An evaluation of the challenges to developing tumour BRCA1 and BRCA2 testing methodologies for clinical practice

Abstract

Ovarian cancer patients with germline or somatic pathogenic variants benefit from treatment with PARP inhibitors. Tumour BRCA1/2 testing is more challenging than germline testing as the majority of samples are formalin fixed paraffin embedded (FFPE), the tumour genome is complex and the allelic fraction of somatic variants can be low.

We collaborated with 10 laboratories testing BRCA1/2 in tumours to compare different approaches to identify clinically important variants within FFPE tumour DNA samples. This was not a proficiency study but an inter-laboratory comparison to identify common issues. Each laboratory received the same tumour DNA samples ranging in genotype, quantity, quality and variant allele frequency (VAF). Each lab 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 hybridisation capture or short amplicon methods are recommended based on a bioinformatic assessment of the data.

The study highlights the importance of establishing standards and standardisation for tBRCA testing particularly when the test results dictate clinical decisions regarding life extending therapies.

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