Validity of whole genomes sequencing results in neoplasms in precision medicine

J Clin Pathol. 2021 Nov;74(11):718-723. doi: 10.1136/jclinpath-2020-206998. Epub 2020 Oct 29.


Objective: To compare the whole genomes sequencing (WGS) results in the 100K Genomes project with the results of routine molecular diagnostics in precision medicine.

Materials and methods: We analysed 374 cancers including a high tumour mutational burden (TMB-high) subgroup, defined as >10 non-synonymous single nucleotide variations per megabase. Colon cancers were evaluated for microsatellite instability (MSI), mismatch repair (MMR) genes and NRAS, KRAS and BRAF mutations using routine molecular diagnostics. Fluorescence in-situ hybridisation/immunohistochemistry was used to evaluate the Her2Neu status in breast cancers.

Results: There was high correlation between WGS and routine diagnostic testing results irrespective of TMB status in colon cancers. Her2Neu status was discordant in 3 out of the 5 TMB-high breast cancers (p=0.049). The presence of ductal carcinoma in-situ correlated significantly with discordance (p=0.04). There were 3 (5%) discordant colorectal cases, all in the KRAS gene, 2 of which were from the non-invasive adenomatous component (p=0.0058). Of the 374 cases we identified 24 tumours with a TMB >10; comprising (colorectal carcinomas (CRCs) n=16, breast carcinomas n=5, bladder urothelial cell cancers n=3). Of the 16 TMB-high colorectal adenocarcinomas, 13 had MSI-high status. The same 13 had defective MMR protein expression. TMB-high colorectal cancers had 100% concordant results between WGS and NGS testing for KRAS, BRAF and NRAS (16/16).

Conclusion: The microsatellite and mutational status of colorectal cancers evaluated by WGS seem to correlate well with the routine diagnostic testing if it is ensured that the invasive component is sequenced. Evaluation of WGS results need to be carefully correlated with histomorphology, as tumour heterogeneity/contamination with pre-malignant components needs to be taken into account.

Keywords: erbB-2; genes; genetics; molecular; neoplasm; pathology.

Publication types

  • Validation Study

MeSH terms

  • Biomarkers, Tumor / genetics
  • DNA Mismatch Repair
  • Female
  • Genes, erbB-2
  • Genes, ras / genetics
  • Humans
  • Male
  • Microsatellite Instability
  • Mutation
  • Neoplasm Grading
  • Neoplasms / genetics*
  • Pathology, Molecular
  • Precision Medicine* / methods
  • Whole Genome Sequencing*


  • Biomarkers, Tumor