Inherited Cancer in the Age of Next-Generation Sequencing

Price, Kristin S.; Svenson, Ashley; King, Elisabeth; Ready, Kaylene; Lazarin, Gabriel A.

doi:10.1177/1099800417750746

Cited by 19 publications

(19 citation statements)

References 105 publications

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“…High penetrance (or high risk) genes are considered those which when mutated, confer a high Relative Risk of cancer development (greater than 4 times the risk of the general population). Moreover, they are included in guidelines for cancer predisposition testing and specific clinical management recommendations for patients carrying pathogenic variants have been formulated by large working groups [5][6][7]. Pathogenic variants in moderate penetrance (or moderate risk) genes confer a 2-4 times risk of cancer development compared to the general population.…”

Section: Gene Selectionmentioning

confidence: 99%

“…Low penetrance/risk genes are those related to less than 2 times risk of cancer or those with limited or yet insufficient data available concerning their association and magnitude of cancer risk. Although this categorization is constantly altered in reflection to the accumulated clinical information, based on the latest published data [3,[5][6][7][8][9][10], the genes analyzed are summarized in Table 1.…”

Section: Gene Selectionmentioning

confidence: 99%

“…5 Attikon University Hospital, Athens, Greece. 6 Athens Medical Center, Athens, Greece. 7 Euromedica General Clinic of Thessaloniki, Thessaloniki, Greece.…”

Section: Additional Filesmentioning

confidence: 99%

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Abstract P4-03-07: Analysis of hereditary cancer syndromes by using a panel of genes: Novel and multiple pathogenic mutations

Tsoulos¹,

Tsaousis²,

Papadopoulou³

et al. 2019

Cancer Research

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Background: Hereditary cancer predisposition syndromes are responsible for approximately 5-10% of all diagnosed cancer cases. In the past, single-gene analysis of specific high risk genes was used for the determination of the genetic cause of cancer heritability in certain families. The application of Next Generation Sequencing (NGS) technology has facilitated multigene panel analysis and is widely used in clinical practice, for the identification of individuals with cancer predisposing gene variants. The purpose of this study was to investigate the extent and nature of variants in genes implicated in hereditary cancer predisposition in individuals referred for testing in our laboratory.Methods: In total, 1197 individuals from Greece, Romania and Turkey were referred to our laboratory for genetic testing in the past 4 years. The majority of referrals included individuals with personal of family history of breast and/or ovarian cancer. The analysis of genes involved in hereditary cancer predisposition was performed using a NGS approach. Genomic DNA was enriched for targeted regions of 36 genes and sequencing was carried out using the Illumina NGS technology. The presence of large genomic rearrangements (LGRs) was investigated by computational analysis and Multiplex Ligation-dependent Probe Amplification (MLPA). Results: A pathogenic variant was identified in 264 of 1197 individuals (22.1%) analyzed while a variant of uncertain significance (VUS) was identified in 34.8% of cases. Clinically significant variants were identified in 29 of the 36 genes analyzed. Concerning the mutation distribution among individuals with positive findings, 43.6% were located in the BRCA1/2 genes whereas 21.6, 19.9, and 15.0% in other high, moderate and low risk genes respectively. Notably, 25 of the 264 positive individuals (9.5%) carried clinically significant variants in two different genes and 6.1% had a LGR. Conclusions:In our cohort, analysis of all the genes in the panel allowed the identification of 4.3 and 8.1% additional pathogenic variants in other high or moderate/low risk genes, respectively, enabling personalized management decisions for these individuals and supporting the clinical significance of multigene panel analysis in hereditary cancer predisposition.

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Section: Gene Selectionmentioning

confidence: 99%

Section: Gene Selectionmentioning

confidence: 99%

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Abstract P4-03-07: Analysis of hereditary cancer syndromes by using a panel of genes: Novel and multiple pathogenic mutations

Tsoulos¹,

Tsaousis²,

Papadopoulou³

et al. 2019

Cancer Research

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“…Genetic testing such as Sanger-based sequencing is used for hereditary cancers. But this traditional approach for genetic testing of hereditary cancers is time consuming and has low throughput and high cost [58]. Although BRCA1 and BRCA2 are the most identified hereditary cancer genes, only an estimated 5%-10% of breast cancers appear in individuals with inherited mutations in these genes in families [59,60].…”

Section: Breast Cancermentioning

confidence: 99%

Strategies, Quality Control and Clinical Applications of Next Generation Sequencing

Khorshidi

Palangi

2018

Multidiscip Cancer Investig

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DNA sequencing is one of the great valuable techniques in molecular biology, which can be used to detect the sequence of nucleotides in a DNA fragment. The high-throughput sequencing known as Next Generation Sequencing (NGS) revolutionized genomic research and molecular biology; therefore, the whole human genome can be sequenced with a low cost in several days. NGS technology is similar to the traditional method, Sanger, which detects small DNA fragments by emitted signals at the time of synthesis of each fragment (from the DNA template), but the difference is that NGS can determine the massive simultaneous sequencing in a few days with high accuracy and the results are directly detected without the need for electrophoresis. In fact, NGS technology combines a variety of steps such as sample preparation, fragmentation of the sample of the studied genome, attachment of adapter to the ends of the fragments, imaging, and data analyses. In recent years, NGS technology continuously expanded the range of applications in different fields by reducing costs, increasing rates, and improving the quality of the data. The current review provided the potential applications of the NGS technology by emphasizing the diagnosis of the genetic diseases, identification of several types of cancers, prenatal screening, epigenetic modifications, personalized medicine, and identification of pathogens.

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“…Though NGS is now mature and widely used for HCS 8,9 , in its nascency NGS was particularly susceptible to false positives, generally resulting from low coverage and high rates of both random errors and systematic errors on early instruments [10][11][12][13] . For instance, NGS data alone could not resolve the genotype at a site with 4x depth and 25% allele fraction (i.e., one read with an alternate base and three reads with reference bases): either a sequencer error occurred in a patient homozygous for the reference allele, or the allele fraction was depressed in a heterozygous patient due to the discreteness of few observations.…”

Section: Introductionmentioning

confidence: 99%

Software-assisted manual review of clinical NGS data: an alternative to routine Sanger sequencing confirmation with equivalent results in >15,000 hereditary cancer screens

Muzzey¹,

Kash²,

Johnson³

et al. 2018

Preprint

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Clinical genomic tests increasingly utilize a next generation sequencing (NGS) platform due in part to the high fidelity of variant calls, yet rare errors are still possible. In hereditary cancer screening, failure to correct such errors could have serious consequences for patients, who may follow an unwarranted screening or surgical-management path. It has been suggested that routine orthogonal confirmation via Sanger sequencing is required to verify NGS results, especially low-confidence positives with depressed allele fraction (<30% of alternate allele). We evaluated whether an alternative method of confirmation-software-assisted manual call review-performed comparably to Sanger confirmation in >15,000 samples. Licensed reviewers manually inspected both raw and processed data at the batch-, sample-, and variant-level, including raw NGS read pileups. Of ambiguous variant calls with <30% allele fraction (1,707 total calls at 38 unique sites), manual call review classified >99% (1,701) as true positives (enriched for long insertions or deletions ("indels") and homopolymers) or true negatives (often conspicuous NGS artifacts), with the remaining <1% (6) being mosaic. Critically, results from software-assisted manual review and retrospective Sanger sequencing were concordant for samples selected from all ambiguous sites. We conclude that the confirmation required for high confidence in NGS-based germline testing can manifest in different ways: a trained NGS expert operating platform-tailored review software achieves quality comparable to routine Sanger confirmation.

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Inherited Cancer in the Age of Next-Generation Sequencing

Cited by 19 publications

References 105 publications

Abstract P4-03-07: Analysis of hereditary cancer syndromes by using a panel of genes: Novel and multiple pathogenic mutations

Abstract P4-03-07: Analysis of hereditary cancer syndromes by using a panel of genes: Novel and multiple pathogenic mutations

Strategies, Quality Control and Clinical Applications of Next Generation Sequencing

Software-assisted manual review of clinical NGS data: an alternative to routine Sanger sequencing confirmation with equivalent results in >15,000 hereditary cancer screens

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