Genetic Testing in Hereditary Breast and Ovarian Cancer Using Massive Parallel Sequencing

Ruiz, Anna; Llort, Gemma; Yagüe, Carmen; Baena, Neus; Viñas, Marina; Torra, Montse; Brunet, Anna; Seguí, M. Á.; Saigí, Eugeni; Guitart, Míriam

doi:10.1155/2014/542541

Cited by 16 publications

(13 citation statements)

References 24 publications

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“…However, because of the limitation of bioinformatic personnel in most clinical laboratories, most of the analysis relies on packaged software. 28 In this study, we have demonstrated that pyrosequencing output data could be amenable to systematic quantitative analysis and pinpointed the drawback of data analysis with only one algorithm. NGS data usually contain a lot of nonspecific signals/errors; therefore, it is important to distinguish systematic error from real variations.…”

Section: Discussionmentioning

confidence: 87%

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

Kwong

Shin

et al. 2016

The Journal of Molecular Diagnostics

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Mutation in BRCA1/BRCA2 genes accounts for 20% of familial breast cancers, 5% to 10% of which may be due to other less penetrant genes which are still incompletely studied. Herein, a four-gene panel was used to examine the prevalence of BRCA1, BRCA2, TP53, and PTEN in hereditary breast and ovarian cancers in Southern Chinese population. In this cohort, 948 high-risk breast and/or ovarian patients were recruited for genetic screening by next-generation sequencing (NGS). The performance of our NGS pipeline was evaluated with 80 Sanger-validated known mutations and eight negative cases. With appropriate bioinformatics analysis pipeline, the detection sensitivity of NGS is comparable with Sanger sequencing. The prevalence of BRCA1/BRCA2 germline mutations was 9.4% in our Chinese cohort, of which 48.8% of the mutations arose from hotspot mutations. With the use of a tailor-made algorithm, HomopolymerQZ, more mutations were detected compared with single mutation detection algorithm. The frequencies of PTEN and TP53 were 0.21% and 0.53%, respectively, in the Southern Chinese patients with breast and/or ovarian cancers. High-throughput NGS approach allows the incorporation of control cohort that provides an ethnicity-specific data for polymorphic variants. Our data suggest that hotspot mutations screening such as SNaPshot could be an effective preliminary screening alternative adopted in a standard clinical laboratory without NGS setup.

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Section: Discussionmentioning

confidence: 87%

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

Kwong

Shin

et al. 2016

The Journal of Molecular Diagnostics

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“…Patients and families with mutations should be informed of the limitations of these approaches and then should be followed up and managed by a multidisciplinary team over an extended time period [ 94 ]. The centralization of genetic testing enables the improvement of access and quality of testing and allows for the creation of a more comprehensive database for research, guiding evidence-based management recommendations [ 89 – 91 ].…”

Section: Discussionmentioning

confidence: 99%

“…Today, several multigene panels that include known ovarian cancer-associated loci have been introduced for the screening of germline mutations [ 89 – 91 ]. Nevertheless, there are significant challenges in interpreting and managing panel results.…”

Section: Next-generation Sequencing With Multigene Panelsmentioning

confidence: 99%

Hereditary Ovarian Cancer: Not OnlyBRCA1 and 2 Genes

Toss

Tomasello

Razzaboni

et al. 2015

BioMed Research International

188

118

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More than one-fifth of ovarian tumors have hereditary susceptibility and, in about 65–85% of these cases, the genetic abnormality is a germline mutation in BRCA genes. Nevertheless, several other suppressor genes and oncogenes have been associated with hereditary ovarian cancers, including the mismatch repair (MMR) genes in Lynch syndrome, the tumor suppressor gene, TP53, in the Li-Fraumeni syndrome, and several other genes involved in the double-strand breaks repair system, such as CHEK2, RAD51, BRIP1, and PALB2. The study of genetic discriminators and deregulated pathways involved in hereditary ovarian syndromes is relevant for the future development of molecular diagnostic strategies and targeted therapeutic approaches. The recent development and implementation of next-generation sequencing technologies have provided the opportunity to simultaneously analyze multiple cancer susceptibility genes, reduce the delay and costs, and optimize the molecular diagnosis of hereditary tumors. Particularly, the identification of mutations in ovarian cancer susceptibility genes in healthy women may result in a more personalized cancer risk management with tailored clinical and radiological surveillance, chemopreventive approaches, and/or prophylactic surgeries. On the other hand, for ovarian cancer patients, the identification of mutations may provide potential targets for biologic agents and guide treatment decision-making.

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“…Sanger sequencing is able to detect small variants such as the deletion or insertion of single bases, whereas MLPA identifies large gene rearrangements, such as the deletion or duplication of one or more exons. However, these methods are time consuming and costly (Ruiz et al 2014) and they generally require a significant input of goodquality DNA. The adoption of next-generation sequencing (NGS) has allowed for massive parallel sequencing of multiple genes, ranging from multi-gene panels to whole exomes and genomes (Feliubadalo et al 2013, Hernan et al 2012.…”

Section: Germ Line Brca Mutationsmentioning

confidence: 99%

Evaluation of the methods to identify patients who may benefit from PARP inhibitor use

Lim

Ngeow

2016

Endocrine-Related Cancer

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The effectiveness of poly (ADP-ribose) polymerase inhibitors (PARPi) in treating cancers associated with BRCA1/2 mutations hinges upon the concept of synthetic lethality and exemplifies the principles of precision medicine. Currently, most clinical trials are recruiting patients based on pathological subtypes or have included BRCA mutation analysis (germ line and/or somatic) as part of the selection criteria. Mounting evidence, however, suggests that these drugs may also be efficacious in tumors with defects in other genes involved in the homologous recombination repair pathway. Advances in molecular profiling techniques together with increased research efforts have led to a better understanding of the molecular aberrations underlying this BRCA-like phenotype and helped broaden the concept of BRCAness. Hence, it is likely that the list of predictive biomarkers for PARPi therapy will increase in future. There is currently no gold standard method of testing for PARPi response and no universal guidelines are in place on how to incorporate biomarker testing into routine clinical diagnostics. In this review, we explore the concept of BRCAness and highlight the different methods that have been used to identify patients who may benefit from the use of these anticancer agents. The identification of predictive biomarkers is crucial in improving patient selection and expanding the clinical applications of PARPi therapy. 23:6 Review D Lim and J NgeowEvaluating BRCAness for PARP inhibitor use

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Genetic Testing in Hereditary Breast and Ovarian Cancer Using Massive Parallel Sequencing

Cited by 16 publications

References 24 publications

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

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

Hereditary Ovarian Cancer: Not OnlyBRCA1 and 2 Genes

Evaluation of the methods to identify patients who may benefit from PARP inhibitor use

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