Ellison, G., Ahdesmaki, M., Luke, S., Waring, P. M., Wallace, A., Wright, R., Rothlisberger, B., Ludin, K., Merkelbach-Bruse, S., Heydt, C., Ligtenberg, M. J. L., Mensenkamp, A. R., de Castro, D. G., Jones, T., Vivancos, A., Kondrashova, O., Pauwels, P., Weyn, C., Hahnen, E., Hauke, J., Soong, R., Lai, Z. W., Dougherty, B., Carr, T. H., Johnson, J., Mills, J., Barrett, J. C. (2018) An evaluation of the challenges to developing tumor BRCA1 and BRCA2 testing methodologies for clinical practice. HUMAN MUTATION, 39 (3). pp. 394-405. ISSN 1059-7794

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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:	Article
All Authors:	Ellison, G., Ahdesmaki, M., Luke, S., Waring, P. M., Wallace, A., Wright, R., Rothlisberger, B., Ludin, K., Merkelbach-Bruse, S., Heydt, C., Ligtenberg, M. J. L., Mensenkamp, A. R., de Castro, D. G., Jones, T., Vivancos, A., Kondrashova, O., Pauwels, P., Weyn, C., Hahnen, E., Hauke, J., Soong, R., Lai, Z. W., Dougherty, B., Carr, T. H., Johnson, J., Mills, J., Barrett, J. C.
Additional Information:	ISI Document Delivery No.: FV8AQ Times Cited: 0 Cited Reference Count: 27 Ellison, Gillian Ahdesmaki, Miika 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 Kondrashova, Olga Pauwels, Patrick Weyn, Christine Hahnen, Eric Hauke, Jan Soong, Richie Lai, Zhongwu Dougherty, Brian Carr, T. Hedley Johnson, Justin Mills, John Barrett, J. Carl Mensenkamp, Arjen/L-4520-2015 Mensenkamp, Arjen/0000-0003-3805-877X AstraZeneca plc. Contract grant sponsor: AstraZeneca plc. 0 Wiley Hoboken 1098-1004
Uncontrolled Keywords:	diagnostic FFPE NGS PARP tBRCA serous ovarian-cancer somatic mutations copy number chemotherapy carcinomas survival genome trial gene Genetics & Heredity
Research teams:	ICR divisions > Clinical Studies > Molecular Haematology (including Cytogenetics Group and Cell Markers) ICR divisions > Molecular Pathology > Molecular Haematology (including Cytogenetics Group and Cell Markers) Clinical Units > Haemato-Oncology Unit
Depositing User:	Barry Jenkins
Date Deposited:	26 Feb 2018 15:23
Last Modified:	26 Feb 2018 15:23
URI:	http://publications.icr.ac.uk/id/eprint/16635

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