Science: There are a large number of mutations and clone amplifications in the normal skin tissue next to cancer, and horse bell acid strongly promotes normal cell DNA mutations.

Cells in various normal tissues in the human body are inevitably accumulating mutations.
the occurrence of these somtic cell mutations is usually associated with dna replication errors during cell division that are not fixed or are not properly repaired.
Usually, these mutations do not have a significant effect on the esoteric and functionality of sophyte cells, however, if some mutations occur in some important genes associated with cell proliferation and death, it is likely that mutant somological cells will gain an advantage in growth and competition, resulting in the formation and expansion of soymic cell mutation cloning, which will eventually lead to disease and aging processes.
most well-known example of cancer is the occurrence of cancer, in which sorocytes gradually accumulate mutations and clone dilation under the influence of endogenetic or exogenetic factors, which eventually lead to the development of cancer.
, it is of great significance to study the process of mutation accumulation and the expansion and evolution of mutation cloning in normal tissues to better understand the early occurrence and development of cancer.
October 2, 2020, the Bai Fan Research Group of The Biomedical Frontier Innovation Center (BIOPIC) of Peking University, the School of Life Sciences, and the Xu Tao Research Group of Urology at Peking University People's Hospital published a research paper in the journal Science entitled: Macroscopic Somatic clonal expansion in Morphologically normal human urothelium.
this work systematically studied the occurrence and accumulation of somatic cell mutations (somatic mutations) in urethra tissues with normal tissue morphology, as well as the expansion and evolution of mutation clones.
the urethra is a "shifting corted tissue" in the bladder and ureter.
the urethra skin tissue is updated at a faster rate and regenerates rapidly in the event of damage.
in a 2017 study on the genome of multi-pathogenic urethra cortical tumors, Bai Fan and Xu Tao team detected a large number of soytic cell mutations in the tissue morphologically normal urethra skin tissue in one of the cases.
the accidental discovery prompted the two teams to conduct more in-depth and comprehensive scientific research on the accumulation of mutant cells in the urethra tissue with normal tissue morphology.
In this study, the researchers used laser microcution and full exon depth sequencing techniques to conduct in-depth studies of 126 tumor tissues from 120 cases of urethra tumors and 161 tissues with normal tissue morphology on the urethra.
analysis of exon data, the researchers found that a large number of solitic cell mutations had accumulated in some of the normal urethra tissues of tissue morphology.
, many mutations have occurred in tumor-related drive genes.
However, compared to tumors, drive gene mutations in normal-form urethra tissue are concentrated in genes associated with chromatin remodeling (e.g. KMT2D and KDM6A genes) and less common in key drive genes for high-frequency mutations in tumors (e.g., the PIK3CA gene and FGFR3 gene).
this difference reflects the development of early cloning in urethra skin tissue and the formation of eventual urethra skin cancer with potentially different molecular mechanisms (Figure 1).
Figure 1, a map of soda cell mutations in urethra skin cancer and normal urethra cortological tissue, the researchers analyzed the single-base mutation characteristics (single-base-substitution mutational signature) to analyze the potential causes of the accumulation of large numbers of soda cell mutations in normal urethra cortential tissue.
researchers found that mutation features SBS1, SBS2, SBS13, SBS5, and SBS22 all contributed to mutations in normal urethra skin tissue to some extent.
, SBS22 led to mutations in most normal urethra skin tissues in this study.
previous studies have shown that the carcinogenic factor associated with SBS22 is the role of the mutagent Aristolochic acid (AA), which has been widely reported to be associated with the occurrence of tumors such as liver and bladder cancer.
study reveals that the variable effects of horse-ring acid can lead to the accumulation of large mutations in normal urethra skin tissue, which can lead to the expansion of cloning.
further mining of external exon data, the researchers analyzed variations in the number of copies of genes in normal urethra cortitological tissue (Figure 2).
, copy number variation, especially genome large-scale copy number variation, is less common in normal morphological urethra skin tissue.
even in urethra skin tissues that already carry large numbers of mutations and drive genetic mutations, copy number variations are rare.
results show that genomic stability and copy number variation are significant differences between normal cortical tissue and tumor tissue, and that the accumulation of mutations alone may not be sufficient to lead to the transformation of normal cortical to malignant tumors.
Figure 2, urethra cancer and copy number variation events in normal urethra skin tissue In a further analysis of mutational load and cloning dilation, the researchers divided normal urethroid skin tissue into two groups: horse-urethra acid-causing mutations (AA group) and other factors leading to mutations (non-AA group).
comparing the AA group with the non-AA group, it was found that the mutant load of the urethra tissue in the AA group was close to the mutant load of the urethra cancer, and was one order of magnitude higher than the mutant load of the normal endodertic tissue in the non-AA group.
based on the proportion of soy cell mutations, the researchers calculated the size of clone dilation in two groups of normal urethra skin tissue, and found that the size of clone dilation in the AA group was significantly higher than that of the non-AA group.
analysis of these two aspects reflects that horse-bell acid promotes the accumulation of mutations in normal urethra skin cells and the expansion of cloning in urethra skin tissue (Figure 3).
Figure 3, the mutant load and clone size of mutant clones in normal urethra cortique tissue, the researchers reconstructed the cloning relationship between multiple normal urethra skin tissues obtained in some cases through the construction of a system-occurring tree and the calculation of the proportion of mutant cells (mutant cell fractions).
results showed that in some cases, mutation clones of multiple normal urethra skin tissue independently originated and expanded and evolved independently, accumulating completely different driver gene mutations, but in some exceptional cases, the researchers found that the mutant clones caused by the acid-induced effects of horse's bells expanded dramatically, reaching a staggering square centimeter in size (Figure 4).
figure 4, the cloning relationship and expansion evolution of mutant cloning in normal urethra skin tissue, combined with laser microcution technology and full exon depth sequencing technology, in-depth systematic research on the accumulation of body cell mutations in urethra tissue with normal tumor tissue morphology and mutation cloning expansion and evolution, to build a comprehensive map of normal urethral cell mutations, to further understand the early occurrence of urethral skin cancer and other tumors.
in particular, the large number of mutation accumulation and cloning expansion observed in normal morphological endotion tissue in this study will lead to deep thinking on how to correspond between the biological esoteric and gene mutations of tumor cells.
It is reported that Li Ruyan (now working at wellcome Sanger Institute, Cambridge, UK), PhD student Chen Zhanghua, phD student Xu Dexuan, Peking University People's Hospital Dr. Du Yiqing and Professor Lin Tianyan of Sun Yat-sen Memorial Hospital of Zhongshan University are the first authors of this paper.
co-author of the research paper, including Professor Bai Fan of the School of Life Sciences and Professor Xu Tao of Peking University People's Hospital, at the Biomedical Frontier Innovation Center (BIOPIC) of Peking University.
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