Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON, Canada.
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
BMC Med. 2020 Oct 29;18(1):283. doi: 10.1186/s12916-020-01763-y.
It has long been known that mutations are at the core of many diseases, most notably cancer. Mutational analysis of tissues and fluids is useful for cancer and other disease diagnosis and management.
The prevailing cancer development hypothesis posits that cancer originates from mutations in cancer-driving genes that accumulate in tissues over time. These mutations then confer special characteristics to cancer cells, known as the hallmarks of cancer. Mutations in specific driver genes can lead to the formation of cancerous subclones and mutation risk increases with age. New research has revealed an unexpectedly large number of mutations in normal tissues; these findings could have significant implications to the understanding of the pathobiology of cancer and for disease diagnosis and therapy. Here, we discuss how the prevalence of mutations in normal tissues provides novel and relevant insights about clonal development in cancer and other diseases. Specifically, this review will focus on discussing mutations in normal tissues in the context of developing specific, circulating tumor DNA (ctDNA) tests for cancer, and evaluating clonal hematopoiesis as a predictor of blood cancers and cardiovascular pathology, as well as their implications to the phenomena of neural mosaicism in the context of Alzheimer's disease.
In view of these new findings, the fundamental differences between the accumulation of genetic alterations in healthy, aging tissues compared to cancer and cardiovascular or neural diseases will need to be better delineated in the future.
长期以来，人们一直知道突变是许多疾病的核心，尤其是癌症。对组织和体液的突变分析可用于癌症和其他疾病的诊断和管理。
目前占主导地位的癌症发展假说认为，癌症起源于随着时间的推移在组织中积累的致癌基因的突变。这些突变随后赋予癌细胞特殊的特征，即癌症的标志。特定驱动基因的突变可导致癌变亚克隆的形成，并且突变风险随年龄的增长而增加。新的研究揭示了正常组织中存在大量意想不到的突变；这些发现可能对理解癌症的病理生物学以及疾病的诊断和治疗具有重要意义。在这里，我们讨论了正常组织中突变的普遍性如何为癌症和其他疾病的克隆发育提供新的、相关的见解。具体而言，本综述将重点讨论在开发用于癌症的特定循环肿瘤 DNA（ctDNA）检测的背景下正常组织中的突变，并评估克隆性造血作为血液癌和心血管病理学预测因子的作用，以及其对阿尔茨海默病背景下神经嵌合体现象的意义。
鉴于这些新发现，未来需要更好地区分健康、衰老组织中遗传改变的积累与癌症以及心血管或神经疾病之间的基本差异。
