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Validity of whole genomes sequencing results in neoplasms in precision medicine
  1. Godwins Echejoh1,
  2. Yiwen Liu1,2,
  3. Guy Chung-Faye3,
  4. Jessica Charlton4,
  5. Jane Moorhead1,
  6. Barnaby Clark4,
  7. Philip Davidson4,
  8. Debashis Sarker5,
  9. Paul Ross5,
  10. Marc Lucas Ooft1,6
  1. 1 Department of Histopathology, King’s College Hospital, King’s College, London, UK
  2. 2 Advanced Diagnostics, Department of Histopathology, Tissue Sciences, Viapath, King’s College Hospital, London, UK
  3. 3 Department of Gastroenterology, King’s College Hospital, London, UK
  4. 4 Precision Medicine, King’s College Hospital, London, UK
  5. 5 Department of Medical Oncology, Guy’s and St Thomas’ NHS Trust, London, UK
  6. 6 School of Cancer & Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, UK
  1. Correspondence to Dr Marc Lucas Ooft, Department of Histopathology, King’s College Hospital, King’sCollege, London, UK; m.ooft{at}


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.

  • genes
  • neoplasm
  • genes
  • erbB-2
  • genetics
  • pathology
  • molecular

Data availability statement

Data may be obtained from a third party and are not publicly available.

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Data availability statement

Data may be obtained from a third party and are not publicly available.

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  • Handling editor Runjan Chetty.

  • Contributors GE and MO conceived the study. The study was designed by GE and MO. Writing was mainly done by GE with contribution by MO, YL, GC-F. Data collection and interpretation were done by GE, MO, YL, JM, BC, PD, DS and PR. Proof reading was done mainly by MO. All authors were involved in the final approval of the manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; internally peer reviewed.