Whole exome sequencing for cancer &amp;ndash; is there evidence of clinical utility?

Malhotra, Alka; Levine, Susan; Allingham-Hawkins, Diane

doi:10.2147/agg.s58809

Cited by 6 publications

(10 citation statements)

References 32 publications

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“…Secondly, a number of articles (9, 6 %) focus generally on genetic or inherited disorders, which may or may not be rare diseases. Thirdly, some articles cover many possible diseases – such as cancer [ 42 , 43 ] or rare diseases [ 44 , 45 ] in general - while others focus specifically on one disease [ 46 – 48 ]. A significant number of articles (42, 29 %) did not focus on any diseases in particular, but addressed the impact of WES on all clinical contexts.…”

Section: Resultsmentioning

confidence: 99%

“…This need for interdisciplinary collaboration, along with the way WES testing may challenge existing professional roles in the clinic, was reported as a challenge by 50 (34 %) articles. To interpret variants, these specialists rely on bioinformatics analysis pipelines made of imperfect algorithms [ 36 , 37 , 42 , 55 ], referring to imperfect databases [ 44 , 50 , 56 , 57 ]. The need to develop more efficient and standardised bioinformatics tools to filter, analyze and interpret WES variants was reported as a challenge by 44 (29.29 %) articles.…”

Section: Resultsmentioning

confidence: 99%

“…Even after mentioning these recommendations, articles published in 2014 refer to the reporting of IF by clinicians as “currently a subject of intense debate” [ 52 ], “one of the current, contentious debates” [ 73 ], or state that “there remains strong debate” [ 56 ] and an “ongoing discussion on how to best proceed with incidental findings” [ 75 ]. Malhotra et al [ 42 ] specifically mention that “the methods of providing [incidental findings] to patients are not entirely clear, although some recommendations have recently been made by the American College of Medical Genetics and Genomics”. Even in 2015, this is still considered to be a “current debate” by Goldberg et al [ 76 ], and Bender state that the discussion of this topic “will undoubtedly continue” [ 77 ].…”

Section: Resultsmentioning

confidence: 99%

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Unsolved challenges of clinical whole-exome sequencing: a systematic literature review of end-users’ views

2016

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BackgroundWhole-exome sequencing (WES) consists in the capture, sequencing and analysis of all exons in the human genome. Originally developed in the research context, this technology is now increasingly used clinically to inform patient care. The implementation of WES into healthcare poses significant organizational, regulatory, and ethical hurdles, which are widely discussed in the literature.MethodsIn order to inform future policy decisions on the integration of WES into standard clinical practice, we performed a systematic literature review to identify the most important challenges directly reported by technology users.ResultsOut of 2094 articles, we selected and analyzed 147 which reported a total of 23 different challenges linked to the production, analysis, reporting and sharing of patients’ WES data. Interpretation of variants of unknown significance, incidental findings, and the cost and reimbursement of WES-based tests were the most reported challenges across all articles.ConclusionsWES is already used in the clinical setting, and may soon be considered the standard of care for specific medical conditions. Yet, technology users are calling for certain standards and guidelines to be published before this technology replaces more focused approaches such as gene panels sequencing. In addition, a number of infrastructural adjustments will have to be made for clinics to store, process and analyze the amounts of data produced by WES.Electronic supplementary materialThe online version of this article (doi:10.1186/s12920-016-0213-6) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Unsolved challenges of clinical whole-exome sequencing: a systematic literature review of end-users’ views

2016

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“…Conversely, and equally instructive, WES can highlight diseases that do not share common genes. Chronic lymphocytic leukemia and acute myeloid leukemia are two such examples [56]. Classification of disease subtypes is also useful as it can identify patient-specific genomic rearrangements such as those found in glioblastoma tumors [57].…”

Section: Cancermentioning

confidence: 99%

Neurological disorders, genetic correlations, and the role of exome sequencing

Brown¹,

Meloche²

2016

J Transl Sci

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Genomic information access and utilization by researchers and clinicians have barely begun the journey for fulfillment of their full potential in the research and clinical arenas. Exciting is the potential depth and breadth of research, clinical applications, and more personalized medicine, that remain on the horizon. Exome sequencing has clarified the responsibilities of over 130 genes, greatly expanding the medical genetics database and enabling the development of orphan diseasebased pharmaceuticals. The focus of our research efforts was to review several literature sources related to rare genomic disease research and exome sequencing, as well as to review the new research and diagnostic strategies that were utilized. Using a systems approach, under discussion are neurology, neuropathy, and the central nervous and musculoskeletal systems. Also discussed will be the topics of inborn errors of metabolism, and the genetic targets related to developmental delay. Recommendations for future research will also be discussed. Exome sequencing A review of new strategies for rare genomic disease researchThis literature review will examine several publications in which the authors demonstrate the success of whole exome sequencing (WES) in circumstances where traditional methods have presented ambiguous interpretations or failed altogether, for instance, single -subject populations, large candidate counts and reduced reproductive fitness [1]. By supporting exome sequencing, we will show that there is an increasing need for polymorphism databases and assay strategies that do not depend on positional information, if genomic medicine is to advance its research and clinical utility. Within our review, we will discuss the research related to neurology, neuropathy, the central nervous system, the musculoskeletal system, inborn errors of metabolism, and the genetic targets related to developmental delay. Recommendations for future research will also be discussed. Disease survey NeurologyPositional cloning techniques have thus far unveiled 19 contributory genes in the study of 31 genetic variations of autosomal dominant spinocerebellar ataxia [2]. The method has yet to overcome the challenges that presented, such as phenotypic and biological manifestations which do not correlate well to molecular mutations due to the exceedingly complex nature of the brain. Exome sequencing has, however, shed additional light on causal mutations for sensory motor neuropathy with ataxia [3], which presents with cerebellar dysfunction, Spinocerebellar Ataxia with Psychomotor Retardation [4], and Spastic Ataxia-Neuropathy syndrome that manifested with remarkable variety between two brothers [5] due to different mutations in the same protease subunits.A United States incidence of 1 in 12,500 live births makes neuronal ceroid lipofuscinoses the most common group of inherited neurological degenerative disorders [6]. Whether examining the mitochondrial defect implicated in prenatal ventriculomegaly [7], the often early-stage atypical presentation...

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“…4 , 5 Even genome and exome sequencing have failed to define a clinically applicable, focused approach for the treatment of a given tumor, at least to date. 6 , 7 …”

Section: Introductionmentioning

confidence: 99%

Molecular heterogeneity in adjacent cells in triple-negative breast cancer

Huebschman¹,

Lane²,

Liu³

et al. 2015

BCTT

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PurposeThis study interrogates the molecular status of individual cells in patients with triple-negative breast cancers and explores the molecular identification and characterization of these tumors to consider the exploitation of a potential-targeted therapeutic approach.Patients and methodsHyperspectral immunologic cell by cell analysis was applied to touch imprint smears obtained from fresh tumors of breast cancer patients.ResultsCell by cell analysis confirms significant intratumoral molecular heterogeneity in cancer markers with differences from polymerase chain reaction marker reporting. The individual cell heterogeneity was recognized in adjacent cells examined with panels of ten molecular markers in each single cell and included some markers that are considered to express “stem-cell” character. In addition, heterogeneity did not relate either to the size or stage of the primary tumor or to the site from within the cancer.ConclusionThere is a very significant molecular heterogeneity when “adjacent cells” are examined in triple-negative breast cancer, thereby making a successful targeted approach unlikely. In addition, it is not reasonable to consider that these changes will provide an answer to tumor dormancy.

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Whole exome sequencing for cancer – is there evidence of clinical utility?

Cited by 6 publications

References 32 publications

Unsolved challenges of clinical whole-exome sequencing: a systematic literature review of end-users’ views

Unsolved challenges of clinical whole-exome sequencing: a systematic literature review of end-users’ views

Neurological disorders, genetic correlations, and the role of exome sequencing

Molecular heterogeneity in adjacent cells in triple-negative breast cancer

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