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Original research
Comprehensive characteristics of somatic mutations in the normal tissues of patients with cancer and existence of somatic mutant clones linked to cancer development
  1. Ji-Hye Oh1,2,
  2. Chang Ohk Sung1,2,3
  1. 1Center for Cancer Genome Discovery, Asan Institute for Life Science, Asan Medical Center, Songpa-gu, Seoul, The Republic of Korea
  2. 2Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, University of Ulsan College of Medicine, Songpa-gu, Seoul, The Republic of Korea
  3. 3Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Songpa-gu, Seoul, The Republic of Korea
  1. Correspondence to Dr Chang Ohk Sung, Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Songpa-gu, Seoul, The Republic of Korea; co.sung{at}


Background Somatic mutations are a major driver of cancer development and many have now been identified in various cancer types, but the comprehensive somatic mutation status of the normal tissues matched to tumours has not been revealed.

Method We analysed the somatic mutations of whole exome sequencing data in 392 patient tumour and normal tissue pairs based on the corresponding blood samples across 10 tumour types.

Results Many of the mutations involved in oncogenic pathways such as PI3K, NOTCH and TP53, were identified in the normal tissues. The ageing-related mutational signature was the most prominent contributing signature found and the mutations in the normal tissues were frequently in genes involved in late replication time (p<0.0001). Variants were rarely overlapping across tissue types but shared variants between normal and matched tumour tissue were present. These shared variants were frequently pathogenic when compared with non-shared variants (p=0.001) and showed a higher variant-allele-fraction (p<0.0001). Normal tissue-specific mutated genes were frequently non-cancer-associated (p=0.009). PIK3CA mutations were identified in 6 normal tissues and were harboured by all of the matched cancer tissues. Multiple types of PIK3CA mutations were found in normal breast and matched cancer tissues. The PIK3CA mutations exclusively present in normal tissue may indicate clonal expansions unrelated to the tumour. In addition, PIK3CA mutation was appeared that they arose before the occurrence of the allelic imbalance.

Conclusion Our current results suggest that somatic mutant clones exist in normal tissues and that their clonal expansion could be linked to cancer development.

  • mutation
  • genetic research
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  • Contributors Project planning and design: COS. Method design and data analysis: J-HO and COS. Manuscript writing and figures: COS and J-HO. Histology image review: COS. All authors reviewed and approved the final manuscript.

  • Funding This work was funded by the Basic Science Research Programme of the National Research Foundation of Korea (NRFK; NRF-2019R1A2C1084460) and the Bio and Medical Technology Development Programme of the NRFK (NRF-2019M3E5D4066900) of the Korean government.

  • Competing interests None declared.

  • Patient consent for publication Not required.

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

  • Data availability statement Data are available in a public, open access repository. All data relevant to the study are included in the article or uploaded as supplementary information. All raw data were downloaded from '' after permission acquired.

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