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
Application of Next-Generation Sequencing in Cancers
share announcement

Application of Next-Generation Sequencing in Cancers

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

Deadline for manuscript submissions: closed (31 July 2019) | Viewed by 113086

Special Issue Editor

Dr. Vivek Subbiah

E-Mail Website
Guest Editor
Department of Investigational Cancer Therapeutics (A Phase 1 Program), Division of Cancer Medicine, The University of MD Anderson Cancer Center, Houston, TX 77030, USA
Interests: adolescent and young adult oncology; clinical trials with molecularly targeted agents; dramatic responses in cancer patients; N–of-ONE studies; deep sequencing; morphoproteomics; next generation sequencing; Phase 1 trials—drug development (targeted therapy, radiopharmaceutical therapy, and immunotherapy); Basket trials; Rare Oncology histology agnostic trials

Special Issue Information

Dear Colleagues,

Cancer is a genetic disease. With the advent of precision medicine, there has been an explosive growth in the availability of potent genomically and immunologically targeted agents. Consequently, comprehensive analysis of every cancer is quickly becoming essential. The advent of clinical next generation sequencing technologies has fueled growth in precision oncology. Genomic testing permits the interrogation of the inside of the cell and the definition of a tumor’s precise coding sequence. Technology is evolving at a breathtaking pace. Sequencing a human genome was first performed for about $3 billion dollars in 2003, yet currently costs about $1000. Because of this rapid evolution, defining the best technology for patients is a moving target. Multiplex, pan-cancer, next-generation sequencing (NGS) has tremendous advantages over the current 1-drug, 1-gene test model: tissue is not wasted with multiple individual tests, a comprehensive genomic portfolio is created, and multiplex testing costs are lower than for numerous individual tests. However, the optimal panels are quickly evolving and include assessment of circulating tumor DNA from blood samples (liquid biopsies). Real-time ongoing reevaluation is needed. In this series, we invite authors to submit papers on:

  1. Next generation sequencing in cancers;
  2. Exceptional responders to precision cancer therapy;
  3. Next generation sequencing for immunotherapy and immuno-oncology;
  4. Broad NGS application in cancers
  5. Basket trials
  6. Genomic and Proteomic data from Public databases like TCGA.

Dr. Vivek Subbiah
Guest Editor

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.

Published Papers (24 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:

Research

Jump to: Review

13 pages, 6258 KiB  
Article
Immunohistochemical and Molecular Features of Melanomas Exhibiting Intratumor and Intertumor Histomorphologic Heterogeneity
by Haider A. Mejbel, Sri Krishna C. Arudra, Dinesh Pradhan, Carlos A. Torres-Cabala, Priyadharsini Nagarajan, Michael T. Tetzlaff, Jonathan L. Curry, Doina Ivan, Dzifa Y. Duose, Raja Luthra, Victor G. Prieto, Leomar Y. Ballester and Phyu P. Aung
Cancers 2019, 11(11), 1714; https://doi.org/10.3390/cancers11111714 - 2 Nov 2019
Cited by 5 | Viewed by 3059
Abstract
Melanoma is a heterogeneous neoplasm at the histomorphologic, immunophenotypic, and molecular levels. Melanoma with extreme histomorphologic heterogeneity can pose a diagnostic challenge in which the diagnosis may predominantly rely on its immunophenotypic profile. However, tumor survival and response to therapy are linked to [...] Read more.
Melanoma is a heterogeneous neoplasm at the histomorphologic, immunophenotypic, and molecular levels. Melanoma with extreme histomorphologic heterogeneity can pose a diagnostic challenge in which the diagnosis may predominantly rely on its immunophenotypic profile. However, tumor survival and response to therapy are linked to tumor genetic heterogeneity rather than tumor morphology. Therefore, understating the molecular characteristics of such melanomas become indispensable. In this study, DNA was extracted from 11 morphologically distinct regions in eight formalin-fixed, paraffin-embedded melanomas. In each region, mutations in 50 cancer-related genes were tested using next-generation sequencing (NGS). A tumor was considered genetically heterogeneous if at least one non-overlapping mutation was identified either between the histologically distinct regions of the same tumor (intratumor heterogeneity) or among the histologically distinct regions of the paired primary and metastatic tumors within the same patient (intertumor heterogeneity). Our results revealed that genetic heterogeneity existed in all tumors as non-overlapping mutations were detected in every tested tumor (n = 5, 100%; intratumor: n = 2, 40%; intertumor: n = 3, 60%). Conversely, overlapping mutations were also detected in all the tested regions (n = 11, 100%). Melanomas exhibiting histomorphologic heterogeneity are often associated with genetic heterogeneity, which might contribute to tumor survival and poor response to therapy. Full article
(This article belongs to the Special Issue Application of Next-Generation Sequencing in Cancers)
►▼ Show Figures

Figure 1

20 pages, 4409 KiB  
Article
Automated Workflow for Somatic and Germline Next Generation Sequencing Analysis in Routine Clinical Cancer Diagnostics
by Lucia Anna Muscarella, Federico Pio Fabrizio, Maria De Bonis, Maria Teresa Mancini, Teresa Balsamo, Paolo Graziano, Flavia Centra, Angelo Sparaneo, Domenico Trombetta, Antonio Bonfitto, Vito Scagliusi, Pietro Larizza, Ettore Domenico Capoluongo and Vito Michele Fazio
Cancers 2019, 11(11), 1691; https://doi.org/10.3390/cancers11111691 - 30 Oct 2019
Cited by 5 | Viewed by 3629
Abstract
Thanks to personalized medicine trends and collaborations between industry, clinical research groups and regulatory agencies, next generation sequencing (NGS) is turning into a common practice faster than one could have originally expected. When considering clinical applications of NGS in oncology, a rapid workflow [...] Read more.
Thanks to personalized medicine trends and collaborations between industry, clinical research groups and regulatory agencies, next generation sequencing (NGS) is turning into a common practice faster than one could have originally expected. When considering clinical applications of NGS in oncology, a rapid workflow for DNA extraction from formalin-fixed paraffin-embedded (FFPE) tissue samples, as well as producing high quality library preparation, can be real challenges. Here we consider these targets and how applying effective automation technology to NGS workflows may help improve yield, timing and quality-control. We firstly evaluated DNA recovery from archived FFPE blocks from three different manual extraction methods and two automated extraction workstations. The workflow was then implemented to somatic (lung/colon panel) and germline (BRCA1/2) library preparation for NGS analysis exploiting two automated workstations. All commercial kits gave good results in terms of DNA yield and quality. On the other hand, the automated workstation workflow has been proven to be a valid automatic extraction system to obtain high quality DNA suitable for NGS analysis (lung/colon Ampli-seq panel). Moreover, it can be efficiently integrated with an open liquid handling platform to provide high-quality libraries from germline DNA with more reproducibility and high coverage for targeted sequences in less time (BRCA1/2). The introduction of automation in routine workflow leads to an improvement of NGS standardization and increased scale up of sample preparations, reducing labor and timing, with optimization of reagents and management. Full article
(This article belongs to the Special Issue Application of Next-Generation Sequencing in Cancers)
►▼ Show Figures

Figure 1

16 pages, 1288 KiB  
Article
A Pan-Cancer Approach to Predict Responsiveness to Immune Checkpoint Inhibitors by Machine Learning
by Maurizio Polano, Marco Chierici, Michele Dal Bo, Davide Gentilini, Federica Di Cintio, Lorena Baboci, David L. Gibbs, Cesare Furlanello and Giuseppe Toffoli
Cancers 2019, 11(10), 1562; https://doi.org/10.3390/cancers11101562 - 15 Oct 2019
Cited by 29 | Viewed by 5533
Abstract
Immunotherapy by using immune checkpoint inhibitors (ICI) has dramatically improved the treatment options in various cancers, increasing survival rates for treated patients. Nevertheless, there are heterogeneous response rates to ICI among different cancer types, and even in the context of patients affected by [...] Read more.
Immunotherapy by using immune checkpoint inhibitors (ICI) has dramatically improved the treatment options in various cancers, increasing survival rates for treated patients. Nevertheless, there are heterogeneous response rates to ICI among different cancer types, and even in the context of patients affected by a specific cancer. Thus, it becomes crucial to identify factors that predict the response to immunotherapeutic approaches. A comprehensive investigation of the mutational and immunological aspects of the tumor can be useful to obtain a robust prediction. By performing a pan-cancer analysis on gene expression data from the Cancer Genome Atlas (TCGA, 8055 cases and 29 cancer types), we set up and validated a machine learning approach to predict the potential for positive response to ICI. Support vector machines (SVM) and extreme gradient boosting (XGboost) models were developed with a 10×5-fold cross-validation schema on 80% of TCGA cases to predict ICI responsiveness defined by a score combining tumor mutational burden and TGF- β signaling. On the remaining 20% validation subset, our SVM model scored 0.88 accuracy and 0.27 Matthews Correlation Coefficient. The proposed machine learning approach could be useful to predict the putative response to ICI treatment by expression data of primary tumors. Full article
(This article belongs to the Special Issue Application of Next-Generation Sequencing in Cancers)
►▼ Show Figures

Figure 1

16 pages, 1002 KiB  
Article
Matched Whole-Genome Sequencing (WGS) and Whole-Exome Sequencing (WES) of Tumor Tissue with Circulating Tumor DNA (ctDNA) Analysis: Complementary Modalities in Clinical Practice
by Robin Imperial, Marjan Nazer, Zaheer Ahmed, Audrey E. Kam, Timothy J. Pluard, Waled Bahaj, Mia Levy, Timothy M. Kuzel, Dana M. Hayden, Sam G. Pappas, Janakiraman Subramanian and Ashiq Masood
Cancers 2019, 11(9), 1399; https://doi.org/10.3390/cancers11091399 - 19 Sep 2019
Cited by 29 | Viewed by 5786
Abstract
Tumor heterogeneity, especially intratumoral heterogeneity, is a primary reason for treatment failure. A single biopsy may not reflect the complete genomic architecture of the tumor needed to make therapeutic decisions. Circulating tumor DNA (ctDNA) is believed to overcome these limitations. We analyzed concordance [...] Read more.
Tumor heterogeneity, especially intratumoral heterogeneity, is a primary reason for treatment failure. A single biopsy may not reflect the complete genomic architecture of the tumor needed to make therapeutic decisions. Circulating tumor DNA (ctDNA) is believed to overcome these limitations. We analyzed concordance between ctDNA and whole-exome sequencing/whole-genome sequencing (WES/WGS) of tumor samples from patients with breast (n = 12), gastrointestinal (n = 20), lung (n = 19), and other tumor types (n = 13). Correlation in the driver, hotspot, and actionable alterations was studied. Three cases in which more-in-depth genomic analysis was required have been presented. A total 58% (37/64) of patients had at least one concordant mutation. Patients who had received systemic therapy before tissue next-generation sequencing (NGS) and ctDNA analysis showed high concordance (78% (21/27) vs. 43% (12/28) p = 0.01, respectively). Obtaining both NGS and ctDNA increased actionable alterations from 28% (18/64) to 52% (33/64) in our patients. Twenty-one patients had mutually exclusive actionable alterations seen only in either tissue NGS or ctDNA samples. Somatic hotspot mutation analysis showed significant discordance between tissue NGS and ctDNA analysis, denoting significant tumor heterogeneity in these malignancies. Increased tissue tumor mutation burden (TMB) positively correlated with the number of ctDNA mutations in patients who had received systemic therapy, but not in treatment-naïve patients. Prior systemic therapy and TMB may affect concordance and should be taken into consideration in future studies. Incorporating driver, actionable, and hotspot analysis may help to further refine the correlation between these two platforms. Tissue NGS and ctDNA are complimentary, and if done in conjunction, may increase the detection rate of actionable alterations and potentially therapeutic targets. Full article
(This article belongs to the Special Issue Application of Next-Generation Sequencing in Cancers)
►▼ Show Figures

Figure 1

8 pages, 630 KiB  
Article
Unique Aberrations in Intimal Sarcoma Identified by Next-Generation Sequencing as Potential Therapy Targets
by Jason Roszik, Abir Khan, Anthony P. Conley, J. Andrew Livingston, Roman Groisberg, Vinod Ravi, Roberto Carmagnani Pestana, Shiraj Sen and Vivek Subbiah
Cancers 2019, 11(9), 1283; https://doi.org/10.3390/cancers11091283 - 31 Aug 2019
Cited by 23 | Viewed by 5277
Abstract
Intimal sarcomas are rare and histologically heterogeneous tumors, commonly arising from the pulmonary arteries. They have remained challenging to treat. Few studies in the literature study the genomics of this cancer. Identifying targetable alterations is an important step in advancing the treatment of [...] Read more.
Intimal sarcomas are rare and histologically heterogeneous tumors, commonly arising from the pulmonary arteries. They have remained challenging to treat. Few studies in the literature study the genomics of this cancer. Identifying targetable alterations is an important step in advancing the treatment of intimal sarcomas. Using data from the American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange (AACR GENIE) database, we cataloged genetic alterations and assessed their clinical utility from thirteen patients with intimal sarcoma. Notable copy number alterations included amplification in MDM2, CDK4, PDGFRA, and NOTCH2, as well as copy number losses in CDKN2A and CDKN2B. Actionable alterations included mutations in ATM/ATR, PTCH1, and PDGFRB. Moreover, genomic rearrangement events, specifically PDE4DIP-NOTCH2 and MRPS30-ARID2 fusions were identified. Co-occurring alterations included a NOTCH2 copy number gain in the PDE4DIP-NOTCH2 fusion positive tumor and PDGFRB mutations in both fusion-positive cases. Our study suggests that PDGFRB may be relevant in the tumorigenesis process. Including genomic profiling in the management of intimal sarcoma and potential enrollment in targeted therapy trials is warranted. Full article
(This article belongs to the Special Issue Application of Next-Generation Sequencing in Cancers)
►▼ Show Figures

Figure 1

13 pages, 3127 KiB  
Article
In-house Implementation of Tumor Mutational Burden Testing to Predict Durable Clinical Benefit in Non-small Cell Lung Cancer and Melanoma Patients
by Simon Heeke, Jonathan Benzaquen, Elodie Long-Mira, Benoit Audelan, Virginie Lespinet, Olivier Bordone, Salomé Lalvée, Katia Zahaf, Michel Poudenx, Olivier Humbert, Henri Montaudié, Pierre-Michel Dugourd, Madleen Chassang, Thierry Passeron, Hervé Delingette, Charles-Hugo Marquette, Véronique Hofman, Albrecht Stenzinger, Marius Ilié and Paul Hofman
Cancers 2019, 11(9), 1271; https://doi.org/10.3390/cancers11091271 - 29 Aug 2019
Cited by 27 | Viewed by 5176
Abstract
Tumor mutational burden (TMB) has emerged as an important potential biomarker for prediction of response to immune-checkpoint inhibitors (ICIs), notably in non-small cell lung cancer (NSCLC). However, its in-house assessment in routine clinical practice is currently challenging and validation is urgently needed. We [...] Read more.
Tumor mutational burden (TMB) has emerged as an important potential biomarker for prediction of response to immune-checkpoint inhibitors (ICIs), notably in non-small cell lung cancer (NSCLC). However, its in-house assessment in routine clinical practice is currently challenging and validation is urgently needed. We have analyzed sixty NSCLC and thirty-six melanoma patients with ICI treatment, using the FoundationOne test (FO) in addition to in-house testing using the Oncomine TML (OTML) panel and evaluated the durable clinical benefit (DCB), defined by >6 months without progressive disease. Comparison of TMB values obtained by both tests demonstrated a high correlation in NSCLC (R2 = 0.73) and melanoma (R2 = 0.94). The association of TMB with DCB was comparable between OTML (area-under the curve (AUC) = 0.67) and FO (AUC = 0.71) in NSCLC. Median TMB was higher in the DCB cohort and progression-free survival (PFS) was prolonged in patients with high TMB (OTML HR = 0.35; FO HR = 0.45). In contrast, we detected no differences in PFS and median TMB in our melanoma cohort. Combining TMB with PD-L1 and CD8-expression by immunohistochemistry improved the predictive value. We conclude that in our cohort both approaches are equally able to assess TMB and to predict DCB in NSCLC. Full article
(This article belongs to the Special Issue Application of Next-Generation Sequencing in Cancers)
►▼ Show Figures

Figure 1

9 pages, 678 KiB  
Article
A Multi-Center Study of BRCA1 and BRCA2 Germline Mutations in Mexican-Mestizo Breast Cancer Families Reveals Mutations Unreported in Latin American Population
by Oliver Millan Catalan, Alma D. Campos-Parra, Rafael Vázquez-Romo, David Cantú de León, Nadia Jacobo-Herrera, Fermín Morales-González, César López-Camarillo, Mauricio Rodríguez-Dorantes, Eduardo López-Urrutia and Carlos Pérez-Plasencia
Cancers 2019, 11(9), 1246; https://doi.org/10.3390/cancers11091246 - 26 Aug 2019
Cited by 8 | Viewed by 4292
Abstract
The presence of germline and somatic deleterious mutations in the BRCA1 and BRCA2 genes has important clinical consequences for breast cancer (BC) patients. Analysis of the mutational status in BRCA genes is not yet common in public Latin American institutions; thus, our objective [...] Read more.
The presence of germline and somatic deleterious mutations in the BRCA1 and BRCA2 genes has important clinical consequences for breast cancer (BC) patients. Analysis of the mutational status in BRCA genes is not yet common in public Latin American institutions; thus, our objective was to implement high-performance technology with highly reliable results with the possibility of analyzing several patients simultaneously, therefore reducing cost and work time. A prospective cohort of 252 unrelated sporadic breast cancer patients from the Mexican-mestizo population were analyzed using next generation sequencing (NGS) based on ion semiconductor sequencing. We found 28 pathogenic mutations (25 in BRCA1 and 13 in BRCA2), 11 of which had not been reported previously in Hispanic or Latin American populations. A total of 38 patients were positive for a pathogenic mutation representing 15% of our Mexican women cohort with breast cancer; 25 for BRCA1; and 13 for BRCA2. Our results revealed that there are mutations not analyzed by mutations panels, and our findings support the suitability of massive sequencing approaches in the public institutions of developing countries. Hence, BRCA screening should be offered to patients with breast cancer regardless of their family history of cancer in order to identify unaffected family carriers. Full article
(This article belongs to the Special Issue Application of Next-Generation Sequencing in Cancers)
►▼ Show Figures

Figure 1

16 pages, 1145 KiB  
Article
Development, Implementation and Assessment of Molecular Diagnostics by Next Generation Sequencing in Personalized Treatment of Cancer: Experience of a Public Reference Healthcare Hospital
by Javier Simarro, Rosa Murria, Gema Pérez-Simó, Marta Llop, Nuria Mancheño, David Ramos, Inmaculada de Juan, Eva Barragán, Begoña Laiz, Enrique Cases, Emilio Ansótegui, José Gómez-Codina, Jorge Aparicio, Carmen Salvador, Óscar Juan and Sarai Palanca
Cancers 2019, 11(8), 1196; https://doi.org/10.3390/cancers11081196 - 16 Aug 2019
Cited by 13 | Viewed by 4969
Abstract
The establishment of precision medicine in cancer patients requires the study of several biomarkers. Single-gene testing approaches are limited by sample availability and turnaround time. Next generation sequencing (NGS) provides an alternative for detecting genetic alterations in several genes with low sample requirements. [...] Read more.
The establishment of precision medicine in cancer patients requires the study of several biomarkers. Single-gene testing approaches are limited by sample availability and turnaround time. Next generation sequencing (NGS) provides an alternative for detecting genetic alterations in several genes with low sample requirements. Here we show the implementation to routine diagnostics of a NGS assay under International Organization for Standardization (UNE-EN ISO 15189:2013) accreditation. For this purpose, 106 non-small cell lung cancer (NSCLC) and 102 metastatic colorectal cancer (mCRC) specimens were selected for NGS analysis with Oncomine Solid Tumor (ThermoFisher). In NSCLC the most prevalently mutated gene was TP53 (49%), followed by KRAS (31%) and EGFR (13%); in mCRC, TP53 (50%), KRAS (48%) and PIK3CA (16%) were the most frequently mutated genes. Moreover, NGS identified actionable genetic alterations in 58% of NSCLC patients, and 49% of mCRC patients did not harbor primary resistance mechanisms to anti-EGFR treatment. Validation with conventional approaches showed an overall agreement >90%. Turnaround time and cost analysis revealed that NGS implementation is feasible in the public healthcare context. Therefore, NGS is a multiplexed molecular diagnostic tool able to overcome the limitations of current molecular diagnosis in advanced cancer, allowing an improved and economically sustainable molecular profiling. Full article
(This article belongs to the Special Issue Application of Next-Generation Sequencing in Cancers)
►▼ Show Figures

Figure 1

16 pages, 11096 KiB  
Article
Targeted Treatment Options of Recurrent Radioactive Iodine Refractory Hürthle Cell Cancer
by Mehtap Derya Aydemirli, Willem Corver, Ruben Beuk, Paul Roepman, Nienke Solleveld-Westerink, Tom van Wezel, Ellen Kapiteijn and Hans Morreau
Cancers 2019, 11(8), 1185; https://doi.org/10.3390/cancers11081185 - 15 Aug 2019
Cited by 7 | Viewed by 4250
Abstract
Objective: To evaluate the efficacy and treatment rationale of Hürthle cell carcinoma (HCC) following a patient with progressive and metastatic HCC. HCC was recently shown to harbor a distinct genetic make-up and the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kiase (PI3K)/AKT signaling [...] Read more.
Objective: To evaluate the efficacy and treatment rationale of Hürthle cell carcinoma (HCC) following a patient with progressive and metastatic HCC. HCC was recently shown to harbor a distinct genetic make-up and the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kiase (PI3K)/AKT signaling pathways are potential targets for anti-cancer agents in the management of recurrent HCC. The presence or absence of gene variants can give a rationale for targeted therapies that could be made available in the context of drug repurposing trials. Methods: Treatment included everolimus, sorafenib, nintedanib, lenvatinib, and panitumumab. Whole genome sequencing (WGS) of metastatic tumor material obtained before administration of the last drug, was performed. We subsequently evaluated the rationale and efficacy of panitumumab in thyroid cancer and control cell lines after epidermal growth factor (EGF) stimulation and treatment with panitumumab using immunofluorescent Western blot analysis. EGF receptor (EGFR) quantification was performed using flow cytometry. Results: WGS revealed a near-homozygous genome (NHG) and a somatic homozygous TSC1 variant, that was absent in the primary tumor. In the absence of RAS variants, panitumumab showed no real-life efficacy. This might be explained by high constitutive AKT signaling in the two thyroid cancer cell lines with NHG, with panitumumab only being a potent inhibitor of pEGFR in all cancer cell lines tested. Conclusions: In progressive HCC, several treatment options outside or inside clinical trials are available. WGS of metastatic tumors might direct the timing of therapy. Unlike other cancers, the absence of RAS variants seems to provide insufficient justification of single-agent panitumumab administration in HCC cases harboring a near-homozygous genome. Full article
(This article belongs to the Special Issue Application of Next-Generation Sequencing in Cancers)
►▼ Show Figures

Figure 1

11 pages, 281 KiB  
Communication
Early Colorectal Cancers Provide New Evidence for a Lynch Syndrome-to-CMMRD Phenotypic Continuum
by Ceres Fernández-Rozadilla, Miriam Alvarez-Barona, Esther Schamschula, Sahra Bodo, Anael Lopez-Novo, Andres Dacal, Consuelo Calviño-Costas, Angel Lancho, Jorge Amigo, Xabier Bello, Jose Manuel Cameselle-Teijeiro, Angel Carracedo, Chrystelle Colas, Martine Muleris, Katharina Wimmer and Clara Ruiz-Ponte
Cancers 2019, 11(8), 1081; https://doi.org/10.3390/cancers11081081 - 30 Jul 2019
Cited by 8 | Viewed by 3729
Abstract
Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRC) syndrome, caused by heterozygous mutations in the mismatch repair (MMR) genes. Biallelic mutations in these genes lead however, to constitutive mismatch repair deficiency (CMMRD). In this study, we follow the diagnostic journey [...] Read more.
Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRC) syndrome, caused by heterozygous mutations in the mismatch repair (MMR) genes. Biallelic mutations in these genes lead however, to constitutive mismatch repair deficiency (CMMRD). In this study, we follow the diagnostic journey of a 12-year old patient with CRC, with a clinical phenotype overlapping CMMRD. We perform molecular and functional assays to discard a CMMRD diagnosis then identify by exome sequencing and validation in a cohort of 134 LS patients, a candidate variant in the MLH1 UTR region in homozygosis. We propose that this variant, together with other candidates, could be responsible for age-of-onset modulation. Our data support the idea that low-risk modifier alleles may influence early development of cancer in LS leading to a LS-to-CMMRD phenotypic continuum. Therefore, it is essential that larger efforts are directed to the identification and study of these genetic modifiers, in order to provide optimal cancer prevention strategies to these patients. Full article
(This article belongs to the Special Issue Application of Next-Generation Sequencing in Cancers)
►▼ Show Figures

Graphical abstract

13 pages, 1290 KiB  
Article
Design and Validation of a Gene-Targeted, Next-Generation Sequencing Panel for Routine Diagnosis in Gliomas
by Nicky D’Haene, Bárbara Meléndez, Oriane Blanchard, Nancy De Nève, Laetitia Lebrun, Claude Van Campenhout and Isabelle Salmon
Cancers 2019, 11(6), 773; https://doi.org/10.3390/cancers11060773 - 4 Jun 2019
Cited by 17 | Viewed by 3725
Abstract
The updated 2016 World Health Organization (WHO) classification system for gliomas integrates molecular alterations and histology to provide a greater diagnostic and prognostic utility than the previous, histology-based classification. The increasing number of markers that are tested in a correct diagnostic procedure makes [...] Read more.
The updated 2016 World Health Organization (WHO) classification system for gliomas integrates molecular alterations and histology to provide a greater diagnostic and prognostic utility than the previous, histology-based classification. The increasing number of markers that are tested in a correct diagnostic procedure makes gene-targeted, next-generation sequencing (NGS) a powerful tool in routine pathology practice. We designed a 14-gene NGS panel specifically aimed at the diagnosis of glioma, which allows simultaneous detection of mutations and copy number variations, including the 1p/19q-codeletion and Epidermal Growth Factor Receptor (EGFR) amplification. To validate this panel, we used reference mutated DNAs, nontumor and non-glioma samples, and 52 glioma samples that were previously characterized. The panel was then prospectively applied to 91 brain lesions. A specificity of 100% and sensitivity of 99.4% was achieved for mutation detection. Orthogonal methods, such as in situ hybridization and immunohistochemical techniques, were used for validation, which showed high concordance. The molecular alterations that were identified allowed diagnosis according to the updated WHO criteria, and helped in the differential diagnosis of difficult cases. This NGS panel is an accurate and sensitive method, which could replace multiple tests for the same sample. Moreover, it is a rapid and cost-effective approach that can be easily implemented in the routine diagnosis of gliomas. Full article
(This article belongs to the Special Issue Application of Next-Generation Sequencing in Cancers)
►▼ Show Figures

Figure 1

25 pages, 4870 KiB  
Article
Detection of Epstein-Barr Virus Infection in Non-Small Cell Lung Cancer
by Fayez Kheir, Mengmeng Zhao, Michael J. Strong, Yi Yu, Asuka Nanbo, Erik K. Flemington, Gilbert F. Morris, Krzysztof Reiss, Li Li and Zhen Lin
Cancers 2019, 11(6), 759; https://doi.org/10.3390/cancers11060759 - 31 May 2019
Cited by 36 | Viewed by 5073
Abstract
Previous investigations proposed a link between the Epstein-Barr virus (EBV) and lung cancer (LC), but the results are highly controversial largely due to the insufficient sample size and the inherent limitation of the traditional viral screening methods such as PCR. Unlike PCR, current [...] Read more.
Previous investigations proposed a link between the Epstein-Barr virus (EBV) and lung cancer (LC), but the results are highly controversial largely due to the insufficient sample size and the inherent limitation of the traditional viral screening methods such as PCR. Unlike PCR, current next-generation sequencing (NGS) utilizes an unbiased method for the global assessment of all exogenous agents within a cancer sample with high sensitivity and specificity. In our current study, we aim to resolve this long-standing controversy by utilizing our unbiased NGS-based informatics approaches in conjunction with traditional molecular methods to investigate the role of EBV in a total of 1127 LC. In situ hybridization analysis of 110 LC and 10 normal lung samples detected EBV transcripts in 3 LC samples. Comprehensive virome analyses of RNA sequencing (RNA-seq) data sets from 1017 LC and 110 paired adjacent normal lung specimens revealed EBV transcripts in three lung squamous cell carcinoma and one lung adenocarcinoma samples. In the sample with the highest EBV coverage, transcripts from the BamHI A region accounted for the majority of EBV reads. Expression of EBNA-1, LMP-1 and LMP-2 was observed. A number of viral circular RNA candidates were also detected. Thus, we for the first time revealed a type II latency-like viral transcriptome in the setting of LC in vivo. The high-level expression of viral BamHI A transcripts in LC suggests a functional role of these transcripts, likely as long non-coding RNA. Analyses of cellular gene expression and stained tissue sections indicated an increased immune cell infiltration in the sample expressing high levels of EBV transcripts compared to samples expressing low EBV transcripts. Increased level of immune checkpoint blockade factors was also detected in the sample with higher levels of EBV transcripts, indicating an induced immune tolerance. Lastly, inhibition of immune pathways and activation of oncogenic pathways were detected in the sample with high EBV transcripts compared to the EBV-low LC indicating the direct regulation of cancer pathways by EBV. Taken together, our data support the notion that EBV likely plays a pathological role in a subset of LC. Full article
(This article belongs to the Special Issue Application of Next-Generation Sequencing in Cancers)
►▼ Show Figures

Figure 1

10 pages, 2064 KiB  
Article
MAGE-A3 Is a Clinically Relevant Target in Undifferentiated Pleomorphic Sarcoma/Myxofibrosarcoma
by Anthony P. Conley, Wei-Lien Wang, John A. Livingston, Vinod Ravi, Jen-Wei Tsai, Ali Ali, Davis R. Ingram, Caitlin D. Lowery, Christina L. Roland, Neeta Somaiah, Patrick Hwu, Cassian Yee, Vivek Subbiah, Andrew Futreal, Alexander J. Lazar, Shreyaskumar Patel and Jason Roszik
Cancers 2019, 11(5), 677; https://doi.org/10.3390/cancers11050677 - 15 May 2019
Cited by 21 | Viewed by 4550
Abstract
Melanoma-associated antigen 3 (MAGE-A3) expression is generally restricted to the placenta and germline cells of the testis, but it may also be expressed in sarcoma and other cancers and is associated with poor prognosis. Immunotherapy approaches targeting MAGE-A3 in other cancers have shown [...] Read more.
Melanoma-associated antigen 3 (MAGE-A3) expression is generally restricted to the placenta and germline cells of the testis, but it may also be expressed in sarcoma and other cancers and is associated with poor prognosis. Immunotherapy approaches targeting MAGE-A3 in other cancers have shown mixed results in the clinic, however, use of cancer testis antigens such as MAGE-A3 may have therapeutic value in the treatment of soft tissue sarcomas. Based on the recent success of anti-programmed death-1 (PD-1) therapy in undifferentiated pleomorphic sarcoma, we hypothesize that MAGE-A3-based immunotherapies may also provide benefits in this sarcoma type. We analyzed MAGE-A3 expression of sarcoma subtypes available in the Cancer Genome Atlas and Cancer Cell Line Encyclopedia and show that undifferentiated pleomorphic sarcoma/myxofibrosarcoma (UPS/MFS) expresses this potential target gene. We have identified high protein expression by tissue microarray of 106 UPS cores. We also found that high MAGE-A3 mRNA and protein expression is associated with worse overall survival in UPS/MFS. Furthermore, our results show no human leukocyte antigen (HLA) expression loss and relatively high lymphocyte infiltration by lymphocyte specific protein tyrosine kinase (LCK) marker expression. Based on these results, we propose targeting MAGE-A3 in UPS/MFS by immunotherapy techniques. Full article
(This article belongs to the Special Issue Application of Next-Generation Sequencing in Cancers)
►▼ Show Figures

Figure 1

18 pages, 1090 KiB  
Article
A Comparison of DNA Mutation and Copy Number Profiles of Primary Breast Cancers and Paired Brain Metastases for Identifying Clinically Relevant Genetic Alterations in Brain Metastases
by Marguerite Tyran, Nadine Carbuccia, Séverine Garnier, Arnaud Guille, José Adelaïde, Pascal Finetti, Julien Touzlian, Patrice Viens, Agnès Tallet, Anthony Goncalves, Philippe Metellus, Daniel Birnbaum, Max Chaffanet and François Bertucci
Cancers 2019, 11(5), 665; https://doi.org/10.3390/cancers11050665 - 13 May 2019
Cited by 22 | Viewed by 3949
Abstract
Improving the systemic treatment of brain metastases (BM) in primary breast cancer (PBC) is impaired by the lack of genomic characterization of BM. To estimate the concordance of DNA copy-number-alterations (CNAs), mutations, and actionable genetic alterations (AGAs) between paired samples, we performed whole-genome [...] Read more.
Improving the systemic treatment of brain metastases (BM) in primary breast cancer (PBC) is impaired by the lack of genomic characterization of BM. To estimate the concordance of DNA copy-number-alterations (CNAs), mutations, and actionable genetic alterations (AGAs) between paired samples, we performed whole-genome array-comparative-genomic-hybridization, and targeted-next-generation-sequencing on 14 clinical PBC–BM pairs. We found more CNAs, more mutations, and higher tumor mutational burden, and more AGAs in BM than in PBC; 92% of the pairs harbored at least one AGA in the BM not observed in the paired PBC. This concerned various therapeutic classes, including tyrosine-kinase-receptor-inhibitors, phosphatidylinositol 3-kinase/AKT/ mammalian Target of Rapamycin (PI3K/AKT/MTOR)-inhibitors, poly ADP ribose polymerase (PARP)-inhibitors, or cyclin-dependent kinase (CDK)-inhibitors. With regards to the PARP-inhibitors, the homologous recombination defect score was positive in 79% of BM, compared to 43% of PBC, discordant in 7 out of 14 pairs, and positive in the BM in 5 out of 14 cases. CDK-inhibitors were associated with the largest percentage of discordant AGA appearing in the BM. When considering the AGA with the highest clinical-evidence level, for each sample, 50% of the pairs harbored an AGA in the BM not detected or not retained from the analysis of the paired PBC. Thus, the profiling of BM provided a more reliable opportunity, than that of PBC, for diagnostic decision-making based on genomic analysis. Patients with BM deserve an investigation of several targeted therapies. Full article
(This article belongs to the Special Issue Application of Next-Generation Sequencing in Cancers)
►▼ Show Figures

Figure 1

11 pages, 959 KiB  
Article
Frequent Occurrence of NRAS and BRAF Mutations in Human Acral Naevi
by Philipp Jansen, Ioana Cosgarea, Rajmohan Murali, Inga Möller, Antje Sucker, Cindy Franklin, Annette Paschen, Anne Zaremba, Titus J. Brinker, Ingo Stoffels, Dirk Schadendorf, Joachim Klode, Eva Hadaschik and Klaus G. Griewank
Cancers 2019, 11(4), 546; https://doi.org/10.3390/cancers11040546 - 16 Apr 2019
Cited by 9 | Viewed by 4174
Abstract
Acral naevi are benign melanocytic tumors occurring at acral sites. Occasionally they can progress to become malignant tumors (melanomas). The genetics of acral naevi have not been assessed in larger studies. In our study, a large cohort of 130 acral naevi was screened [...] Read more.
Acral naevi are benign melanocytic tumors occurring at acral sites. Occasionally they can progress to become malignant tumors (melanomas). The genetics of acral naevi have not been assessed in larger studies. In our study, a large cohort of 130 acral naevi was screened for gene mutations known to be important in other naevi and melanoma subtypes by targeted next-generation sequencing. Mutation status was correlated with clinicopathological parameters. Frequent mutations in genes activating the MAP kinase pathway were identified, including n = 87 (67%) BRAF, n = 24 (18%) NRAS, and one (1%) MAP2K1 mutations. BRAF mutations were almost exclusively V600E (n = 86, 99%) and primarily found in junctional and compound naevi. NRAS mutations were either Q61K or Q61R and frequently identified in dermal naevi. Recurrent non-V600E BRAF, KIT, NF1, and TERT promoter mutations, present in acral melanoma, were not identified. Our study identifies BRAF and NRAS mutations as the primary pathogenic event in acral naevi, however, distributed differently to those in non-acral naevi. The mutational profile of acral naevi is distinct from acral melanoma, which may be of diagnostic value in distinguishing these entities. Full article
(This article belongs to the Special Issue Application of Next-Generation Sequencing in Cancers)
►▼ Show Figures

Figure 1

18 pages, 1770 KiB  
Article
Integrated Somatic and Germline Whole-Exome Sequencing Analysis in Women with Lung Cancer after a Previous Breast Cancer
by Simona Coco, Silvia Bonfiglio, Davide Cittaro, Irene Vanni, Marco Mora, Carlo Genova, Maria Giovanna Dal Bello, Simona Boccardo, Angela Alama, Erika Rijavec, Claudio Sini, Valeria Rossella, Giulia Barletta, Federica Biello, Anna Truini, Cristina Bruzzo, Maurizio Gallo, Dejan Lazarevic, Alberto Ballestrero and Francesco Grossi
Cancers 2019, 11(4), 441; https://doi.org/10.3390/cancers11040441 - 28 Mar 2019
Cited by 3 | Viewed by 4295
Abstract
Women treated for breast cancer (BC) are at risk of developing secondary tumors, such as lung cancer (LC). Since rare germline variants have been linked to multiple cancer development, we hypothesized that BC survivors might be prone to develop LC as a result [...] Read more.
Women treated for breast cancer (BC) are at risk of developing secondary tumors, such as lung cancer (LC). Since rare germline variants have been linked to multiple cancer development, we hypothesized that BC survivors might be prone to develop LC as a result of harboring rare variants. Sixty patients with LC with previous BC (the study population; SP) and 53 women with either BC or LC and no secondary cancer (control population; CP) were enrolled. Whole exome sequencing was performed in both tumors and unaffected tissues from 28/60 SP patients, and in germline DNA from 32/53 CP. Candidate genes were validated in the remaining individuals from both populations. We found two main mutational signature profiles: S1 (C>T) in all BCs and 16/28 LCs, and S2 (C>A) which is strongly associated with smoking, in 12/28 LCs. The burden test over rare germline variants in S1-LC vs CP identified 248 genes. Validation confirmed GSN as significantly associated with LC in never-smokers. In conclusion, our data suggest two signatures involved in LC onset in women with previous BC. One of these signatures is linked to smoking. Conversely, regardless of smoking habit, in a subgroup of BC survivors genetic susceptibility may contribute to LC risk. Full article
(This article belongs to the Special Issue Application of Next-Generation Sequencing in Cancers)
►▼ Show Figures

Figure 1

12 pages, 1041 KiB  
Article
A Simplified Genomic Profiling Approach Predicts Outcome in Metastatic Colorectal Cancer
by Carlo Capalbo, Francesca Belardinilli, Domenico Raimondo, Edoardo Milanetti, Umberto Malapelle, Pasquale Pisapia, Valentina Magri, Alessandra Prete, Silvia Pecorari, Mariarosaria Colella, Anna Coppa, Caterina Bonfiglio, Arianna Nicolussi, Virginia Valentini, Alessandra Tessitore, Beatrice Cardinali, Marialaura Petroni, Paola Infante, Matteo Santoni, Marco Filetti, Valeria Colicchia, Paola Paci, Silvia Mezi, Flavia Longo, Enrico Cortesi, Paolo Marchetti, Giancarlo Troncone, Diana Bellavia, Gianluca Canettieri and Giuseppe Gianniniadd Show full author list remove Hide full author list
Cancers 2019, 11(2), 147; https://doi.org/10.3390/cancers11020147 - 27 Jan 2019
Cited by 10 | Viewed by 3653
Abstract
The response of metastatic colorectal cancer (mCRC) to the first-line conventional combination therapy is highly variable, reflecting the elevated heterogeneity of the disease. The genetic alterations underlying this heterogeneity have been thoroughly characterized through omic approaches requiring elevated efforts and costs. In order [...] Read more.
The response of metastatic colorectal cancer (mCRC) to the first-line conventional combination therapy is highly variable, reflecting the elevated heterogeneity of the disease. The genetic alterations underlying this heterogeneity have been thoroughly characterized through omic approaches requiring elevated efforts and costs. In order to translate the knowledge of CRC molecular heterogeneity into a practical clinical approach, we utilized a simplified Next Generation Sequencing (NGS) based platform to screen a cohort of 77 patients treated with first-line conventional therapy. Samples were sequenced using a panel of hotspots and targeted regions of 22 genes commonly involved in CRC. This revealed 51 patients carrying actionable gene mutations, 22 of which carried druggable alterations. These mutations were frequently associated with additional genetic alterations. To take into account this molecular complexity and assisted by an unbiased bioinformatic analysis, we defined three subgroups of patients carrying distinct molecular patterns. We demonstrated these three molecular subgroups are associated with a different response to first-line conventional combination therapies. The best outcome was achieved in patients exclusively carrying mutations on TP53 and/or RAS genes. By contrast, in patients carrying mutations in any of the other genes, alone or associated with mutations of TP53/RAS, the expected response is much worse compared to patients with exclusive TP53/RAS mutations. Additionally, our data indicate that the standard approach has limited efficacy in patients without any mutations in the genes included in the panel. In conclusion, we identified a reliable and easy-to-use approach for a simplified molecular-based stratification of mCRC patients that predicts the efficacy of the first-line conventional combination therapy. Full article
(This article belongs to the Special Issue Application of Next-Generation Sequencing in Cancers)
►▼ Show Figures

Figure 1

17 pages, 3255 KiB  
Article
Comprehensive Genomic Profiling Reveals Diverse but Actionable Molecular Portfolios across Hematologic Malignancies: Implications for Next Generation Clinical Trials
by Natalie Galanina, Rafael Bejar, Michael Choi, Aaron Goodman, Matthew Wieduwilt, Carolyn Mulroney, Lisa Kim, Huwate Yeerna, Pablo Tamayo, Jo-Anne Vergilio, Tariq I. Mughal, Vincent Miller, Catriona Jamieson and Razelle Kurzrock
Cancers 2019, 11(1), 11; https://doi.org/10.3390/cancers11010011 - 21 Dec 2018
Cited by 22 | Viewed by 5173
Abstract
Background: The translation of genomic discoveries to the clinic is the cornerstone of precision medicine. However, incorporating next generation sequencing (NGS) of hematologic malignancies into clinical management remains limited. Methods: We describe 235 patients who underwent integrated NGS profiling (406 genes) [...] Read more.
Background: The translation of genomic discoveries to the clinic is the cornerstone of precision medicine. However, incorporating next generation sequencing (NGS) of hematologic malignancies into clinical management remains limited. Methods: We describe 235 patients who underwent integrated NGS profiling (406 genes) and analyze the alterations and their potential actionability. Results: Overall, 227 patients (96.5%) had adequate tissue. Most common diagnoses included myelodysplastic syndrome (22.9%), chronic lymphocytic leukemia (17.2%), non-Hodgkin lymphoma (13.2%), acute myeloid leukemia (11%), myeloproliferative neoplasm (9.2%), acute lymphoblastic leukemia (8.8%), and multiple myeloma (7.5%). Most patients (N = 197/227 (87%)) harbored ≥1 genomic alteration(s); 170/227 (75%), ≥1 potentially actionable alteration(s) targetable by an FDA-approved (mostly off-label) or an investigational agent. Altogether, 546 distinct alterations were seen, most commonly involving TP53 (10.8%), TET2 (4.6%), and DNMT3A (4.2%). The median tumor mutational burden (TMB) was low (1.7 alterations/megabase); 12% of patients had intermediate or high TMB (higher TMB correlates with favorable response to anti-PD1/PDL1 inhibition in solid tumors). In conclusion, 96.5% of patients with hematologic malignancies have adequate tissue for comprehensive genomic profiling. Most patients had unique molecular signatures, and 75% had alterations that may be pharmacologically tractable with gene- or immune-targeted agents. Full article
(This article belongs to the Special Issue Application of Next-Generation Sequencing in Cancers)
►▼ Show Figures

Figure 1

Review

Jump to: Research

20 pages, 3072 KiB  
Review
Cancer Genetics and Therapeutic Opportunities in Urologic Practice
by Jacob J. Adashek, Alex Leonard, Jason Roszik, Arjun K. Menta, Giannicola Genovese, Vivek Subbiah and Pavlos Msaouel
Cancers 2020, 12(3), 710; https://doi.org/10.3390/cancers12030710 - 18 Mar 2020
Cited by 3 | Viewed by 4325
Abstract
This article aims to summarize the current literature on genetic alterations related to tumors of the genitourinary tract. Novel associations have recently been reported between specific DNA alterations and genitourinary malignancies. The most common cause of chromosome 3p loss in clear cell renal [...] Read more.
This article aims to summarize the current literature on genetic alterations related to tumors of the genitourinary tract. Novel associations have recently been reported between specific DNA alterations and genitourinary malignancies. The most common cause of chromosome 3p loss in clear cell renal cell carcinoma is a chromothripsis event, which concurrently generates a chromosome 5q gain. Specific patterns of clear cell renal cell carcinoma metastatic evolution have been uncovered. The first therapy targeting a specific molecular alteration has now been approved for urothelial carcinoma. Germline mutations in DNA damage repair genes and the transcription factor HOXB13 are associated with prostate cancer and may be targeted therapeutically. The genetic associations noted across different genitourinary cancers can inform potential screening approaches and guide novel targeted treatment strategies. Full article
(This article belongs to the Special Issue Application of Next-Generation Sequencing in Cancers)
►▼ Show Figures

Figure 1

21 pages, 583 KiB  
Review
Bulk and Single-Cell Next-Generation Sequencing: Individualizing Treatment for Colorectal Cancer
by Ioannis D. Kyrochristos, Demosthenes E. Ziogas, Anna Goussia, Georgios K. Glantzounis and Dimitrios H. Roukos
Cancers 2019, 11(11), 1809; https://doi.org/10.3390/cancers11111809 - 18 Nov 2019
Cited by 17 | Viewed by 5092
Abstract
The increasing incidence combined with constant rates of early diagnosis and mortality of colorectal cancer (CRC) over the past decade worldwide, as well as minor overall survival improvements in the industrialized world, suggest the need to shift from conventional research and clinical practice [...] Read more.
The increasing incidence combined with constant rates of early diagnosis and mortality of colorectal cancer (CRC) over the past decade worldwide, as well as minor overall survival improvements in the industrialized world, suggest the need to shift from conventional research and clinical practice to the innovative development of screening, predictive and therapeutic tools. Explosive integration of next-generation sequencing (NGS) systems into basic, translational and, more recently, basket trials is transforming biomedical and cancer research, aiming for substantial clinical implementation as well. Shifting from inter-patient tumor variability to the precise characterization of intra-tumor genetic, genomic and transcriptional heterogeneity (ITH) via multi-regional bulk tissue NGS and emerging single-cell transcriptomics, coupled with NGS of circulating cell-free DNA (cfDNA), unravels novel strategies for therapeutic response prediction and drug development. Remarkably, underway and future genomic/transcriptomic studies and trials exploring spatiotemporal clonal evolution represent most rational expectations to discover novel prognostic, predictive and therapeutic tools. This review describes latest advancements and future perspectives of integrated sequencing systems for genome and transcriptome exploration to overcome unmet research and clinical challenges towards Precision Oncology. Full article
(This article belongs to the Special Issue Application of Next-Generation Sequencing in Cancers)
►▼ Show Figures

Figure 1

20 pages, 1633 KiB  
Review
Comprehensive Outline of Whole Exome Sequencing Data Analysis Tools Available in Clinical Oncology
by Áron Bartha and Balázs Győrffy
Cancers 2019, 11(11), 1725; https://doi.org/10.3390/cancers11111725 - 4 Nov 2019
Cited by 25 | Viewed by 11162
Abstract
Whole exome sequencing (WES) enables the analysis of all protein coding sequences in the human genome. This technology enables the investigation of cancer-related genetic aberrations that are predominantly located in the exonic regions. WES delivers high-throughput results at a reasonable price. Here, we [...] Read more.
Whole exome sequencing (WES) enables the analysis of all protein coding sequences in the human genome. This technology enables the investigation of cancer-related genetic aberrations that are predominantly located in the exonic regions. WES delivers high-throughput results at a reasonable price. Here, we review analysis tools enabling utilization of WES data in clinical and research settings. Technically, WES initially allows the detection of single nucleotide variants (SNVs) and copy number variations (CNVs), and data obtained through these methods can be combined and further utilized. Variant calling algorithms for SNVs range from standalone tools to machine learning-based combined pipelines. Tools for CNV detection compare the number of reads aligned to a dedicated segment. Both SNVs and CNVs help to identify mutations resulting in pharmacologically druggable alterations. The identification of homologous recombination deficiency enables the use of PARP inhibitors. Determining microsatellite instability and tumor mutation burden helps to select patients eligible for immunotherapy. To pave the way for clinical applications, we have to recognize some limitations of WES, including its restricted ability to detect CNVs, low coverage compared to targeted sequencing, and the missing consensus regarding references and minimal application requirements. Recently, Galaxy became the leading platform in non-command line-based WES data processing. The maturation of next-generation sequencing is reinforced by Food and Drug Administration (FDA)-approved methods for cancer screening, detection, and follow-up. WES is on the verge of becoming an affordable and sufficiently evolved technology for everyday clinical use. Full article
(This article belongs to the Special Issue Application of Next-Generation Sequencing in Cancers)
►▼ Show Figures

Figure 1

19 pages, 574 KiB  
Review
Clinical Application of Next-Generation Sequencing as A Liquid Biopsy Technique in Advanced Colorectal Cancer: A Trick or A Treat?
by Myrto Kastrisiou, George Zarkavelis, George Pentheroudakis and Angeliki Magklara
Cancers 2019, 11(10), 1573; https://doi.org/10.3390/cancers11101573 - 16 Oct 2019
Cited by 18 | Viewed by 4001
Abstract
Owing to its advantages over prior relevant technologies, massive parallel or next-generation sequencing (NGS) is rapidly evolving, with growing applications in a wide range of human diseases. The burst in actionable molecular alterations in many cancer types advocates for the practicality of using [...] Read more.
Owing to its advantages over prior relevant technologies, massive parallel or next-generation sequencing (NGS) is rapidly evolving, with growing applications in a wide range of human diseases. The burst in actionable molecular alterations in many cancer types advocates for the practicality of using NGS in the clinical setting, as it permits the parallel characterization of multiple genes in a cost- and time-effective way, starting from low-input DNA. In advanced clinical practice, the oncological management of colorectal cancer requires prior knowledge of KRAS, NRAS, and BRAF status, for the design of appropriate therapeutic strategies, with more gene mutations still surfacing as potential biomarkers. Tumor heterogeneity, as well as the need for serial gene profiling due to tumor evolution and the emergence of novel genetic alterations, have promoted the use of liquid biopsies—especially in the form of circulating tumor DNA (ctDNA)—as a promising alternative to tissue molecular analysis. This review discusses recent studies that have used plasma NGS in advanced colorectal cancer and summarizes the clinical applications, as well as the technical challenges involved in adopting this technique in a clinically beneficial oncological practice. Full article
(This article belongs to the Special Issue Application of Next-Generation Sequencing in Cancers)
►▼ Show Figures

Figure 1

14 pages, 1313 KiB  
Review
Protecting Tumors by Preventing Human Papilloma Virus Antigen Presentation: Insights from Emerging Bioinformatics Algorithms
by Elizabeth Gensterblum-Miller and J. Chad Brenner
Cancers 2019, 11(10), 1543; https://doi.org/10.3390/cancers11101543 - 12 Oct 2019
Cited by 4 | Viewed by 2969
Abstract
Recent developments in bioinformatics technologies have led to advances in our understanding of how oncogenic viruses such as the human papilloma virus drive cancer progression and evade the host immune system. Here, we focus our review on understanding how these emerging bioinformatics technologies [...] Read more.
Recent developments in bioinformatics technologies have led to advances in our understanding of how oncogenic viruses such as the human papilloma virus drive cancer progression and evade the host immune system. Here, we focus our review on understanding how these emerging bioinformatics technologies influence our understanding of how human papilloma virus (HPV) drives immune escape in cancers of the head and neck, and how these new informatics approaches may be generally applicable to other virally driven cancers. Indeed, these tools enable researchers to put existing data from genome wide association studies, in which high risk alleles have been identified, in the context of our current understanding of cellular processes regulating neoantigen presentation. In the future, these new bioinformatics approaches are highly likely to influence precision medicine-based decision making for the use of immunotherapies in virally driven cancers. Full article
(This article belongs to the Special Issue Application of Next-Generation Sequencing in Cancers)
►▼ Show Figures

Figure 1

9 pages, 653 KiB  
Review
New Era for Next-Generation Sequencing in Japan
by Masayuki Takeda, Kazuko Sakai, Takayuki Takahama, Kazuya Fukuoka, Kazuhiko Nakagawa and Kazuto Nishio
Cancers 2019, 11(6), 742; https://doi.org/10.3390/cancers11060742 - 28 May 2019
Cited by 22 | Viewed by 4251
Abstract
Recent progress in understanding the molecular basis of cancer—including the discovery of cancer-associated genes such as oncogenes and tumor suppressor genes—has suggested that cancer can become a treatable disease. The identification of driver oncogenes such as EGFR, ALK, ROS1, BRAF [...] Read more.
Recent progress in understanding the molecular basis of cancer—including the discovery of cancer-associated genes such as oncogenes and tumor suppressor genes—has suggested that cancer can become a treatable disease. The identification of driver oncogenes such as EGFR, ALK, ROS1, BRAF and HER2 has already been successfully translated into clinical practice for individuals with solid tumor. Next-generation sequencing (NGS) technologies have led to the ability to test for multiple cancer-related genes at once with a small amount of cells and tissues. In Japan, several hospitals have started NGS-based mutational profiling screening in patients with solid tumor in order to guide patients to relevant clinical trials. The Ministry of Health, Labor, and Welfare of Japan has also approved several cancer gene panels for use in clinical practice. However, there is an urgent need to develop a medical curriculum of clinical variant interpretation and reporting. We review recent progress in the implementation of NGS in Japan. Full article
(This article belongs to the Special Issue Application of Next-Generation Sequencing in Cancers)
►▼ Show Figures

Figure 1

Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:
 
Displaying articles 1-24
Back to TopTop