BRCA1 and BRCA2 genetic testing—pitfalls and recommendations for managing variants of uncertain clinical significance

Eccles, Diana; Mitchell, Gillian; Monteiro, Alvaro N.A.; Schmutzler, Rita K.; Couch, Fergus J.; Spurdle, Amanda B.; Gómez-García, Encarna B.

doi:10.1093/annonc/mdv278

Cited by 172 publications

(140 citation statements)

References 39 publications

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“…Variants of unknown importance occur in BRCA1 and BRCA2, as well as other high risk genes implicated in ovarian cancer, but the effects of these variants on ovarian tumorigenesis are currently unknown (75). Variants of unknown importance represent dilemmas for women who are diagnosed with them, as these variants carry an unknown cancer risk, meaning patients and their family members cannot be accurately counseled about risk reduction and preventative surgeries.…”

Section: [H2]screeningmentioning

confidence: 99%

Ovarian cancer

Matulonis

Sood

Fallowfield

et al. 2016

Nat Rev Dis Primers

890

787

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Ovarian cancer is not a single disease and can be subdivided into at least five different 2 histological subtypes that have different identifiable risk factors, cells of origin, molecular compositions, clinical features and treatments. Ovarian cancer is a global problem, is typically diagnosed at late stage, and has no effective screening strategy. Standard treatments for newly diagnosed cancer consist of cytoreductive surgery and platinum-based chemotherapy. In recurrent cancer, chemotherapy, anti-angiogenic agents, and poly (ADP ribose) polymerase (PARP) inhibitors are used and immunological therapies are currently being tested. High-grade serous carcinoma (HGSC) is the most commonly diagnosed form of ovarian cancer and is typically very responsive to platinum-based chemotherapy at diagnosis. However, in addition to the other histologies, HGSCs frequently relapse and become increasingly resistant to chemotherapy.Consequently, understanding the mechanisms underlying platinum resistance and finding ways to overcome them are active areas of study in ovarian cancer. Significant progress has been made in identifying genes associated with high risk of ovarian cancer (such as BRCA1 and BRCA2) as well as a precursor lesion of HGSC called a serous tubal intraepithelial carcinoma, which hold promise for identifying individuals at high risk of developing the disease and for developing prevention strategies. Competing interestsU.A.M. has served as a consultant for AstraZeneca, ImmunoGen, Pfizer, Genentech, and Merck.

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Section: [H2]screeningmentioning

confidence: 99%

Ovarian cancer

Matulonis

Sood

Fallowfield

et al. 2016

Nat Rev Dis Primers

890

787

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“…Any such lists of disease-related genes and mutations therein are, however, also a moving target. While for some mutations a clear clinical significance has been established, the level of evidence is not always so clear [119,120]. Furthermore, the identity of genes within such negative gene list is impacted by the respective scientific state-of-the-art at the time.…”

Section: An Informed Consent?mentioning

confidence: 99%

Findings made in gene panel to whole genome sequencing: data, knowledge, ethics – and consequences?

Winkler

Wiemann

2016

Expert Review of Molecular Diagnostics

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“…As well as the above-mentioned genetic alterations, large rearrangements should be identified by MLPA (Multiplex Ligation Probe Assay) or massive sequencing techniques (NGS, Next-Generation Sequencing), because the Sanger method cannot detect large rearrangements [43]. Given the crucial nature of the result, it is important for BRCA mutation tests to be done in accredited laboratories, with internal and external qualitycontrol systems [44].…”

Section: Germline Mutations In Brca1 and Brca2mentioning

confidence: 99%

Recommendations for biomarker testing in epithelial ovarian cancer: a National Consensus Statement by the Spanish Society of Pathology and the Spanish Society of Medical Oncology

Oaknin

Guarch²,

Barretina-Ginesta

et al. 2017

Clin Transl Oncol

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Because of advances in the understanding of histological and molecular characteristics in ovarian cancer, it is now possible to recognize the existence of five subtypes, which in turn has allowed a more refined therapeutic approach and better design of clinical trials. Each of these five subtypes has specific histological features and a particular biomarker expression, as well as mutations in different genes, some of which have prognostic and predictive value. CA125 and HE4 are examples of ovarian cancer biomarkers used in the diagnosis and follow-up of these malignancies. Currently, somatic or germinal mutations on BRCA1 and BRCA2 genes are the most important biomarkers in epithelial ovarian cancer having prognostic and predictive value. This article will review the histological and molecular characteristics of the five subtypes of ovarian cancer, describing the most important biomarkers and mutations that can guide in diagnosis, screening and tailored treatment strategy.

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BRCA1 and BRCA2 genetic testing—pitfalls and recommendations for managing variants of uncertain clinical significance

Cited by 172 publications

References 39 publications

Ovarian cancer

Ovarian cancer

Findings made in gene panel to whole genome sequencing: data, knowledge, ethics – and consequences?

Recommendations for biomarker testing in epithelial ovarian cancer: a National Consensus Statement by the Spanish Society of Pathology and the Spanish Society of Medical Oncology

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