An evaluation of the challenges to developing tumor BRCA1 and BRCA2 testing methodologies for clinical practice
AuthorEllison, G; Ahdesmaki, M; Luke, S; Waring, PM; Wallace, A; Wright, R; Rothlisberger, B; Ludin, K; Merkelbach-Bruse, S; Heydt, C; ...
Source TitleHuman Mutation
Medical Biology (W.E.H.I.)
Document TypeJournal Article
CitationsEllison, 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. ,... 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. https://doi.org/10.1002/humu.23375.
Access StatusOpen Access
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.
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