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Scientific Publications on Next Generation Sequencing Applications in Cancer Genetics 

This page introduces a selection of scientific publications related to next generation sequencing (NGS) application in cancer genetics. The publications cover the aspects of cancer research, screening, and diagnosis.


Publications on NGS applications in Cancer Genetics 

Advantages of a next generation sequencing targeted approach for the molecular diagnosis of retinoblastoma

This publication reports on a study of 65 patients with retinoblastoma (RB) applying NGS and RB1 custom array Comparative Genome Hybridization (GCH). For targeted sequencing the TruSeq Custom Amplicon, the Illumina Design Studio and MiSeq Reporter software were applied.
Several known as well as new mutations were detected by NGS including nonsense and splice side mutations.
In summary, NGS in combination with GCH will optimise overall diagnostic of RB. Major advantages of NGS are high performance capacity and accuracy of the generated data.
NGS sensitivity for mosaicism frequency identification described in this study was down to 1%. NGS enables the multiplexing of hundreds of samples and analysing different targets simultaneously and makes it to a powerful tool for the study of rare diseases.
Grotta et al. 2015

Clinical applications of next generation sequencing in cancer: from panels, to exomes, to genomes

This review first introduces the history of sequencing applications in cancer research and diagnostics, before presenting an overview of genetic mutations associated with selected cancers. A number of different cancer panel tests and NGS service providers offering cancer-specific tests are introduced.
In summary, the review suggests that the clinical usefulness of genomic sequencing requires advancements in genome knowledge and in bioinformatics systems for data processing.
Shen et al 2015

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Genetic heterogeneity in cholangiocarcinoma: a major challenge for targeted therapies

This publication addresses the epithelial cancer cholangiocarcinoma, and presents a number of studies with therapeutic aims. Different mutations and risk factors related to or associated with cholangiocarcinoma are presented and discussed in detail.
Overall, the paper concludes that the identification of cholangiocarcinoma candidate mutations remains challenging due to the variety of factors potentially contributing to genetic heterogeneity in this form of malignancy.
Brandi et al 2015

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Genetic susceptibility to lung cancer and co-morbidities

This review discusses latest concepts of genetic susceptibility to lung cancer. Different genome wide association studies (GWAS) conducted in the last years in the field of lung cancer are introduced and candidate genes are described.
The challenges of GWAS study design for lung cancer are highlighted.
Results of GWAS studies of susceptibility to lung cancer in smokers showed that many key SNPs were independent of the smoking status.
Additionally, GWAS studies conducted in never smokers populations are introduced.
Some potential candidate genes for lung cancer susceptibility are nAChR, CHRNA3, CHRNA5, TERT, CLPTM1L, BAT3, MSH5, ROS1, and VTI1A. For more information a table showing potential candidate genes discovered in latest GWAS studies is presented.
In further GWAS studies different genes and regions were found to be potentially related with smoking behaviour, these are for example BDNF, 6p21 (HLA) and 2q21 (intergenic region).
The intensity of smoking could be associated with nAChR genes.
As chronic obstructive pulmonary disease (COPD) frequently coexist with lung cancer GWAS studies of COPD are also presented and candidate genes are discussed.
Finally, an brief outlook for future directions is given.

Yang et al. 2013

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Less frequently mutated genes in colorectal cancer: evidences from next-generation sequencing of 653 routine cases

As mutations in certain genes are already well described to be associated with higher risk for developing colorectal cancer this study was performed in order to obtain more information about mutations of genes that are less frequently associated with colorectal cancer.
In this study the next generation sequencing (NGS ) technology was applied in order to investigate 653 clinical samples by a targeted PCR approach. In the experimental settings 91 hot spot regions located in 22 genes were sequenced. This study included the already described genes KRAS, NRAS, BRAF, PIK3CA andTP53 as well as the receptor tyrosine kinase (RTK) genes (ALK, EGFR, ERBB2, ERBB4, FGFR1, FGFR2, FGFR3, MET, DDR2) and the RTK signalling genes (AKT1, PTEN, MAP2K1, STK11) and the know cancer related genes (NOTCH1, CTNNB1, SMAD4, FBXW7).
In total 796 mutations were observed in 499 tumours. This study demonstrated that in a number of genes less frequently mutations were found that can be associated with the occurrence of colorectal cancer.
In conclusion the application of NGS targeted gen panels in routine clinical cancer diagnostics has the potential to identify reliable and reproducible biomarkers of response/resistance to the targeted treatments for certain cancers as colorectal cancer.

Malapelle et al. 2016

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Metagenomics: A new horizon in cancer research

A considerable number of cancers have been shown to be associated with microbial infections. This paper describes how metagenomic analysis can be applied to study the link between cancer and microbial infections. A number of microbes and their associated cancers are introduced and discussed.
Banerjee et al 2015

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Multiplex PCR and Next Generation Sequencing for the Non-Invasive Detection of Bladder Cancer

22. February 2016, PlosOne published the study from Ward et al. " Multiplex PCR and Next Generation Sequencing for the Non-Invasive Detection of Bladder Cancer".

This publication reports on the developed of an assay based on high-throughput deep-sequencing of six genes (FGFR3, PIK3CA, TP53, HRAS, RXRA and KDM6A) which contain mutation hotspots and are associated with bladder cancer. The urinary DNA from 232 patients was analyzed in order to evaluate the ability to non-invasively detect bladder cancer with the multiplex PCR and NGS based approach.
The results of the NGS mutation analyses for detection bladder cancer based on the six genes and the TERT promoter region showed 70% sensitivity and 97% specificity.
In summary, this study showed that mutations in multiple genes can be detected in urine DNA of bladder cancer patients using multiplex PCR and NGS analysis.
It is stated that multiplexing samples with barcode approach will be a reasonable diagnostic solution especially for central testing laboratories with the existing infrastructure. Furthermore, it is stated that a larger panel of genes with bladder cancer related mutations will increase the sensitivity of the test. The performed test was applicable for 96% of the tested samples. Starting with more sample material and implementing a DNA concentration steps could further improve the test. Limitations of this study such as the overall sensitivity of 70% are briefly discussed.
As conclusion, it is recommended to improve the sensitivity of the test by adding additional genetic or epigenetic markers to the introduced test.

The publication is free available at NCBI

Precision medicine for cancer with next-generation functional diagnostics


Precision medicine is about finding the right drugs for the right patient and disease. In cancer precision medicine and research is closely related to genomics.
This review discusses latest discoveries and progress in the field of next generation cancer diagnostics including next generation sequencing (NGS) based technologies and its applications.
Currently, only a small number of patients used clinical validated and approved therapies matched to cancer related mutations. Cancer development is microevolutionary process driven during replication and thus differ from other rare genetic diseases.
This review discussed the limitations of NGS application for targeted cancer therapy. For example NGS will support the identification of cancer related genetic variations but the finding and testing of the right drug therapy is a long process and validation in clinical trials correlating the drug to specific or rare mutations is challenging.
This review introduced first generation functional diagnostic test for cancer and new methods including: Mouse models for functional testing , assays of ex vivo tumour responses, Functional assays for leukaemia, and In situ functional diagnostics assays.
In summary, the author recommended to use additionally diagnostics technologies to complement NGS for guiding better cancer therapies.

Friedman et al. 2015
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Scenario drafting for early technology assessment of next generation sequencing in clinical oncology

"Scenario drafting for early technology assessment of next generation sequencing in clinical oncology" published in BMC Cancer on 6. of February 2016 by Joosten et al.

This publication reports on scenario drafting for implementation of next generation sequencing (NGS) gene panels in clinical oncology in order to identify critical barriers and facilitators that could affect speed of adoption of NGS panels in clinical application. Furthermore, modeling for future cost effectiveness of NGS panel clinical application was investigated.
In the scenario testing a questionnaire was developed based on expert interviews and literature search. The questionnaire contained one basis scenario and twelve what if scenarios considering different possible developments. The questionnaire was distributed to NGS experts focusing on technical experts and clinicians.
The questionnaire included aspects of social factors, technical factors, reimbursement, clinical utility and evidence generation, and market access.
The results showed that most physicians are probably willing to use NGS panels in clinical applications. One major barrier is the low likelihood of reimbursement reducing the cost for NGS application might increase the likelihood for reimbursement. Another expectation was that a novel technology might be competitive to NGS.
Limitations of this study are the relative low number of participants and the homogeneity of the polled stakeholder. Groups, such as patients, clinical geneticists, pharmaceutical companies or health insurers were not included in this survey.

The publication is free available at MBC Cancer

The promise of liquid biopsy in cancer: a clinical perspective

This publication introduces two case studies were NGS was used to detect circulating tumour cells (CTCs) in breast cancer patients by applying liquid biopsy. The results showed that NGS can be used to detect CTC and characterize the cancer by liquid blood biopsy. The major challenge is to use the NGS information in order to define the most appropriate treatments. Different problems are discussed, these are the spatial heterogeneity within the same tissue and/or sites of metastasis and a prospective longitudinal heterogeneity in the context of biopsies performed in sequential time periods of the cancer natural history.
In summary, liquid biopsy can offer real-time assessment in cancer diagnostics. It should not only help to diagnose the cancer type but should also guide decision making for cancer treatments.
Cortesi et al. 2015

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Use of molecular studies for treatment of metastatic pleomorphic large cell pancreatic cancers-a novel strategy

April 2016, J. Gastrointest Oncol. published the study of Padhi et al.
"Use of molecular studies for treatment of metastatic pleomorphic large cell pancreatic cancers-a novel strategy."

This study describes the application of next generation sequencing for molecular testing in order to support chemotherapeutic decision making in a case of metastatic undifferentiated pleomorphic large cell pancreatic cancer.
At the time point of investigation there was no proven treatment for this type of cancer available. The outcome of these cancer type is very poor. Therefore, samples were investigated by NGS based molecular testing. NGS studies showed cancer related mutations in the TLE3, EGFR, KRAS, PD1, TP53 and TOP2A genes. No cancer related mutations were found in the Her2Neu, RRM1, BRAF, RET, and PI3KCA genes. Based on the molecular findings together with other clinical investigations in this case it was supposed that the tumour is sensitive to gemcitabine, paclitaxel, docetaxel, temozolamide, dacarbazine and doxorubicin. The decision was made to treat this patient with gemcitabine and nab-paclitaxel.
In conclusion, molecular testing such as NGS can not only be used for diagnostics but can also support decision making for chemotherapeutic treatment strategies.

The publication is free available at NCBI

Whole exome sequencing (WES) on formalin fixed, paraffin-embedded (FFPE) tumour tissue in gastrointestinal stromal tumours (GIST)

This study was performed in order to evaluate if NGS data generated from FFPE samples can be reliable generated and used for clinical routine settings. Therefore, whole exome sequencing was performed on samples of gastrointestinal stromal tumours. Sequencing of FFPE and FF (fresh frozen) samples showed comparable results. The quality in terms of DNA degradation in the FFPE was investigated prior sequencing. The quality of raw sequencing data were comparable between FF samples and high quality FFPE samples.
Low quality FFPE samples showed higher numbers of false positive SNPs due to artefacts introduced during formalin fixation.
Different advantages of WES over targeted specific sequencing approaches on FFPE samples are discussed.
The results of this study will help to transfer WES of FFPE into clinical practise.
Astolfi et al. 2015

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