Feasibility of whole‐genome sequencing‐based tumor diagnostics in routine pathology practice

Abstract

The current increase in number and diversity of targeted anticancer agents poses challenges to the logistics and timeliness of molecular diagnostics (MolDx), resulting in underdiagnosis and treatment. Whole‐genome sequencing (WGS) may provide a sustainable solution for addressing current as well as future diagnostic challenges. The present study therefore aimed to prospectively assess feasibility, validity, and value of WGS in routine clinical practice. WGS was conducted independently of, and in parallel with, standard of care (SOC) diagnostics on routinely obtained tumor samples from 1,200 consecutive patients with metastatic cancer. Results from both tests were compared and discussed in a dedicated tumor board. From 1,200 patients, 1,302 samples were obtained, of which 1,216 contained tumor cells. WGS was successful in 70% (854/1,216) of samples with a median turnaround time of 11 days. Low tumor purity (<20%) was the main reason for not completing WGS. WGS identified 99.2% and SOC MolDx 99.7% of the total of 896 biomarkers found in genomic regions covered by both tests. Actionable biomarkers were found in 603/848 patients (71%). Of the 936 associated therapy options identified by WGS, 343 were identified with SOC MolDx (36.6%). Biomarker‐based therapy was started in 147 patients. WGS revealed 49 not previously identified pathogenic germline variants. Fresh‐frozen, instead of formalin‐fixed and paraffin‐embedded, sample logistics were easily adopted as experienced by the professionals involved. WGS for patients with metastatic cancer is well feasible in routine clinical practice, successfully yielding comprehensive genomic profiling for the vast majority of patients. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Implementation of Whole-Genome and Transcriptome Sequencing Into Clinical Cancer Care

“…For instance, targeted next-generation sequencing approaches are better at detecting mutations with lower allele frequencies than WGS due to higher sequencing depth but are less comprehensive than WES and WGS and less effective for identification of large genomic aberrations such as SVs. 5 Recent feasibility studies of clinical WGTS across pediatric cancers 5 and adult solid tumors 6 demonstrated that despite 5- to 10-fold lower average sequencing depth typically used for panels, WGTS of matched tissue samples was able to call out all clinically relevant variants (Data Supplement). Karyotyping has limited ability to detect smaller (under 5 Mb), clinically relevant copy number aberrations.…”

Tobacco Smoking-Related Mutational Signatures in Classifying Smoking-Associated and Nonsmoking-Associated NSCLC

“…In addition, the WIDE study investigators have recently found that WGS for patients with metastatic cancer is feasible in routine clinical practice. 13 We do, however, appreciate that the implementation in clinical trials would still be a hurdle to overcome. Currently, many clinical trials already require archival or fresh tumor tissue to be sent in for genome testing during the screening period.…”

“…The handling, processing, and sequencing of the samples have previously been described in detail for these cohorts. [11][12][13] The WGS data were made available by the Hartwig Medical Foundation.…”

Precision medicine: affording the successes of science

“…Biomarker screening is also evolving rapidly. Beyond comprehensive genomic panels, whole genome and transcriptome sequencing approaches are being evaluated, and offer potential advantages 27 . While routine pathology processing and costs make focused panels more practical currently, the technology is rapidly evolving and costs of whole genome sequencing are falling, and routine practice will likely adapt over time.…”