer’s disease (AD), which are leading causes of human morbidity and mortality. We analyzed the SEER (Surveillance, Epidemiology, and End Results) data to estimate the risk of AD death in (i) cancer patients [...] Read more.
Previous studies have reported an inverse association between cancer and Alzheimer’s disease (AD), which are leading causes of human morbidity and mortality. We analyzed the SEER (Surveillance, Epidemiology, and End Results) data to estimate the risk of AD death in (i) cancer patients relative to reference populations stratified on demographic and clinical variables, and (ii) female breast cancer (BC) patients treated with chemotherapy or radiotherapy, relative to those with no/unknown treatment status. Our results demonstrate the impact of race, cancer type, age and time since cancer diagnosis on the risk of AD death in cancer patients. While the risk of AD death was decreased in white patients diagnosed with various cancers at 45 or more years of age, it was increased in black patients diagnosed with cancers before 45 years of age (likely due to early onset AD). Chemotherapy decreased the risk of AD death in white women diagnosed with BC at the age of 65 or more, however radiotherapy displayed a more complex pattern with early decrease and late increase in the risk of AD death during a prolonged time interval after the treatment. Our data point to links between molecular mechanisms involved in cancer and AD, and to the potential applicability of some anti-cancer treatments against AD. Full article
(This article belongs to the Special Issue The Study of Cancer Susceptibility Genes)
►▼ Show Figures

Figure 1

23 pages, 6515 KiB  
Article
Mutation Enrichment and Transcriptomic Activation Signatures of 419 Molecular Pathways in Cancer
by Marianna A. Zolotovskaia, Victor S. Tkachev, Alexander P. Seryakov, Denis V. Kuzmin, Dmitry E. Kamashev, Maxim I. Sorokin, Sergey A. Roumiantsev and Anton A. Buzdin
Cancers 2020, 12(2), 271; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12020271 - 22 Jan 2020
Cited by 13 | Viewed by 2478
Abstract
Carcinogenesis is linked with massive changes in regulation of gene networks. We used high throughput mutation and gene expression data to interrogate involvement of 278 signaling, 72 metabolic, 48 DNA repair and 47 cytoskeleton molecular pathways in cancer. Totally, we analyzed 4910 primary [...] Read more.
Carcinogenesis is linked with massive changes in regulation of gene networks. We used high throughput mutation and gene expression data to interrogate involvement of 278 signaling, 72 metabolic, 48 DNA repair and 47 cytoskeleton molecular pathways in cancer. Totally, we analyzed 4910 primary tumor samples with individual cancer RNA sequencing and whole exome sequencing profiles including ~1.3 million DNA mutations and representing thirteen cancer types. Gene expression in cancers was compared with the corresponding 655 normal tissue profiles. For the first time, we calculated mutation enrichment values and activation levels for these pathways. We found that pathway activation profiles were largely congruent among the different cancer types. However, we observed no correlation between mutation enrichment and expression changes both at the gene and at the pathway levels. Overall, positive median cancer-specific activation levels were seen in the DNA repair, versus similar slightly negative values in the other types of pathways. The DNA repair pathways also demonstrated the highest values of mutation enrichment. However, the signaling and cytoskeleton pathways had the biggest proportions of representatives among the outstandingly frequently mutated genes thus suggesting their initiator roles in carcinogenesis and the auxiliary/supporting roles for the other groups of molecular pathways. Full article
(This article belongs to the Special Issue The Study of Cancer Susceptibility Genes)
►▼ Show Figures

Figure 1

10 pages, 218 KiB  
Article
Should Genetic Testing for Cancer Predisposition Be Standard-of-Care for Women with Invasive Breast Cancer? The Murtha Cancer Center Experience
by Seth K. Rummel, Leann A. Lovejoy, Clesson E. Turner, Craig D. Shriver and Rachel E. Ellsworth
Cancers 2020, 12(1), 234; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12010234 - 17 Jan 2020
Cited by 7 | Viewed by 3605
Abstract
Currently, genetic testing is offered only to women diagnosed with breast cancer who meet a defined set of criteria and is not included as standard-of-care treatment at the time of diagnosis. Thus, a significant number of women diagnosed with breast cancer may miss [...] Read more.
Currently, genetic testing is offered only to women diagnosed with breast cancer who meet a defined set of criteria and is not included as standard-of-care treatment at the time of diagnosis. Thus, a significant number of women diagnosed with breast cancer may miss the opportunity for precision medical treatment and risk management. The effects of eligibility, timing, and uptake of genetic testing were evaluated in a cohort of women with invasive breast cancer diagnosed between 2001–2018. Risk status was estimated using NCCN BRCA1/2 testing criteria and panel testing was performed for all women who had genomic DNA available. Of the 1231 women, 57.8% were eligible for genetic testing. Uptake of testing within high-risk women was 42.7% of which 6.6% pursued clinical testing only after a second tumor event. Mutation frequencies were 15.8%, 5.5%, and 4.0% in high-risk women with clinical testing, high-risk women without clinical testing, and low-risk women, respectively. More than 4% of all patients harbored pathogenic or likely pathogenic mutations detected only in the research setting. Inclusion of panel testing at the time of diagnosis would allow for appropriate surveillance and treatment strategies to be employed to reduce the risk of secondary tumors and improve patient outcome. Full article
(This article belongs to the Special Issue The Study of Cancer Susceptibility Genes)
►▼ Show Figures

Graphical abstract

14 pages, 1379 KiB  
Article
Single Nucleotide Polymorphism rs6942067 Is a Risk Factor in Young and in Non-Smoking Patients with HPV Negative Head and Neck Squamous Cell Carcinoma
by Guillaume B. Cardin, Monique Bernard, Houda Bahig, Phuc Felix Nguyen-Tan, Olivier Ballivy, Edith Filion, Denis Soulieres, Pierre Philouze, Tareck Ayad, Louis Guertin, Eric Bissada, Francis Rodier and Apostolos Christopoulos
Cancers 2020, 12(1), 55; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12010055 - 24 Dec 2019
Cited by 11 | Viewed by 2955
Abstract
Genetic factors behind the increasing incidence of human papillomavirus (HPV) negative head and neck squamous cell carcinoma (HNSCC) in young non-smokers are suspected, but have not been identified. Recently, rs6942067, a single nucleotide polymorphism (SNP) located upstream of the DCBLD1 gene, was found [...] Read more.
Genetic factors behind the increasing incidence of human papillomavirus (HPV) negative head and neck squamous cell carcinoma (HNSCC) in young non-smokers are suspected, but have not been identified. Recently, rs6942067, a single nucleotide polymorphism (SNP) located upstream of the DCBLD1 gene, was found associated with non-smoking lung adenocarcinoma. To validate if this SNP is also implicated in HNSCC, participants of The Cancer Genome Atlas HNSCC cohort were investigated for rs6942067 status, associated DCBLD1 expression, and clinical characteristics. Occurrence of the rs6942067 GG genotype is significantly higher in young and in HPV negative non-smoking HNSCC than in other HNSCC. Additionally, rs6942067 GG is associated with higher DCBLD1 expression in HNSCC and patients with high DCBLD1 expression have a worse overall survival at three years, both in univariate and multivariate analysis. Furthermore, high DCBLD1 expression is associated with activation of the integrin signaling pathway and its phosphorylation with EGFR and MET. Collectively, these findings suggest that DCBLD1 plays a critical role in HNSCC and demonstrate an association between rs6942067 and clinical characteristics of young age and HPV negative non-smoking status in HNSCC patients. Full article
(This article belongs to the Special Issue The Study of Cancer Susceptibility Genes)
►▼ Show Figures

Figure 1

Review

Jump to: Editorial, Research

17 pages, 470 KiB  
Review
DNA Methylation in Ovarian Cancer Susceptibility
by Brett M. Reid and Brooke L. Fridley
Cancers 2021, 13(1), 108; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13010108 - 31 Dec 2020
Cited by 12 | Viewed by 3495
Abstract
Epigenetic alterations are somatically acquired over the lifetime and during neoplastic transformation but may also be inherited as widespread ‘constitutional’ alterations in normal tissues that can cause cancer predisposition. Epithelial ovarian cancer (EOC) has an established genetic susceptibility and mounting epidemiological evidence demonstrates [...] Read more.
Epigenetic alterations are somatically acquired over the lifetime and during neoplastic transformation but may also be inherited as widespread ‘constitutional’ alterations in normal tissues that can cause cancer predisposition. Epithelial ovarian cancer (EOC) has an established genetic susceptibility and mounting epidemiological evidence demonstrates that DNA methylation (DNAm) intermediates as well as independently contributes to risk. Targeted studies of known EOC susceptibility genes (CSGs) indicate rare, constitutional BRCA1 promoter methylation increases familial and sporadic EOC risk. Blood-based epigenome-wide association studies (EWAS) for EOC have detected a total of 2846 differentially methylated probes (DMPs) with 71 genes replicated across studies despite significant heterogeneity. While EWAS detect both symptomatic and etiologic DMPs, adjustments and analytic techniques may enrich risk associations, as evidenced by the detection of dysregulated methylation of BNC2—a known CSG identified by genome-wide associations studies (GWAS). Integrative genetic–epigenetic approaches have mapped methylation quantitative trait loci (meQTL) to EOC risk, revealing DNAm variations that are associated with nine GWAS loci and, further, one novel risk locus. Increasing efforts to mapping epigenome variation across populations and cell types will be key to decoding both the genomic and epigenomic causal pathways to EOC. Full article
(This article belongs to the Special Issue The Study of Cancer Susceptibility Genes)
►▼ Show Figures

Figure 1

20 pages, 2229 KiB  
Review
DNA Polymerases at the Eukaryotic Replication Fork Thirty Years after: Connection to Cancer
by Youri I. Pavlov, Anna S. Zhuk and Elena I. Stepchenkova
Cancers 2020, 12(12), 3489; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12123489 - 24 Nov 2020
Cited by 13 | Viewed by 3182 | Correction
Abstract
Recent studies on tumor genomes revealed that mutations in genes of replicative DNA polymerases cause a predisposition for cancer by increasing genome instability. The past 10 years have uncovered exciting details about the structure and function of replicative DNA polymerases and the replication [...] Read more.
Recent studies on tumor genomes revealed that mutations in genes of replicative DNA polymerases cause a predisposition for cancer by increasing genome instability. The past 10 years have uncovered exciting details about the structure and function of replicative DNA polymerases and the replication fork organization. The principal idea of participation of different polymerases in specific transactions at the fork proposed by Morrison and coauthors 30 years ago and later named “division of labor,” remains standing, with an amendment of the broader role of polymerase δ in the replication of both the lagging and leading DNA strands. However, cancer-associated mutations predominantly affect the catalytic subunit of polymerase ε that participates in leading strand DNA synthesis. We analyze how new findings in the DNA replication field help elucidate the polymerase variants’ effects on cancer. Full article
(This article belongs to the Special Issue The Study of Cancer Susceptibility Genes)
►▼ Show Figures

Figure 1

16 pages, 506 KiB  
Review
A Gene Expression High-Throughput Screen (GE-HTS) for Coordinated Detection of Functionally Similar Effectors in Cancer
by Chaitra Rao, Dianna H. Huisman, Heidi M. Vieira, Danielle E. Frodyma, Beth K. Neilsen, Binita Chakraborty, Suzie K. Hight, Michael A. White, Kurt W. Fisher and Robert E. Lewis
Cancers 2020, 12(11), 3143; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12113143 - 27 Oct 2020
Cited by 6 | Viewed by 2987
Abstract
Genome-wide, loss-of-function screening can be used to identify novel vulnerabilities upon which specific tumor cells depend for survival. Functional Signature Ontology (FUSION) is a gene expression-based high-throughput screening (GE-HTS) method that allows researchers to identify functionally similar proteins, small molecules, and microRNA mimics, [...] Read more.
Genome-wide, loss-of-function screening can be used to identify novel vulnerabilities upon which specific tumor cells depend for survival. Functional Signature Ontology (FUSION) is a gene expression-based high-throughput screening (GE-HTS) method that allows researchers to identify functionally similar proteins, small molecules, and microRNA mimics, revealing novel therapeutic targets. FUSION uses cell-based high-throughput screening and computational analysis to match gene expression signatures produced by natural products to those produced by small interfering RNA (siRNA) and synthetic microRNA libraries to identify putative protein targets and mechanisms of action (MoA) for several previously undescribed natural products. We have used FUSION to screen for functional analogues to Kinase suppressor of Ras 1 (KSR1), a scaffold protein downstream of Ras in the Raf-MEK-ERK kinase cascade, and biologically validated several proteins with functional similarity to KSR1. FUSION incorporates bioinformatics analysis that may offer higher resolution of the endpoint readout than other screens which utilize Boolean outputs regarding a single pathway activation (i.e., synthetic lethal and cell proliferation). Challenges associated with FUSION and other high-content genome-wide screens include variation, batch effects, and controlling for potential off-target effects. In this review, we discuss the efficacy of FUSION to identify novel inhibitors and oncogene-induced changes that may be cancer cell-specific as well as several potential pitfalls within FUSION and best practices to avoid them. Full article
(This article belongs to the Special Issue The Study of Cancer Susceptibility Genes)
►▼ Show Figures

Figure 1

23 pages, 1651 KiB  
Review
Canonical and Noncanonical Roles of Fanconi Anemia Proteins: Implications in Cancer Predisposition
by Giacomo Milletti, Luisa Strocchio, Daria Pagliara, Katia Girardi, Roberto Carta, Angela Mastronuzzi, Franco Locatelli and Francesca Nazio
Cancers 2020, 12(9), 2684; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12092684 - 20 Sep 2020
Cited by 26 | Viewed by 5146
Abstract
Fanconi anemia (FA) is a clinically and genetically heterogeneous disorder characterized by the variable presence of congenital somatic abnormalities, bone marrow failure (BMF), and a predisposition to develop cancer. Monoallelic germline mutations in at least five genes involved in the FA pathway are [...] Read more.
Fanconi anemia (FA) is a clinically and genetically heterogeneous disorder characterized by the variable presence of congenital somatic abnormalities, bone marrow failure (BMF), and a predisposition to develop cancer. Monoallelic germline mutations in at least five genes involved in the FA pathway are associated with the development of sporadic hematological and solid malignancies. The key function of the FA pathway is to orchestrate proteins involved in the repair of interstrand cross-links (ICLs), to prevent genomic instability and replication stress. Recently, many studies have highlighted the importance of FA genes in noncanonical pathways, such as mitochondria homeostasis, inflammation, and virophagy, which act, in some cases, independently of DNA repair processes. Thus, primary defects in DNA repair mechanisms of FA patients are typically exacerbated by an impairment of other cytoprotective pathways that contribute to the multifaceted clinical phenotype of this disease. In this review, we summarize recent advances in the understanding of the pathogenesis of FA, with a focus on the cytosolic noncanonical roles of FA genes, discussing how they may contribute to cancer development, thus suggesting opportunities to envisage novel therapeutic approaches. Full article
(This article belongs to the Special Issue The Study of Cancer Susceptibility Genes)
►▼ Show Figures

Figure 1

16 pages, 1085 KiB  
Review
The Multifaceted Roles of the Tumor Susceptibility Gene 101 (TSG101) in Normal Development and Disease
by Rosa-Maria Ferraiuolo, Karoline C. Manthey, Marissa J. Stanton, Aleata A. Triplett and Kay-Uwe Wagner
Cancers 2020, 12(2), 450; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12020450 - 14 Feb 2020
Cited by 20 | Viewed by 3454
Abstract
The multidomain protein encoded by the Tumor Susceptibility Gene 101 (TSG101) is ubiquitously expressed and is suggested to function in diverse intracellular processes. In this review, we provide a succinct overview of the main structural features of the protein and their [...] Read more.
The multidomain protein encoded by the Tumor Susceptibility Gene 101 (TSG101) is ubiquitously expressed and is suggested to function in diverse intracellular processes. In this review, we provide a succinct overview of the main structural features of the protein and their suggested roles in molecular and cellular functions. We then summarize, in more detail, key findings from studies using genetically engineered animal models that demonstrate essential functions of TSG101 in cell proliferation and survival, normal tissue homeostasis, and tumorigenesis. Despite studies on cell lines that provide insight into the molecular underpinnings by which TSG101 might function as a negative growth regulator, a biologically significant role of TSG101 as a tumor suppressor has yet to be confirmed using genuine in vivo cancer models. More recent observations from several cancer research teams suggest that TSG101 might function as an oncoprotein. A potential role of post-translational mechanisms that control the expression of the TSG101 protein in cancer is being discussed. In the final section of the review, we summarize critical issues that need to be addressed to gain a better understanding of biologically significant roles of TSG101 in cancer. Full article
(This article belongs to the Special Issue The Study of Cancer Susceptibility Genes)
►▼ Show Figures

Figure 1

Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:
 
Displaying articles 1-19
Back to TopTop