Development and analytical validation of a 25-gene next generation sequencing panel that includes the BRCA1 and BRCA2 genes to assess hereditary cancer risk

Judkins, Thaddeus; Leclair, Benoît; Bowles, Karla R.; Gutin, Natalia; Trost, Jeff; McCulloch, James; Bhatnagar, S. K.; Murray, Adam; Craft, Jonathan; Wardell, Bryan; Bastian, Mark; Mitchell, Jeffrey T.; Chen, Jian; Tran, Thanh V.; Williams, D. R.; Potter, Jennifer; Jammulapati, Srikanth; Perry, M. D.; Morris, Brian J.; Roa, Benjamin B.; Timms, Kirsten M.

doi:10.1186/s12885-015-1224-y

Cited by 103 publications

(98 citation statements)

References 16 publications

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“…This corresponds with the Royal Marsden empirical data and published literature [42], [43].Relatives with a BRCA mutation had the same BRCA mutation as the index case.Relatives considered in the model had no previous ovarian or breast cancer and had not undergone RRS.The 5- and 10-year risks for breast cancer and ovarian cancer, respectively, were constant over the 5 or 10 years. This is a simplifying assumption arising from the 5- and 10-year risk data used in the model for breast cancer and ovarian cancer.…”

Section: Methodssupporting

confidence: 69%

A Cost-Effectiveness Evaluation of Germline BRCA1 and BRCA2 Testing in UK Women with Ovarian Cancer

Eccleston¹,

Bentley²,

Dyer

et al. 2017

Value in Health

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ObjectivesTo evaluate the long-term cost-effectiveness of germline BRCA1 and BRCA2 (collectively termed “BRCA”) testing in women with epithelial ovarian cancer, and testing for the relevant mutation in first- and second-degree relatives of BRCA mutation–positive individuals, compared with no testing. Female BRCA mutation–positive relatives of patients with ovarian cancer could undergo risk-reducing mastectomy and/or bilateral salpingo-oophorectomy.MethodsA cost-effectiveness model was developed that included the risks of breast and ovarian cancer; the costs, utilities, and effects of risk-reducing surgery on cancer rates; and the costs, utilities, and mortality rates associated with cancer.ResultsBRCA testing of all women with epithelial ovarian cancer each year is cost-effective at a UK willingness-to-pay threshold of £20,000/quality-adjusted life-year (QALY) compared with no testing, with an incremental cost-effectiveness ratio of £4,339/QALY. The result was primarily driven by fewer cases of breast cancer (142) and ovarian cancer (141) and associated reductions in mortality (77 fewer deaths) in relatives over the subsequent 50 years. Sensitivity analyses showed that the results were robust to variations in the input parameters. Probabilistic sensitivity analysis showed that the probability of germline BRCA mutation testing being cost-effective at a threshold of £20,000/QALY was 99.9%.ConclusionsImplementing germline BRCA testing in all patients with ovarian cancer would be cost-effective in the United Kingdom. The consequent reduction in future cases of breast and ovarian cancer in relatives of mutation–positive individuals would ease the burden of cancer treatments in subsequent years and result in significantly better outcomes and reduced mortality rates for these individuals.

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Section: Methodssupporting

confidence: 69%

A Cost-Effectiveness Evaluation of Germline BRCA1 and BRCA2 Testing in UK Women with Ovarian Cancer

Eccleston¹,

Bentley²,

Dyer

et al. 2017

Value in Health

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“…In addition, deletions and duplications were identified using a custom microarray comparative genomic hybridization (CGH) chip (Agilent Technologies, Santa Clara, California). Multiplex ligation-dependent probe amplification analysis for large rearrangements in PMS2 and CHEK2 was performed to distinguish homologous pseudo genes and actual gene regions (30). Variants were classified using American College of Medical Genetics and Genomics recommendations and Myriad Genetics, Inc. data (31, 32).…”

Section: Methodsmentioning

confidence: 99%

Germline multi-gene hereditary cancer panel testing in an unselected endometrial cancer cohort

et al. 2016

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Hereditary endometrial carcinoma is associated with germline mutations in Lynch syndrome genes. The role of other cancer predisposition genes is unclear. We aimed to determine the prevalence of cancer predisposition gene mutations in an unselected endometrial carcinoma patient cohort. Mutations in 25 genes were identified using a next generation sequencing based panel applied in 381 endometrial carcinoma patients who had undergone tumor testing to screen for Lynch syndrome. Thirty five patients (9.2%) had a deleterious mutation: 22 (5.8%) in Lynch syndrome genes (3 MLH1, 5 MSH2, 2 EPCAM-MSH2, 6 MSH6, 6 PMS2) and 13 (3.4%) in 10 non-Lynch syndrome genes (4 CHEK2, 1 each in APC, ATM, BARD1, BRCA1, BRCA2, BRIP1, NBN, PTEN, RAD51C). Of 21 patients with deleterious mutations in Lynch syndrome genes with tumor testing, 2 (9.5%) had tumor testing results suggestive of sporadic cancer. Of 12 patients with deleterious mutations in MSH6 and PMS2, 10 were diagnosed at age >50 and 8 did not have a family history of Lynch syndrome associated cancers. Patients with deleterious mutations in non-Lynch syndrome genes were more likely to have serous tumor histology (23.1% v 6.4%, p=0.02). The 3 patients with non-Lynch syndrome deleterious mutations and serous histology had mutations in BRCA2, BRIP1, and RAD51C. Current clinical criteria fail to identify a portion of actionable mutations in Lynch syndrome and other hereditary cancer syndromes. Performance characteristics of tumor testing are sufficiently robust to implement universal tumor testing to identify patients with Lynch syndrome. Germline multi-gene panel testing is feasible and informative, leading to the identification of additional actionable mutations.

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“…More genes have gradually been included to solve problems like genetic heterogeneity or overlapping clinical manifestations among distinct cancer predisposition syndromes5678910. Today, gene panels represent a good compromise between testing just a few genes and obtaining information from the whole exome for routine hereditary cancer testing111213.…”

mentioning

confidence: 99%

A comprehensive custom panel design for routine hereditary cancer testing: preserving control, improving diagnostics and revealing a complex variation landscape

Castellanos

Gel

Rosas

et al. 2017

Sci Rep

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We wanted to implement an NGS strategy to globally analyze hereditary cancer with diagnostic quality while retaining the same degree of understanding and control we had in pre-NGS strategies. To do this, we developed the I2HCP panel, a custom bait library covering 122 hereditary cancer genes. We improved bait design, tested different NGS platforms and created a clinically driven custom data analysis pipeline. The I2HCP panel was developed using a training set of hereditary colorectal cancer, hereditary breast and ovarian cancer and neurofibromatosis patients and reached an accuracy, analytical sensitivity and specificity greater than 99%, which was maintained in a validation set. I2HCP changed our diagnostic approach, involving clinicians and a genetic diagnostics team from panel design to reporting. The new strategy improved diagnostic sensitivity, solved uncertain clinical diagnoses and identified mutations in new genes. We assessed the genetic variation in the complete set of hereditary cancer genes, revealing a complex variation landscape that coexists with the disease-causing mutation. We developed, validated and implemented a custom NGS-based strategy for hereditary cancer diagnostics that improved our previous workflows. Additionally, the existence of a rich genetic variation in hereditary cancer genes favors the use of this panel to investigate their role in cancer risk.

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Development and analytical validation of a 25-gene next generation sequencing panel that includes the BRCA1 and BRCA2 genes to assess hereditary cancer risk

Cited by 103 publications

References 16 publications

A Cost-Effectiveness Evaluation of Germline BRCA1 and BRCA2 Testing in UK Women with Ovarian Cancer

A Cost-Effectiveness Evaluation of Germline BRCA1 and BRCA2 Testing in UK Women with Ovarian Cancer

Germline multi-gene hereditary cancer panel testing in an unselected endometrial cancer cohort

A comprehensive custom panel design for routine hereditary cancer testing: preserving control, improving diagnostics and revealing a complex variation landscape

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