Next-Generation Sequencing for Cancer Genomics

2013 ◽  
pp. 55-74
Author(s):  
Aarti N. Desai ◽  
Abhay Jere
Keyword(s):  
Next Generation Sequencing ◽  
Cancer Genomics ◽  
Next Generation ◽  
Generation Sequencing

Enabling Precision Oncology Through Precision Diagnostics

2020 ◽  
Vol 15 (1) ◽  
pp. 97-121 ◽  
Author(s):  
Noah A. Brown ◽  
Kojo S.J. Elenitoba-Johnson
Keyword(s):  
Next Generation Sequencing ◽  
Cancer Patients ◽  
Cancer Genomics ◽  
Cost Effective ◽  
Routine Clinical Practice ◽  
Precision Oncology ◽  
Next Generation ◽  
Sequencing Data ◽  
Molecular Alterations ◽  
Generation Sequencing

Genomic testing enables clinical management to be tailored to individual cancer patients based on the molecular alterations present within cancer cells. Genomic sequencing results can be applied to detect and classify cancer, predict prognosis, and target therapies. Next-generation sequencing has revolutionized the field of cancer genomics by enabling rapid and cost-effective sequencing of large portions of the genome. With this technology, precision oncology is quickly becoming a realized paradigm for managing the treatment of cancer patients. However, many challenges must be overcome to efficiently implement the transition of next-generation sequencing from research applications to routine clinical practice, including using specimens commonly available in the clinical setting; determining how to process, store, and manage large amounts of sequencing data; determining how to interpret and prioritize molecular findings; and coordinating health professionals from multiple disciplines.

scholarly journals BCO App: tools for generating BioCompute Objects from next-generation sequencing workflows and computations

F1000Research ◽  
2020 ◽  
Vol 9 ◽  
pp. 1144
Author(s):  
Nan Xiao ◽  
Soner Koc ◽  
David Roberson ◽  
Phillip Brooks ◽  
Manisha Ray ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Cancer Genomics ◽  
Next Generation Sequencing Data ◽  
Next Generation ◽  
Sequencing Data ◽  
Task Execution ◽  
Regulatory Submissions ◽  
Time Required ◽  
Computational Platform ◽  
Generation Sequencing

The BioCompute Object (BCO) standard is an IEEE standard (IEEE 2791-2020) designed to facilitate the communication of next-generation sequencing data analysis with applications across academia, government agencies, and industry. For example, the Food and Drug Administration (FDA) supports the standard for regulatory submissions and includes the standard in their Data Standards Catalog for the submission of HTS data. We created the BCO App to facilitate BCO generation in a range of computational environments and, in part, to participate in the Advanced Track of the precisionFDA BioCompute Object App-a-thon. The application facilitates the generation of BCOs from both workflow metadata provided as plaintext and from workflow contents written in the Common Workflow Language. The application can also access and ingest task execution results from the Cancer Genomics Cloud (CGC), an NCI funded computational platform. Creating a BCO from a CGC task significantly reduces the time required to generate a BCO on the CGC by auto-populating workflow information fields from CGC workflow and task execution results. The BCO App supports exporting BCOs as JSON or PDF files and publishing BCOs to both the CGC platform and to GitHub repositories.

scholarly journals Targeted Next Generation Sequencing Expands Genotype in Patients with PIK3CA-Related Overgrowth Spectrum (PROS)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1880-1880
Author(s):  
Kelly Barry ◽  
Melisa Ruiz-Gutierrez ◽  
Whitney Eng
Keyword(s):  
Next Generation Sequencing ◽  
Somatic Mutations ◽  
Cancer Genomics ◽  
Vascular Anomalies ◽  
Leg Length Discrepancy ◽  
Next Generation ◽  
Leg Length ◽  
Targeted Next Generation Sequencing ◽  
Length Discrepancy ◽  
Generation Sequencing

Abstract Background: Disorders of somatic mosaicism (DoSM) are caused by mutations that arise post-zygotically and are present in only a specific part of the body. These mutations alter the function and regulation of key genes in cell proliferation pathways, including the PI3K/AKT/mTOR pathway, and show significant overlap with mutations identified in cancer(McNulty et al. Am J Hum Genet, 2019). PIK3CA-Related Overgrowth Spectrum (PROS) is an umbrella term that encompasses a variety of overgrowth syndromes caused by post-zygotic, somatic gain-of-function PIK3CA mutations with low-level mosaicism (Luks et al. J Pediatr, 2015). The clinical phenotype of PROS is heterogeneous and many tissue types can be affected. This often makes clinical diagnosis challenging. The use of cancer genomics in patients with vascular anomalies may aid in establishing a genetic diagnosis and expand use of targeted medical therapies. Methods: Three patients who presented with clinical symptoms of PROS underwent targeted next generation sequencing of affected tissue using OncoPanel. Oncopanel is a genomic assay that detects somatic mutations, copy number variations and structural variants in 447 genes implicated in cancer. Results: Three patients with a PROS phenotype demonstrated somatic mutations in genes distinct from PIK3CA. Case 1: A 15-year-old female presented with a painful right leg mass, calf atrophy, contracture of the knee, leg-length discrepancy, and severe limp. Histology was consistent with fibroadipose vascular anomaly (FAVA) versus kaposiform hemangioendothelioma (KHE). Given her significant functional impairment, treatment with Sirolimus was initiated with significant improvement in appearance and functionality. OncoPanel testing revealed a PIK3C2B c.2881G>A (p.G961S) mutation. Case 2: A 12-month-old male was noted at birth to have a diffuse capillary malformation, multiple lymphatic malformations, macrodactyly of his bilateral hands and leg length-discrepancy, consistent with Congenital Lipomatous Overgrowth, Vascular Malformations, Epidermal Nevi, Spinal/Skeletal Anomalies/Scoliosis (CLOVES) syndrome. He underwent numerous surgical de-bulking procedures, epiphysiodesis, sclerotherapy, and laser therapy with continued disease progression. OncoPanel revealed a PIK3R1c.1731_1738delAGACCAATinsATGTAAGAAAG (p.D578_Y580delinsCKKD) mutation. Case 3: A 10-month-old female presented with a diffuse capillary malformation and leg-length discrepancy. She subsequently developed multiple painful and progressive lymphatic lesions over her left arm and chest which did not respond to sclerotherapy. Due to high clinical suspicion for PROS, she underwent targeted genetic testing via droplet digital PCR (ddPCR) to detect the five most common variants (C420R, E542K, E545K, H1047L, H1047R) in PIK3CA, but no hotspot mutations were identified. Over the next year and a half, the patient had two biopsies performed, PIK3CA ddPCR testing performed twice, and OncoPanel testing performed twice. OncoPanel testing of the second tissue biopsy ultimately resulted in the identification of a PIK3R1 c.1723-1731del p.K575_R577del mutation. Conclusion: The clinical diagnosis of DoSM is often challenging. While the use of cancer genomics for diagnostic purposes in vascular anomalies is uncommon, its use continues to broaden our understanding of syndromes related to alterations in the PI3K/AKT/mTOR pathway. PIK3CB encodes a catalytic subunit of PI3K, p110β, and is dysregulated in certain types of cancer. PIK3R1 encodes multiple regulatory subunits of PI3K and acts as a negative regulator of PIK3CA function. Both gain-of-function of PIK3CB or loss-of-function of PIK3R1 lead to inappropriate activation of PIK3CA, and our cases highlight that mutations in other genes can lead to the clinical phenotype of PROS. It is reasonable to expect that patients with alterations in genes that activate PIK3CA may benefit from medical treatment with direct PIK3CA inhibitors. Limiting diagnostic testing to evaluation of the PIK3CA gene alone may yield negative results and preclude patient eligibility for treatment with novel therapies. The use of next-generation sequencing (NGS) designed to detect somatic variations in cancer will likely play a pivotal role in detecting variants in vascular anomalies in the future and in expanding our understanding of genetic alterations involved in PROS. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Sirolimus is used off-label for the treatment of vascular anomalies.

scholarly journals Diagnostic Utility of Targeted Next Generation Sequencing in Patients with Vascular Anomalies

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 8-9
Author(s):  
Whitney Eng ◽  
Sophie Dilek ◽  
Abigail Ward ◽  
Harry PW Kozakewich ◽  
Alyaa Al-Ibraheemi ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Next Generation Sequencing ◽  
Dna Sequences ◽  
Cancer Genomics ◽  
Massively Parallel Sequencing ◽  
Genetic Diagnosis ◽  
Vascular Anomalies ◽  
Next Generation ◽  
Targeted Next Generation Sequencing ◽  
Generation Sequencing

Background: Vascular anomalies are diverse entities and can range in severity from self-limiting to life-threatening. Diagnosis and care of these patients is challenging due to overlapping clinical and histologic features. Recently, it has been established that many vascular anomalies arise from somatic mutations in cancer genes (PIK3CA, AKT, NRAS). Use of cancer genomics in patients with vascular anomalies may establish a genetic diagnosis and expand use of targeted medical therapies. We evaluated the utility of targeted next generation sequencing for vascular anomalies patients at a single pediatric center. Methods: Using OncoPanel, a hybrid-capture and massively parallel sequencing assay that surveys DNA sequences of 447 genes implicated in cancer, we analyzed genetic variants in lesional tissue from vascular anomalies patients evaluated at Boston Children's Hospital between 5/2/2017 and 3/23/2020. Results: A total of 276 patients were consented and sequenced under the Dana Farber Cancer Institute Profile protocols DFCI 11-104 (n= 68) and DFCI 17-000 (n= 208). Clinical diagnoses prior to testing were varied and 11 patients (7%) had an unknown diagnosis. Tissue was analyzed for 138 patients. Targeted sequencing resulted in diagnostically significant alterations in 80 of 138 (57%) of patients and therapeutically significant alterations in 58 of 138 (42%) patients. To date, 18 patients in our cohort have been treated with medical therapy informed by their genetic diagnosis. Several more await enrollment on clinical trials. For patients with diagnoses previously categorized as unknown (n=11), sequencing led to identification of a genetic variant in 6 patients (54%). Additionally, 8/138 patients had variants requiring further evaluation for potential germline involvement. Discussion: Next generation sequencing in vascular anomalies patients identified actionable variants in a large proportion of the patients in our cohort. The mTOR inhibitor sirolimus has been used to treat a variety of vascular anomalies, but not all patients respond to this treatment. Targeted therapies based on specific genotypes hold promise as clinical trials in vascular anomalies are emerging. Additionally, sequencing in this cohort identified several variants suggesting a germline cancer predisposition requiring follow-up. Use of next generation sequencing has clinical utility and increased use of this testing may improve diagnosis, prognosis, and treatment for patients with vascular anomalies. Disclosures Adams: Novartis: Consultancy; Venthura: Consultancy. OffLabel Disclosure: Sirolimus is used off-label for the treatment of vascular anomalies.

scholarly journals Detection of somatic structural variants from short-read next-generation sequencing data

2019 ◽  
Author(s):  
Tingting Gong ◽  
Vanessa M Hayes ◽  
Eva KF Chan
Keyword(s):  
Next Generation Sequencing ◽  
Cancer Genomics ◽  
Next Generation Sequencing Data ◽  
Next Generation ◽  
Structural Variants ◽  
Sequencing Data ◽  
Short Read ◽  
Factors Affecting ◽  
Ngs Data ◽  
Generation Sequencing

AbstractSomatic structural variants (SVs) play a significant role in cancer development and evolution, but are notoriously more difficult to detect than small variants from short-read next-generation sequencing (NGS) data. This is due to a combination of challenges attributed to the purity of tumour samples, tumour heterogeneity, limitations of short-read information from NGS, and sequence alignment ambiguities. In spite of active development of SV detection tools (callers) over the past few years, each method has inherent advantages and limitations. In this review, we highlight some of the important factors affecting somatic SV detection and compared the performance of eight commonly used SV callers. In particular, we focus on the extent of change in sensitivity and precision for detecting different SV types and size ranges from samples with differing variant allele frequencies and sequencing depths of coverage. We highlight the reasons for why some SV callers perform well in some settings but not others, allowing our evaluation findings to be extended beyond the eight SV callers examined in this paper. As the importance of large structural variants become increasingly recognised in cancer genomics, this paper provides a timely review on some of the most impactful factors influencing somatic SV detection and guidance on selecting an appropriate SV caller.

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