Penetrance and outcomes at 1-year following return of actionable variants identified by genome sequencing

BackgroundIn precision medicine, somatic and germline DNA sequencing are essential to make genome-guided treatment decisions in patients with cancer. However, it can also uncover unsolicited findings (UFs) in germline DNA that could have a substantial impact on the lives of patients and their relatives. It is therefore critical to understand the preferences of patients with cancer concerning UFs derived from whole-exome (WES) or whole-genome sequencing (WGS).MethodsIn a quantitative multicentre study, adult patients with cancer (any stage and origin of disease) were surveyed through a digital questionnaire based on previous semi-structured interviews. Background knowledge was provided by showing two videos, introducing basic concepts of genetics and general information about different categories of UFs (actionable, non-actionable, reproductive significance, unknown significance).ResultsIn total 1072 patients were included of whom 701 participants completed the whole questionnaire. Overall, 686 (85.1%) participants wanted to be informed about UFs in general. After introduction of four UFs categories, 113 participants (14.8%) changed their answer: 718 (94.2%) participants opted for actionable variants, 537 (72.4%) for non-actionable variants, 635 (87.0%) participants for UFs of reproductive significance and 521 (71.8%) for UFs of unknown significance. Men were more interested in receiving certain UFs than women: non-actionable: OR 3.32; 95% CI 2.05 to 5.37, reproductive significance: OR 1.97; 95% CI 1.05 to 3.67 and unknown significance: OR 2.00; 95% CI 1.25 to 3.21. In total, 244 (33%) participants conceded family members to have access to their UFs while still alive. 603 (82%) participants agreed to information being shared with relatives, after they would pass away.ConclusionOur study showed that the vast majority of patients with cancer desires to receive all UFs of genome testing, although a substantial minority does not wish to receive non-actionable findings. Incorporation of categories in informed consent procedures supports patients in making informed decisions on UFs.

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From Days to Hours: Reporting Clinically Actionable Variants from Whole Genome Sequencing

PLoS ONE ◽

10.1371/journal.pone.0086803 ◽

2014 ◽

Vol 9 (2) ◽

pp. e86803 ◽

Cited By ~ 3

Author(s):

Sumit Middha ◽

Saurabh Baheti ◽

Steven N. Hart ◽

Jean-Pierre A. Kocher

Keyword(s):

Whole Genome Sequencing ◽

Genome Sequencing ◽

Whole Genome ◽

Actionable Variants

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Use of an integrated pan-cancer oncology enrichment NGS assay to measure tumour mutational burden and detect clinically actionable variants

10.1101/2020.02.01.20019992 ◽

2020 ◽

Author(s):

Valerie Pestinger ◽

Matthew Smith ◽

Toju Sillo ◽

John M Findlay ◽

Jean-Francois Laes ◽

...

Keyword(s):

Whole Genome Sequencing ◽

Genome Sequencing ◽

Whole Genome ◽

Tier 2 ◽

Single Nucleotide Variants ◽

Genomic Assays ◽

Mutational Burden ◽

Clinical Annotation ◽

And Control ◽

Actionable Variants

AbstractIntroductionThe identification of tumour mutational burden (TMB) as a biomarker of response to PD-1 immunotherapy has necessitated the development of genomic assays to measure this. We carried out comprehensive molecular profiling of cancers using the Illumina TruSight Oncology panel (TSO500) and compared to whole genome sequencing.MethodsCancer samples derived from formalin fixed material were profiled on the TSO500 panel, sequenced on an Illumina NextSeq 500 instrument and processed through the TSO500 Docker Pipeline. Either FASTQ files (PierianDx) or VCF files (OncoKDM) were processed to understand clinical actionabilityResultsIn total, 108 samples (a mixture of colorectal, lung, oesophageal and control samples) were processed via the DNA panel. There was good correlation between TMB, SNV, indels and CNV as predicted by TSO500 and WGS (R2>0.9) and good reproducibility, with less than 5% variability between repeated controls. For the RNA panel, 13 samples were processed, with all known fusions observed via orthogonal techniques detected. For clinical actionability 72 Tier 1 variants and 297 Tier 2 variants were identified with clinical trials identified for all patients.ConclusionsThe TruSight Oncology 500 assay accurately measures TMB, MSI, single nucleotide variants, indels, copy number/structural variation and gene fusions when compared to whole genome sequencing and orthogonal technologies. Coupled with a clinical annotation pipeline this provides a powerful methodology for identification of clinically actionable variants.

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