Ellison, Gillian, Ahdesmaki, Miika ORCID: 0000-0002-9091-7773, Luke, Sally, Waring, Paul M., Wallace, Andrew, Wright, Ronnie, Rothlisberger, Benno, Ludin, Katja, Merkelbach-Bruse, Sabine, Heydt, Carina, Ligtenberg, Marjolijn J. L., Mensenkamp, Arjen R., de Castro, David Gonzalez, Jones, Thomas, Vivancos, Ana ORCID: 0000-0003-2888-6512, Kondrashova, Olga ORCID: 0000-0003-0022-5149, Pauwels, Patrick, Weyn, Christine, Hahnen, Eric, Hauke, Jan, Soong, Richie, Lai, Zhongwu, Dougherty, Brian, Carr, T. Hedley, Johnson, Justin, Mills, John and Barrett, J. Carl (2018). An evaluation of the challenges to developing tumor BRCA1 and BRCA2 testing methodologies for clinical practice. Hum. Mutat., 39 (3). S. 394 - 406. HOBOKEN: WILEY. ISSN 1098-1004

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Abstract

Ovarian cancer patients with germline or somatic pathogenic variants benefit from treatment with poly ADP ribose polymerase (PARP) inhibitors. Tumor BRCA1/2 testing is more challenging than germline testing as the majority of samples are formalin-fixed paraffin embedded (FFPE), the tumor genome is complex, and the allelic fraction of somatic variants can be low. We collaborated with 10 laboratories testing BRCA1/2 in tumors to compare different approaches to identify clinically important variants within FFPE tumor DNA samples. This was not a proficiency study but an inter-laboratory comparison to identify common issues. Each laboratory received the same tumor DNA samples ranging in genotype, quantity, quality, and variant allele frequency (VAF). Each laboratory performed their preferred next-generation sequencing method to report on the variants. No false positive results were reported in this small study and the majority of methods detected the low VAF variants. A number of variants were not detected due to the bioinformatics analysis, variant classification, or insufficient DNA. The use of hybridization capture or short amplicon methods are recommended based on a bioinformatic assessment of the data. The study highlights the importance of establishing standards and standardization for tBRCA testing particularly when the test results dictate clinical decisions regarding life extending therapies.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Ellison, GillianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ahdesmaki, MiikaUNSPECIFIEDorcid.org/0000-0002-9091-7773UNSPECIFIED
Luke, SallyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Waring, Paul M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wallace, AndrewUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wright, RonnieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rothlisberger, BennoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ludin, KatjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Merkelbach-Bruse, SabineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heydt, CarinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ligtenberg, Marjolijn J. L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mensenkamp, Arjen R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Castro, David GonzalezUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jones, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vivancos, AnaUNSPECIFIEDorcid.org/0000-0003-2888-6512UNSPECIFIED
Kondrashova, OlgaUNSPECIFIEDorcid.org/0000-0003-0022-5149UNSPECIFIED
Pauwels, PatrickUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weyn, ChristineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hahnen, EricUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hauke, JanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Soong, RichieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lai, ZhongwuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dougherty, BrianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Carr, T. HedleyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Johnson, JustinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mills, JohnUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Barrett, J. CarlUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-193413
DOI: 10.1002/humu.23375
Journal or Publication Title: Hum. Mutat.
Volume: 39
Number: 3
Page Range: S. 394 - 406
Date: 2018
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 1098-1004
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
SEROUS OVARIAN-CANCER; SOMATIC MUTATIONS; COPY NUMBER; CHEMOTHERAPY; CARCINOMAS; SURVIVAL; GENOME; TRIAL; GENEMultiple languages
Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/19341

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