Detection of Germline Mutation in Hereditary Breast and/or Ovarian Cancers by Next-Generation Sequencing on a Four-Gene Panel

Kwong, Ava; Shin, Vivian Y.; Au, Chun Hang; Law, Fian B.F.; Ho, Dona N.; Ip, Bui Kar; Wong, Anthony T.C.; Lau, Silvia; To, Rene M.Y.; Choy, Gigi; Ford, James M.; S.K., Edmond; Chan, Tsun Leung

doi:10.1016/j.jmoldx.2016.03.005

Cited by 39 publications

(49 citation statements)

References 29 publications

(31 reference statements)

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“…INDELseek was applied to a hereditary breast and/or ovarian cancer (HBOC) panel dataset of 239 probands [6]. The 4-gene panel targeted germline mutations (Illumina MiSeq).…”

Section: Resultsmentioning

confidence: 99%

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INDELseek: detection of complex insertions and deletions from next-generation sequencing data

Leung

Kwong

et al. 2017

BMC Genomics

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BackgroundComplex insertions and deletions (indels) from next-generation sequencing (NGS) data were prone to escape detection by currently available variant callers as shown by large-scale human genomics studies. Somatic and germline complex indels in key disease driver genes could be missed in NGS-based genomics studies.ResultsINDELseek is an open-source complex indel caller designed for NGS data of random fragments and PCR amplicons. The key differentiating factor of INDELseek is that each NGS read alignment was examined as a whole instead of “pileup” of each reference position across multiple alignments. In benchmarking against the reference material NA12878 genome (n = 160 derived from high-confidence variant calls), GATK, SAMtools and INDELseek showed complex indel detection sensitivities of 0%, 0% and 100%, respectively. INDELseek also detected all known germline (BRCA1 and BRCA2) and somatic (CALR and JAK2) complex indels in human clinical samples (n = 8). Further experiments validated all 10 detected KIT complex indels in a discovery cohort of clinical samples. In silico semi-simulation showed sensitivities of 93.7–96.2% based on 8671 unique complex indels in >5000 genes from dbSNP and COSMIC. We also demonstrated the importance of complex indel detection in accurately annotating BRCA1, BRCA2 and TP53 mutations with gained or rescued protein-truncating effects.ConclusionsINDELseek is an accurate and versatile tool for complex indel detection in NGS data. It complements other variant callers in NGS-based genomics studies targeting a wide spectrum of genetic variations.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-3449-9) contains supplementary material, which is available to authorized users.

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“…INDELseek was applied to a hereditary breast and/or ovarian cancer (HBOC) panel dataset of 239 probands [6]. The 4-gene panel targeted germline mutations (Illumina MiSeq).…”

Section: Resultsmentioning

confidence: 99%

“…Important mutations in key disease driver genes could be missed in NGS-based genomics studies (e.g. somatic CALR complex indels in myeloproliferative neoplasms [5] and germline BRCA1/BRCA2 complex indels in hereditary breast and/or ovarian cancer [6]).…”

Section: Introductionmentioning

confidence: 99%

INDELseek: detection of complex insertions and deletions from next-generation sequencing data

Leung

Kwong

et al. 2017

BMC Genomics

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“…On the one hand, recent manuscripts reporting the findings of clinical panel testing for genes involved in hereditary cancer risk suggests some answers (Chong et al, 2014, Dewey et al, 2014, Judkins et al, 2015, Kurian et al, 2014, Kwong et al, 2016, Laduca et al, 2014, Lincoln et al, 2015, Mannan et al, 2016, Maxwell et al, 2014, Shirts et al, 2016, Susswein et al, 2015, Tung et al, 2014, Yorczyk et al, 2014). The main conclusion of each of these manuscripts is that panel testing for multiple known cancer risk genes increases diagnostic success rate by identifying more medically actionable family-specific genetic findings than testing one or a few genes.…”

Section: Are Rare Genetic Variants Medically Important?mentioning

confidence: 99%

“…Data were collected from published manuscripts by clinical laboratories performing sequence interpretation. (Kwong et al, 2016, Laduca et al, 2014, Lincoln et al, 2015, Mannan et al, 2016, Maxwell et al, 2014, Shirts et al, 2016, Susswein et al, 2015, Tung et al, 2014)…”

Section: Figurementioning

confidence: 99%

Family-Specific Variants and the Limits of Human Genetics

Shirts

Pritchard

Walsh

2016

Trends in Molecular Medicine

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Every single nucleotide change compatible with life is present in the human population today. Understanding these rare human variants defines an extraordinary challenge for genetics and medicine. The new clinical practice of sequencing many genes for hereditary cancer risk has illustrated the utility of clinical next-generation sequencing in adults, identifying more medically actionable variants than single gene testing. However, it has also revealed a linear relationship between length of DNA evaluated and number of rare “variants of uncertain significance” reported. We propose that careful approaches to phenotype-genotype inference, distinguishing between diagnostic and screening intent, and expanded use of family-scale genetics studies as a source of information on family-specific variants will reduce variants of uncertain significance reported to patients.

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“…DNA sequencing is one of the promising approaches or building blocks in development of systems medicine. The successful development of next-generation sequencing (NGS) technology [4][5][6][7] is a step forward in search of the linkage between human disorders and genetic defects arising from DNA mutation. The availability of supercomputers in handling the big data analysis of the NGS raw data of DNA/ RNA extracted from patient biological samples is making the technique feasible as a routine molecular pathological test.…”

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confidence: 99%

Systems medicine for the delivery of better healthcare Services- International Union for Physical and Engineering Sciences (IUPESM) perspective

Cheung

2016

Health Technol.

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Medicine has ever been evolving in accordance with the clinical needs and the knowledge and philosophical attitude of the healthcare practitioners and service providers and at the same time influenced by geographical specific social, economic, political and environmental factors. The process is primarily aimed at improving human health through better access to quality medicine. One of the key indicators for quality medicine is clinical outcome, which is often determined by how early and accurate a disease is diagnosed and its staging determined and the efficacy of the clinical modalities used in treatment and post-treatment management of the patient. Biomedical engineers and medical physicists have played an important role in the development and operation of global healthcare services. One of their important contributions is in the research and development of better and more effective medical technologies in meeting clinical needs. They have close collaboration with healthcare professionals and medical scientists in development of the better tools and equipment to solve clinical challenges.A major limitation in today's medicine is that the uniqueness of the biological properties and conditions of the individual patients are not properly accounted for when making disease diagnosis or medical intervention. The large variation in patient response to treatments observed in the clinics, particularly in cancer patients, indicates that current medical technologies and the associated physical and chemical interventional procedures alone cannot resolve all the clinical problems satisfactorily. A better understanding of the biology of the diseases at the genetic and DNA level is essentially required in order to be able to develop the optimal preventive and therapeutic modalities.Current biological models are considered inadequate in fully explaining the multi-factorial nature and complex behavior of many human disorders and in predicting their response to the various forms of medical intervention. There is a need to develop a more systematic biological approach to address clinical problems. Systems medicine [1-3] is one of the approaches or concepts based on knowledge of systems biology being developed to guide treatment and prevention of diseases. Systems biology involves the analysis and understanding of the cellular and pathogenetic mechanisms and pattern of disease progression and remission, treatment responses and adverse effects at the individual patient level. The approach is aimed at providing the biological foundation or model needed by medical professionals for interpretation of biological and physical data collected from clinical investigations of the individual patients for making early disease diagnosis well before appearance of any symptoms or physical abnormalities. The biological information can also be used to guide any needed medical intervention and to predict and optimize treatment outcome on a personalized basis. Systems medicine, when realized will likely make a paradigm shift in medical practice and...

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Detection of Germline Mutation in Hereditary Breast and/or Ovarian Cancers by Next-Generation Sequencing on a Four-Gene Panel

Cited by 39 publications

References 29 publications

INDELseek: detection of complex insertions and deletions from next-generation sequencing data

INDELseek: detection of complex insertions and deletions from next-generation sequencing data

Family-Specific Variants and the Limits of Human Genetics

Systems medicine for the delivery of better healthcare Services- International Union for Physical and Engineering Sciences (IUPESM) perspective

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