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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


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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