受精後に細胞に生じる遺伝子変化である体細胞変異は、健康な組織にも広く見られるが、従来は前がん病変の兆候、あるいは単なる老化の結果と考えられてきた。しかし、近年の研究により、体細胞変異が疾患を引き起こす一方で、疾患を予防することも示されており、新たな治療戦略の創出につながる可能性がある。
例えば、変異した造血細胞は炎症性疾患を悪化させ、変異した肝細胞は肝疾患を予防する。これは、体細胞変異が、不適応性のものであろうと有益性のものであろうと、疾患のメカニズム、病歴、そして治療戦略に関する重要な知見をもたらす可能性を示唆している。体細胞遺伝学は、生物医学と医薬品開発に多大な影響を与えてきた従来の生殖細胞遺伝学を補完する強力なアプローチを提供する。
Quotient Therapeutics Incを主とする研究チームによるレビューでは、体細胞モザイクの様相を形作る要因を探り、疾患を引き起こしたり、疾患を予防したりする体細胞変異について考察し、体細胞変異が疾患遺伝学の重要な発見エンジンとなり、薬剤ターゲットの特定と臨床応用に向けて急速に進歩していることを強調する。
[構成]
Introduction: Somatic mutations are widespread in health and disease
Intrinsic and extrinsic factors that shape the landscape of somatic mosaicism
Tissue architecture and proliferation regulate somatic mosaicism
Inflammation shapes and is shaped by somatic mosaicism
Chemicals, toxins, and chemotherapies are selective pressures that mediate clonal expansion
Metabolic disease shapes somatic mosaicism in the liver and esophagus
Somatic mutations can drive disease
Somatic mutations are implicated in diverse neuropathologies
Somatic mutations can cause vascular, lymphatic, and limb malformations
Somatic mutations can drive autoimmune and autoinflammatory conditions
Somatic mutations can protect against or counter disease
NOTCH mutations in the esophagus compete against cancer
Somatic mutations in liver disease protect against tissue injury
IL-17 resistance mutations may exacerbate colitis but inhibit transformation
Mutations in the immune system can promote anti-cancer immunity
Somatic variants can counteract the detrimental effects of monogenic diseases
Somatic mutations can have divergent influences on clones and individuals
Systematic target discovery using somatic genomics
Somatic genomics is a new way to identify pathways with human disease relevance
A framework to systematically identify somatic gene targets that impact disease
Future outlook for somatic genomics
Somatic and germline genetic data can be integrated to nominate targets
Context-specific somatic mutations could inform therapeutic strategies
Overcoming technical and biological challenges of somatic genomics
[図表リスト]
- Figure 1 Somatic mutations are ubiquitous, permitting the sampling of most gene perturbations at the organ level
- Figure 2
- Figure 3 Somatic genomics uncovers the outcomes of evolutionary competitions within our tissues, which can drive disease, counter monogenic disease, or protect from common diseases
- Figure 4 A four-step framework to systematically identify somatic gene targets that impact disease and inform therapeutic strategies
- Figure 5 Patterns of somatic selection and clustering of mutations can inform therapeutic hypotheses
- Table 1 Illustrative list of genes under selection in different organ and disease contexts
[出典]
- REVIEW "Somatic genomics as a discovery engine for biomedicine" Brunner SF [..] Zhu H. Cell. 2026-03-05. https://doi.org/10.1016/j.cell.2026.01.032 [所属] Quotient Therapeutics Inc (米国), Flagship Pioneering Inc, Wellcome Sanger Institute (英国), University of Texas Southwestern Medical Center (Children’s Research Institute/Center for Regenerative Science and Medicine)
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