Mutational selection in normal urothelium

doi:10.1126/science.abe0955

GSTDTAP > 气候变化

DOI	10.1126/science.abe0955
	Mutational selection in normal urothelium
	Steven G. Rozen
	2020-10-02
发表期刊	Science
出版年	2020
英文摘要	Cells have elaborate machinery to preserve the integrity of their genomes, which nevertheless relentlessly gather new mutations over time. Recent technical advances have enabled high-resolution delineation of these accumulated mutations and their spatial organization in tissues ([ 1 ][1]–[ 8 ][2]). It is now possible to deduce which mutations in which genes allowed cells to outcompete their neighbors and colonize nearby regions of normal tissue (clonal expansion). One can also sometimes ascertain which endogenous mutational processes or external mutagens caused these somatic mutations. These recent findings have profound implications for understanding aging and the early stages of cancer initiation. On pages 75 and 82 of this issue, Lawson et al. ([ 9 ][3]) and Li et al. ([ 10 ][4]), respectively, delve into the somatic mutations lurking in the normal urothelium—the lining of the bladder and ureter—and relate them to cancers in these tissues. Although the findings of the two studies are broadly consistent, substantial methodological differences account for some divergence. Lawson et al. studied the urothelium of the bladder, primarily in organ donors from Europe, whereas Li et al. studied the nonmalignant urothelium of both the bladder and the ureter in cancer patients from China. Additionally, Lawson et al. studied an average of ∼100 tiny (∼0.01 mm2) urothelial samples each from 15 organ donors and 5 cancer patients; by contrast, Li et al. studied an average of 1.3 large (∼2 mm2) samples of normal tissue from 120 cancer patients. The studies also differed in their sequencing approaches. Lawson et al. sequenced a mix of whole genomes, whole exomes, and a targeted panel of 321 cancer-associated genes, whereas Li et al. sequenced whole exomes. Despite the methodological differences, both studies analyzed somatic mutations in normal urothelium to show that clonal expansion occurred. Both studies found that a selective advantage (indicated by high prevalence of a clone) usually stemmed from mutations in genes encoding proteins involved in histone modification and chromatin remodeling. Within these genes, truncating, and presumably inactivating, mutations were often strongly selected. The affected genes prominently included KMT2D (histone-lysine N -methyltransferase 2D) and KDM6A (lysine-specific demethylase 6A). These chromatin remodeling genes are also mutated in many cancers of the urothelium, suggesting that the nonmalignant expanded clones driven by these genes regularly, but not frequently, become malignant. This contrasts with the esophagus, in which some genes that often drive clonal expansion in the normal tissue only rarely act as drivers in cancers ([ 3 ][5], [ 6 ][6]). By examining many samples per individual, Lawson et al. found that, in some individuals, the urothelium showed strong selective preference for mutations in particular genes. For example, one person had 35 distinct KDM6A mutations distributed over multiple clones and 2 different ARID1A (AT-rich interactive domain-containing protein 1A, also involved in chromatin remodeling) mutations, whereas another person had 4 different KDM6A mutations and 20 different ARID1A mutations distributed over multiple clones. It was not possible to make such observations with the study design of Li et al. , but with a larger sample of individuals, Li et al. may have been better able to assess the prevalence of mutations in different genes. Both studies found that, with the exception of the chromatin remodeling genes, most other genes that are commonly mutated in urothelial cancers were rarely mutated in normal urothelium. These include the well-established cancer driver genes PIK3CA (phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit α), FGFR3 (fibroblast growth factor receptor 3), and RB1 (RB transcriptional corepressor 1). Thus, mutations in these driver genes might be later events that finally trigger malignant transformation of cells harboring mutations that drive clonal expansion (see the figure). Both studies also found few large-scale copy number alterations in the normal urothelium, in contrast to the abundant large-scale copy number alterations found in urothelial cancers. Lawson et al. detected copy number alterations in only 28% of exomes, whereas the average bladder cancer has 200 per exome. Thus, genome instability occurs late in the malignant transformation of the urothelium, a pattern also seen in skin, esophageal, and colon transformation ([ 1 ][1], [ 3 ][5], [ 5 ][7]). ![Figure][8] Mutations in the bladder and ureter linings Cells in the normal urothelium that lines the ureter and bladder accumulate mutations caused by endogenous mutagenic processes (e.g., APOBEC cytidine deaminases) or by exogenous mutagens (e.g., AA or tobacco smoke). Some mutations (e.g., in the chromatin modifying genes KMT2D and KDM6A ) confer competitive advantages that drive cells to colonize larger regions of the urothelium. Additional mutations (e.g., in the genes TP53 , PIK3CA , FGFR3 , or RB1 ) and perhaps other changes are needed to trigger malignant transformation. GRAPHIC: MELISSA THOMAS BAUM/ SCIENCE Slowing the accumulation of mutations in normal tissue might slow aging and reduce the risk of cancer, and therefore it is important to understand the causes of these mutations. The two studies analyzed their respective sequencing data for “mutational signatures” that might point to these causes. Mutational signatures are the patterns of single base mutations within distinct sequences of preceding and following bases that can distinguish various mutational processes. Both studies identified the mutational signature caused by APOBEC cytidine deaminase activity in more than half of the individuals studied, although it was not found in every sample from those individuals. This signature is almost always found in bladder cancer and often in cancer of the ureter; it is also found in many other cancer types ([ 11 ][9]). The two studies show that increased APOBEC activity seems to accompany malignant transformation in urothelial cancer. The mechanisms responsible for this activation, and whether it is a cause or an effect of transformation, are unknown. Lawson et al. sequenced the entire genomes of a subset of the urothelial samples, which enabled them to uncover previously unknown mutational signatures. One of these signatures correlated with tobacco smoking. This may solve the puzzle that no specific smoking-associated mutational signature has been identified in bladder cancer, even though tobacco smoking is a well-established risk factor for bladder cancer and causes a highly recognizable signature in lung cancer. The smoking signature in lung cancer bears no resemblance to the smoking-associated signature identified by Lawson et al. , and the mechanisms by which tobacco might cause it are unknown. Li et al. did not detect this signature, possibly because they analyzed whole exomes rather than whole genomes. A prominent difference between the mutational signatures detected in the two studies is the presence of the signature caused by aristolochic acid (AA) in more than half of the ureter samples and about a third of the bladder samples examined by Li et al. AA is a kidney toxin and carcinogen that occurs naturally in some herbs used as medicine. AA exposure is widespread in East Asia, including China (the location of patients studied by Li et al. ), but very limited in Europe (the location of individuals studied by Lawson et al. ) ([ 11 ][9]–[ 13 ][10]). AA mutagenesis was previously detected in a few normal urothelial samples ([ 13 ][10], [ 14 ][11]), and Li et al. now show that AA mutagenesis is widespread in normal urothelium. This suggests that it may be possible to reliably assess the AA mutational signature in cells or DNA shed from normal urothelium and, using this signature, noninvasively assess previous AA exposure ([ 13 ][10]). A noninvasive test for AA exposure would offer substantial benefits to research into the epidemiology of AA-associated disease and to secondary prevention of cancer and kidney failure in AA-exposed individuals. An unexpected finding was the strong difference in driver mutation preferences between individuals, with, for example, one person having multiple independent mutations in KDM6A and few in ARID1A , and another person with the opposite pattern. It will be interesting to see how general this phenomenon is and whether driver preferences can predict cancer risk or, very speculatively, suggest prophylactic therapies. Each study explored mutations in a different dimension. One studied one or two samples from a broad swath of individuals, and the other was a deep study of many samples from a few individuals. To understand the implications of differences in preferences of driver gene mutations between individuals, a study that is simultaneously broad and deep is required. Nevertheless, the shared message of Li et al. and Lawson et al. is that histologically normal urothelium contains many clones that are only a few steps away from turning malignant but that rarely do. Studies using mouse models of the development of urothelial cancers, similar to a recent study of the development of esophageal cancer ([ 15 ][12]), would further delineate the mechanisms by which mutations in the normal human urothelium sometimes give rise to cancer. 1. [↵][13]1. I. Martincorena et al ., Science 348,, 880 (2015). [OpenUrl][14][Abstract/FREE Full Text][15] 2. 1. M. A. Lodato et al ., Science 359, 555 (2018). [OpenUrl][16][Abstract/FREE Full Text][17] 3. [↵][18]1. I. Martincorena et al ., Science 362, 911 (2018). [OpenUrl][19][Abstract/FREE Full Text][20] 4. 1. S. F. Brunner et al ., Nature 574, 538 (2019). [OpenUrl][21][CrossRef][22][PubMed][23] 5. [↵][24]1. H. Lee-Six et al ., Nature 574, 532 (2019). [OpenUrl][25][CrossRef][26][PubMed][27] 6. [↵][28]1. A. Yokoyama et al ., Nature 565, 312 (2019). [OpenUrl][29][CrossRef][30][PubMed][31] 7. 1. L. Moore et al ., Nature 580, 640 (2020). [OpenUrl][32][CrossRef][33][PubMed][34] 8. [↵][35]1. K. 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领域	气候变化 ; 资源环境
URL	查看原文
引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/298049
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Steven G. Rozen. Mutational selection in normal urothelium[J]. Science,2020.
APA	Steven G. Rozen.(2020).Mutational selection in normal urothelium.Science.
MLA	Steven G. Rozen."Mutational selection in normal urothelium".Science (2020).