Gene-Panel Sequencing and the Prediction of Breast-Cancer Risk

Easton, Douglas F.; Pharoah, Paul D.P.; Antoniou, Antonis C.; Tischkowitz, Marc; Tavtigian, Sean V.; Nathanson, Katherine L.; Devilee, Peter; Meindl, Alfons; Couch, Fergus J.; Southey, Melissa C.; Goldgar, David E.; Evans, D. Gareth; Chenevix-Trench, Georgia; Rahman, Nazneen; Robson, Mark E.; Domchek, Susan M.; Foulkes, William D.

doi:10.1056/nejmsr1501341

Cited by 781 publications

(818 citation statements)

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“…The ATM variant p.Val2424Gly has been shown to confer high risk of breast cancer and segregate with breast cancer in families. 17 Interestingly, the proband identified with the variant in the present report also had a granulosa cell tumour of the ovary. Granulosa cell tumours unlike other germ cell tumours have been associated with BRCA1/2 variants.…”

Section: Discussionmentioning

confidence: 48%

“…As such granulosa cell tumours should not be overlooked like other germ cell tumours and mucinous tumours in assessing high-risk breast/ ovarian families. 9 Although the CHEK2 variant identified in a male breast cancer family is likely to have contributed to the risk, it is highly unlikely that it accounts for the full pattern in the family as a similar variant 1100delC only confers around a 30% lifetime risk 17 and we do not propose offering this as a presymptomatic test in this family.…”

Section: Discussionmentioning

confidence: 90%

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Sensitivity of BRCA1/2 testing in high-risk breast/ovarian/male breast cancer families: little contribution of comprehensive RNA/NGS panel testing

Byers

Wallis²,

Veen

et al. 2016

Eur J Hum Genet

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The sensitivity of testing BRCA1 and BRCA2 remains unresolved as the frequency of deep intronic splicing variants has not been defined in high-risk familial breast/ovarian cancer families. This variant category is reported at significant frequency in other tumour predisposition genes, including NF1 and MSH2. We carried out comprehensive whole gene RNA analysis on 45 high-risk breast/ovary and male breast cancer families with no identified pathogenic variant on exonic sequencing and copy number analysis of BRCA1/2. In addition, we undertook variant screening of a 10-gene high/moderate risk breast/ovarian cancer panel by nextgeneration sequencing. DNA testing identified the causative variant in 50/56 (89%) breast/ovarian/male breast cancer families with Manchester scores of ≥ 50 with two variants being confirmed to affect splicing on RNA analysis. RNA sequencing of BRCA1/BRCA2 on 45 individuals from high-risk families identified no deep intronic variants and did not suggest loss of RNA expression as a cause of lost sensitivity. Panel testing in 42 samples identified a known RAD51D variant, a high-risk ATM variant in another breast ovary family and a truncating CHEK2 mutation. Current exonic sequencing and copy number analysis variant detection methods of BRCA1/2 have high sensitivity in high-risk breast/ovarian cancer families. Sequence analysis of RNA does not identify any variants undetected by current analysis of BRCA1/2. However, RNA analysis clarified the pathogenicity of variants of unknown significance detected by current methods. The low diagnostic uplift achieved through sequence analysis of the other known breast/ovarian cancer susceptibility genes indicates that further high-risk genes remain to be identified. INTRODUCTIONFunctional variants in BRCA1 and BRCA2 account for 2-3% of all cases of breast cancer and 10-15% of epithelial ovarian cancer. 1,2 While the relationship between the two genes and cancer predisposition has been known for over 20 years and variant screening is offered routinely by a number of diagnostic laboratories worldwide, the sensitivity of variant detection is unresolved. This is mainly due to the heterogeneity of breast cancer with BRCA1/2 contributing only about 15-20% of the hereditary component. 3 Loss of function variants in two genes, RAD51C 4 and RAD51D, 5 confer a high risk of ovarian cancer; however, their contribution to breast cancer risk is less clear. 5,6 Until the discovery of functional variants in these two genes, it was assumed that the majority, if not all, of the inherited link between breast and ovarian cancer was due to variants in BRCA1 or BRCA2. 7 Ninety-five percent of families with the Breast Cancer Linkage Consortium (BCLC) criteria of at least four individuals with breast/ ovarian cancer, with the breast cancers diagnosed o60 years of age and at least one case of ovarian cancer in the family, were predicted to have a variant in either BRCA1 or BRCA2. This increased to 100% for families with two or more women with ovarian cancer. Similarly, 95% of male b...

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Section: Discussionmentioning

confidence: 48%

Section: Discussionmentioning

confidence: 90%

Sensitivity of BRCA1/2 testing in high-risk breast/ovarian/male breast cancer families: little contribution of comprehensive RNA/NGS panel testing

Byers

Wallis²,

Veen

et al. 2016

Eur J Hum Genet

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“…The process of informed consent for genetic testing for inherited cancer susceptibility is well described 3,11,16,28 . In order for an individual to give fully informed consent for genetic testing, the following educational elements must be provided: (1) information on the specific gene(s) or gene mutations(s) being tested including a description of associated cancers and other potential health risks; (2) inheritance patterns associated with genes being tested.…”

Section: Genetic Testing For Cancer Susceptibilitymentioning

confidence: 99%

Genetic evaluation and testing for hereditary forms of cancer in the era of next-generation sequencing

Stanislaw¹,

Xue²,

Wilcox³

2016

Cancer Biology &Amp; Medicine

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The introduction of next-generation sequencing (NGS) technology in testing for hereditary cancer susceptibility allows testing of multiple cancer susceptibility genes simultaneously. While there are many potential benefits to utilizing this technology in the hereditary cancer clinic, including efficiency of time and cost, there are also important limitations that must be considered. The best panel for the given clinical situation should be selected to minimize the number of variants of unknown significance. The inclusion in panels of low penetrance or newly identified genes without specific actionability can be problematic for interpretation. Genetic counselors are an essential part of the hereditary cancer risk assessment team, helping the medical team select the most appropriate test and interpret the often complex results. Genetic counselors obtain an extended family history, counsel patients on the available tests and the potential implications of results for themselves and their family members (pre-test counseling), explain to patients the implications of the test results (post-test counseling), and assist in testing family members at risk.

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“…A publication in the New England Journal of Medicine in 2015, authored by experts from the United States, United Kingdom, the Netherlands, Germany, Australia, and Canada, thoughtfully reviewed the issues that must be addressed when considering multigene panels. 45 Additionally, ASCO released a policy statement on genetic and genomic testing for cancer susceptibility to reflect the impact of advances in this field. 5 …”

Section: Single/limited Gene Versus Multigene Panel Testingmentioning

confidence: 99%

How Far Do We Go With Genetic Evaluation? Gene, Panel, and Tumor Testing

Lynce

Isaacs

2016

American Society of Clinical Oncology Educational Book

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OVERVIEW The traditional model by which an individual was identified as harboring a hereditary susceptibility to cancer was to test for a mutation in a single gene or a finite number of genes associated with a particular syndrome (e.g., BRCA1 and BRCA2 for hereditary breast and ovarian cancer or mismatch repair genes for Lynch syndrome). The decision regarding which gene or genes to test for was based on a review of the patient’s personal medical history and their family history. With advances in next-generation DNA sequencing technology, offering simultaneous testing for multiple genes associated with a hereditary susceptibility to cancer is now possible. These panels typically include high-penetrance genes, but they also often include moderate- and low-penetrance genes. A number of the genes included in these panels have not been fully characterized either in terms of their cancer risks or their management options. Another way some patients are unexpectedly identified as carrying a germline mutation in a cancer susceptibility gene is at the time they undergo molecular profiling of their tumor, which typically has been carried out to guide treatment choices for their cancer. This article first focuses on the issues that need to be considered when deciding between recommending more targeted testing of a single or a small number of genes associated with a particular syndrome (single/limited gene testing) versus performing a multigene panel. This article also reviews the issues regarding germline risk that occur within the setting of ordering molecular profiling of tumors.

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Gene-Panel Sequencing and the Prediction of Breast-Cancer Risk

Cited by 781 publications

References 72 publications

Sensitivity of BRCA1/2 testing in high-risk breast/ovarian/male breast cancer families: little contribution of comprehensive RNA/NGS panel testing

Sensitivity of BRCA1/2 testing in high-risk breast/ovarian/male breast cancer families: little contribution of comprehensive RNA/NGS panel testing

Genetic evaluation and testing for hereditary forms of cancer in the era of next-generation sequencing

How Far Do We Go With Genetic Evaluation? Gene, Panel, and Tumor Testing

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