A body map of somatic mutagenesis in morphologically normal human tissues

Li, Ruoyan; Lin, Dachuan; Li, Jie; Fan, Wenyi; Liu, Yachen; Guo, Wenjia; Liu, Weiling; Liu, Lu; Li, Qiong; Chen, Liping; Chen, Yamei; Miao, Chuanwang; Liu, Hongjin; Wang, Yuqian; Ma, Yuling; Xu, Deshu; Lin, Dong; Huang, Yanyi; Wang, Jianbin; Bai, Fan; Wu, Chen

doi:10.1038/s41586-021-03836-1

Cited by 112 publications

(50 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While most, if not all, tissues gradually accumulate SBS1 and SBS5 mutations throughout life, their ratios differ between tissues. Differences in cell turnover rate between tissues have been suggested to be one possible cause for this (Alexandrov et al, 2015;Blokzijl et al, 2016;Li et al, 2021;Moore et al, 2021). Some cells also showed contributions of additional mutational signatures caused by both exogenous and endogenous factors, which explain part of the variation in the mutation rate and spectra between tissues.…”

Section: Tissue-specific Mutational Processes In Adult Stem Cellsmentioning

confidence: 99%

The Dynamics of Somatic Mutagenesis During Life in Humans

2021

View full text Add to dashboard Cite

From conception to death, human cells accumulate somatic mutations in their genomes. These mutations can contribute to the development of cancer and non-malignant diseases and have also been associated with aging. Rapid technological developments in sequencing approaches in the last few years and their application to normal tissues have greatly advanced our knowledge about the accumulation of these mutations during healthy aging. Whole genome sequencing studies have revealed that there are significant differences in mutation burden and patterns across tissues, but also that the mutation rates within tissues are surprisingly constant during adult life. In contrast, recent lineage-tracing studies based on whole-genome sequencing have shown that the rate of mutation accumulation is strongly increased early in life before birth. These early mutations, which can be shared by many cells in the body, may have a large impact on development and the origin of somatic diseases. For example, cancer driver mutations can arise early in life, decades before the detection of the malignancy. Here, we review the recent insights in mutation accumulation and mutagenic processes in normal tissues. We compare mutagenesis early and later in life and discuss how mutation rates and patterns evolve during aging. Additionally, we outline the potential impact of these mutations on development, aging and disease.

show abstract

Section: Tissue-specific Mutational Processes In Adult Stem Cellsmentioning

confidence: 99%

The Dynamics of Somatic Mutagenesis During Life in Humans

2021

View full text Add to dashboard Cite

show abstract

“…By performing WGS of single-cell-derived organoid cultures we observed selective acquisition of T > G and T > C conversion in BE clones that correspond to the previously described SBS17a and SBS17b ( 24 , 25 , 31 , 32 ). While some mutational signatures such as SBS1 and SBS5 accumulate as a result of aging, SBS17-related alterations were not detected in esophageal cells of individuals (>85 y of age) ( 42 , 43 ). In agreement with these observations, SBS17-specific alterations were absent in matching nondiseased esophageal and gastric tissues including the adjacent cardia region, located on the gastric side of the gastroesophageal junction.…”

Section: Discussionmentioning

confidence: 94%

Molecular characterization of Barrett’s esophagus at single-cell resolution

Busslinger

Barbanson

Oka

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Barrett’s esophagus (BE) is categorized, based on morphological appearance, into different stages, which correlate with the risk of developing esophageal adenocarcinoma. More advanced stages are more likely to acquire chromosomal instabilities, but stage-specific markers remain elusive. Here, we performed single-cell DNA-sequencing experiments (scDNAseq) with fresh BE biopsies. Dysplastic BE cells frequently contained chromosomal instability (CIN) regions, and these CIN cells carried mutations corresponding to the COSMIC mutational signature SBS17, which were not present in biopsy-matched chromosomally stable (CS) cells or patient-matched nondiseased control cells. CS cells were predominantly found in nondysplastic BE biopsies. The single-base substitution (SBS) signatures of all CS BE cells analyzed were indistinguishable from those of nondiseased esophageal or gastric cells. Single-cell RNA-sequencing (scRNAseq) experiments with BE biopsies identified two sets of marker genes which facilitate the distinction between columnar BE epithelium and nondysplastic/dysplastic stages. Moreover, histological validation confirmed a correlation between increased CLDN2 expression and the presence of dysplastic BE stages. Our scDNAseq and scRNAseq datasets, which are a useful resource for the community, provide insight into the mutational landscape and gene expression pattern at different stages of BE development.

show abstract

“…SBS5 was clock-like in that the number of mutations in most cancers and normal cells correlates with the age of the individual [35]. A recently study by Chinese scholars reported that endogenous mutational processes with the SBS5 mutational signatures were ubiquitous among normal tissues [36]. The increasing of SBS5 mutational burden in young LUAD group might indicate premature accumulation of aging mechanisms in the body, thereby promoting tumor formation.…”

Section: Discussionmentioning

confidence: 98%

Next-generation Sequencing Reveals Age-dependent Genetic Underpinnings in Lung adenocarcinoma

Wu¹,

Zhao²,

Yang³

et al. 2022

J. Cancer

View full text Add to dashboard Cite

Background: More than 40% of lung cancer patients are diagnosed at ages over 70. However, the genomic and clinical characteristics among them remain elusive. Here, we performed targeted capture sequence to characterize the mutational spectrum of Chinese lung adenocarcinoma (LUAD) patients across ages. Patients and Methods: 2025 LUAD patients were divided into three groups: young (≤50 years old) (n=416, 20.54%), intermediate (51~69 years old) (n=1271, 62.77%), and aged (≥70 years old) (n=338, 16.69%). 1,021-gene panel and 59-gene panel were used for sequencing with tissue samples. Genetic alterations and tumor mutation burden (TMB) in LUAD patients were investigated. Results:The frequency of mutations affecting 20 genes were significantly higher in aged group than in young group, and fourteen of them were not reported before, including involved in cell cycle/apoptosis signaling (FAT1, FAT2), DNA damage repair (FANCA and FANCM), chromatin histone modification (KDM6A), RTK/RAS/PI3K signaling (FLT4 and MTOR), NOTCH signaling (NOTCH1, NOTCH2 and NOTCH4) and other signaling pathway or cellular regulatory factor (KEAP1, ASXL1, EPHB1 and ABCB1). Six previously reported mutated genes (RBM10, KRAS, LRP1B, CDKN2A and KMT2C/D) were also significantly more frequent in aged group. Among clinical actionable mutation sites, KRAS mutation was presented more common in aged group; both MET exon 14 skipping and MET amplification were significantly positively correlated with old age; the fusions of ALK, ROS1, RET and ERBB2 exon 20 insertion were less frequent in aged group. Furthermore, a higher level of TMB was found in aged group compared with young group. Conclusion:In this study, we revealed the differences of somatic genetic mutations and TMB between young and aged LUAD patients, which may provide directions of targeted therapy and advantages of immunotherapy for the elderly in the future.

show abstract

A body map of somatic mutagenesis in morphologically normal human tissues

Cited by 112 publications

References 53 publications

The Dynamics of Somatic Mutagenesis During Life in Humans

The Dynamics of Somatic Mutagenesis During Life in Humans

Molecular characterization of Barrett’s esophagus at single-cell resolution

Next-generation Sequencing Reveals Age-dependent Genetic Underpinnings in Lung adenocarcinoma

Contact Info

Product

Resources

About