Comprehensive characteristics of somatic mutations in the normal tissues of patients with cancer and existence of somatic mutant clones linked to cancer development.
genetic research
mutation
Journal
Journal of medical genetics
ISSN: 1468-6244
Titre abrégé: J Med Genet
Pays: England
ID NLM: 2985087R
Informations de publication
Date de publication:
07 2021
07 2021
Historique:
received:
10
02
2020
revised:
02
06
2020
accepted:
04
06
2020
pubmed:
29
7
2020
medline:
28
1
2022
entrez:
29
7
2020
Statut:
ppublish
Résumé
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. 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. 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). Our current results suggest that somatic mutant clones exist in normal tissues and that their clonal expansion could be linked to cancer development.
Sections du résumé
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).
CONCLUSION
Our current results suggest that somatic mutant clones exist in normal tissues and that their clonal expansion could be linked to cancer development.
Identifiants
pubmed: 32719100
pii: jmedgenet-2020-106905
doi: 10.1136/jmedgenet-2020-106905
doi:
Substances chimiques
Class I Phosphatidylinositol 3-Kinases
EC 2.7.1.137
PIK3CA protein, human
EC 2.7.1.137
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
433-441Informations de copyright
© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.
Déclaration de conflit d'intérêts
Competing interests: None declared.