Clonal Evolution

克隆演化
  • 文章类型: Journal Article
    两种类型的颅咽管瘤,金刚瘤(ACP)和乳头状(PCP),是儿童和成人的临床相关肿瘤。尽管原发性颅咽管瘤的生物学开始被揭开,对复发的生物学知之甚少。为了填补这一知识空白,我们通过甲基化阵列分析,RNA测序和pERK1/2免疫组织化学成对的原发和复发样本(32个样本来自14例ACP和4例PCP)的队列。我们显示6例ACP患者中存在拷贝数改变和克隆进化,对来自儿童脑肿瘤网络的其他全基因组测序数据的分析证实了至少7/67例ACP病例中染色体臂拷贝数的变化。MAPK/ERK通路的激活,先前在主要ACP中显示的功能,除1例ACP复发病例外,所有病例均观察到。唯一没有MAPK激活的ACP是具有CTNNB1突变和TP53丢失的复发性恶性人颅咽管瘤的侵袭性病例。为TP53突变的功能作用提供支持,我们表明,在ACP的小鼠模型中,Trp53丢失导致侵袭性肿瘤和降低小鼠存活率。最后,我们表征了肿瘤免疫浸润,显示ACP和PCP之间的细胞组成和空间分布差异。一起,这些分析揭示了对复发性颅咽管瘤的新见解,并提供了临床前证据,支持在抗复发性ACP的临床试验中评估MAPK通路抑制剂和免疫调节方法.
    The two types of craniopharyngioma, adamantinomatous (ACP) and papillary (PCP), are clinically relevant tumours in children and adults. Although the biology of primary craniopharyngioma is starting to be unravelled, little is known about the biology of recurrence. To fill this gap in knowledge, we have analysed through methylation array, RNA sequencing and pERK1/2 immunohistochemistry a cohort of paired primary and recurrent samples (32 samples from 14 cases of ACP and 4 cases of PCP). We show the presence of copy number alterations and clonal evolution across recurrence in 6 cases of ACP, and analysis of additional whole genome sequencing data from the Children\'s Brain Tumour Network confirms chromosomal arm copy number changes in at least 7/67 ACP cases. The activation of the MAPK/ERK pathway, a feature previously shown in primary ACP, is observed in all but one recurrent cases of ACP. The only ACP without MAPK activation is an aggressive case of recurrent malignant human craniopharyngioma harbouring a CTNNB1 mutation and loss of TP53. Providing support for a functional role of this TP53 mutation, we show that Trp53 loss in a murine model of ACP results in aggressive tumours and reduced mouse survival. Finally, we characterise the tumour immune infiltrate showing differences in the cellular composition and spatial distribution between ACP and PCP. Together, these analyses have revealed novel insights into recurrent craniopharyngioma and provided preclinical evidence supporting the evaluation of MAPK pathway inhibitors and immunomodulatory approaches in clinical trials in against recurrent ACP.
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  • 文章类型: Journal Article
    克隆造血(CH),突变克隆的相对扩增,来自造血干细胞(HSC),具有获得性体细胞或细胞遗传学改变,可改善细胞适应性。患有CH的个体患血液病和非血液病的风险较高,比如心血管疾病,总体死亡率较高。最初被认为仅限于一小部分老年人,单细胞测序和生物信息学的最新进展表明,具有多个扩展突变克隆的CH在老年人群中普遍存在。就在几年前,人类生命周期的系统发育重建和新的敏感测序技术表明,CH可以在生命早期开始,几十年前,它被认为是可能的。这些研究还表明,通过异常炎症起作用的环境因素可能是促进克隆扩展和疾病进展的共同主题。然而,这种现象的许多方面仍有待阐明,确切的机制,特定于上下文的驱动程序,和克隆扩增的途径仍有待建立。这里,我们回顾了我们目前对驱动CH的细胞机制的理解,并特别关注促炎因子如何影响正常和突变的HSC命运以促进克隆选择.
    Clonal hematopoiesis (CH), the relative expansion of mutant clones, is derived from hematopoietic stem cells (HSCs) with acquired somatic or cytogenetic alterations that improve cellular fitness. Individuals with CH have a higher risk for hematological and non-hematological diseases, such as cardiovascular disease, and have an overall higher mortality rate. Originally thought to be restricted to a small fraction of elderly people, recent advances in single-cell sequencing and bioinformatics have revealed that CH with multiple expanded mutant clones is universal in the elderly population. Just a few years ago, phylogenetic reconstruction across the human lifespan and novel sensitive sequencing techniques showed that CH can start earlier in life, decades before it was thought possible. These studies also suggest that environmental factors acting through aberrant inflammation might be a common theme promoting clonal expansion and disease progression. However, numerous aspects of this phenomenon remain to be elucidated and the precise mechanisms, context-specific drivers, and pathways of clonal expansion remain to be established. Here, we review our current understanding of the cellular mechanisms driving CH and specifically focus on how pro-inflammatory factors affect normal and mutant HSC fates to promote clonal selection.
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  • 文章类型: Journal Article
    JAK2V617F是费城染色体阴性骨髓增殖性肿瘤(Ph-MPNs)中普遍存在的驱动突变,显著影响疾病进展,免疫表型,和患者结果。世界卫生组织(WHO)指南强调JAK2V617F突变是Ph-MPN的关键诊断标准之一。在这项研究中,我们分析了283个具有JAK2V617F突变的MPN样本,以评估三种检测技术的有效性:基于芯片的数字PCR(cdPCR),实时定量PCR(qPCR),和下一代测序(NGS)。此外,我们调查了JAK2V617F突变等位基因负荷(%JAK2V617F)与各种实验室特征之间的关系,以阐明在MPN诊断中的潜在意义.我们的发现表明cdPCR与qPCR/NGS检测%JAK2V617F的高度一致性,但是qPCR/NGS检测到的突变等位基因负担低于cdPCR检测到的等位基因。此外,cdPCR表现出高灵敏度,在MPN中检测%JAK2V617F的检测限(LoD)为0.08%,定量限(LoQ)为0.2%。通过将%JAK2V617F与MPN患者的各种实验室特征相关联来探索临床意义,揭示与白细胞计数的显著关联,乳酸脱氢酶水平,特别是β2-微球蛋白(β2-MG)水平。最后,一个病例报告说明了cdPCR在检测具有隐藏的JAK2V617F亚克隆的从头慢性粒细胞白血病(CML)患者中的低等位基因负荷中的应用,在酪氨酸激酶抑制剂(TKI)治疗期间扩大。我们的发现强调了cdPCR的优越的灵敏度和准确性,使其成为早期诊断和监测克隆进化的有价值的工具。
    The JAK2 V617F is a prevalent driver mutation in Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-MPNs), significantly affecting disease progression, immunophenotype, and patient outcomes. The World Health Organization (WHO) guidelines highlight the JAK2 V617F mutation as one of the key diagnostic criterions for Ph-MPNs. In this study, we analyzed 283 MPN samples with the JAK2 V617F mutation to assess the effectiveness of three detection technologies: chip-based digital PCR (cdPCR), real-time quantitative PCR (qPCR), and next-generation sequencing (NGS). Additionally, we investigated the relationship between JAK2 V617F mutant allele burden (% JAK2 V617F) and various laboratory characteristics to elucidate potential implications in MPN diagnosis. Our findings demonstrated high conformance of cdPCR with qPCR/NGS for detecting % JAK2 V617F, but the mutant allele burdens detected by qPCR/NGS were lower than those detected by cdPCR. Moreover, the cdPCR exhibited high sensitivity with a limit of detection (LoD) of 0.08% and a limit of quantification (LoQ) of 0.2% for detecting % JAK2 V617F in MPNs. Clinical implications were explored by correlating % JAK2 V617F with various laboratory characteristics in MPN patients, revealing significant associations with white blood cell counts, lactate dehydrogenase levels, and particularly β2-microglobulin (β2-MG) levels. Finally, a case report illustrated the application of cdPCR in detecting low-allele burdens in a de novo chronic myeloid leukemia (CML) patient with a hidden JAK2 V617F subclone, which expanded during tyrosine kinase inhibitor (TKI) treatment. Our findings underscore the superior sensitivity and accuracy of cdPCR, making it a valuable tool for early diagnosis and monitoring clonal evolution.
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  • 文章类型: Journal Article
    家族性腺瘤性息肉病(FAP)是一种遗传综合征,其特征是在各个进化阶段的多个息肉,which,如果不及时治疗,不可避免地进展为结直肠癌(CRC)。在这项研究中,我们对FAP-CRC从癌前腺瘤到癌的进化历史进行了全面分析.
    从胃肠内窥镜检查或手术切除收集组织。对腺癌的多个区域(n=8)进行外显子组测序,绒毛状腺瘤(n=10),从属于7个中国FAP家族的9例患者中获得了管状腺瘤(n=9)和血液样本。重建了系统发育树,并进行进化分析以揭示导致CRC的事件的时间顺序。
    在FAP01中鉴定了APC基因中的遗传种系突变位点(p。S1281*,COSM19212),FAP03(p.S384Tfs*19),FAP04(p.E1538*,COSM6041693),FAP05(p.Q1062*,COSM3696862),和FAP07-FAP09(第V677Sfs*3)。值得注意的是,p.V677Sfs*3突变在APC中被认为是一种新的种系突变,家系分析中基因型-表型相关性的证据支持。腺瘤表现出比FAP-CRC更低的突变率,并且在众所周知的染色体不稳定性(CIN)基因(APC,RAS,SMAD4和TP53)和DNA损伤修复基因(SUZ12,KMT2C,BCLAF1、RUNX1和ARID1B),表明基因组不稳定的存在。此外,从管状腺瘤到绒毛状腺瘤,以及最终到癌,观察到HRD评分逐渐增加(“基因组疤痕”的量度).TP53成为腺瘤-癌转变的主要驱动基因,驱动突变始终同时出现,而不是从腺瘤到癌依次出现。克隆进化表明,肝转移可能源于原发癌性病变中存在的相同的癌引发细胞。
    我们在APC中发现了一种新的致病变异,即,p.V677Sfs*3。FAP-CRC的癌变过程支持经典的癌变模型,其中初始APC突变导致WNT信号通路和CIN的激活。随后,其他假定的CIN基因中会发生其他突变(例如,DNA修复,染色质重塑),最终导致微卫星稳定(MSS)肿瘤的发展。我们的研究提供了从腺瘤到癌过渡的基因组景观的全面理解。
    UNASSIGNED: Familial adenomatous polyposis (FAP) is a genetic syndrome characterized by multiple polyps at various evolutionary stages, which, if left untreated, inevitably progress to colorectal cancer (CRC). In this study, we present a comprehensive analysis of the evolutionary history of FAP-CRC from precancerous adenoma to carcinoma.
    UNASSIGNED: Tissues were collected from gastrointestinal endoscopy or surgical resection. Exome sequencing was performed on multiple regions of adenocarcinoma (n = 8), villous adenoma (n = 10), tubular adenoma (n = 9) and blood samples were obtained from 9 patients belonging to 7 Chinese FAP families. Phylogenetic trees were reconstructed, and evolutionary analysis was conducted to reveal the temporal sequence of events leading to CRC.
    UNASSIGNED: Inherited germline mutation sites in APC gene were identified in FAP01 (p.S1281*, COSM19212), FAP03 (p.S384Tfs*19), FAP04 (p.E1538*, COSM6041693), FAP05 (p.Q1062*, COSM3696862), and FAP07-FAP09 (p.V677Sfs*3). Notably, p.V677Sfs*3 mutation was recognized as a novel germline mutation in APC, supported by evidence of genotype-phenotype correlation in pedigree analysis. Adenomas exhibited lower mutational rates than FAP-CRC and displayed recurrent alterations in well-known chromosomal instability (CIN) genes (APC, RAS, SMAD4 and TP53) and DNA damage repair genes (SUZ12, KMT2C, BCLAF1, RUNX1, and ARID1B), suggesting the presence of genomic instability. Furthermore, a progressive increase in the HRD score (a measure of \"genomic scars\") was observed from tubular adenomas to villous adenomas and ultimately to carcinomas. TP53 emerged as the primary driver gene for adenoma-carcinoma transition, with driver mutations consistently appearing simultaneously rather than sequentially acquired from adenomas to carcinomas. Clonal evolution demonstrated that liver metastases can originate from the same cancer-primed cell present in a primary cancerous lesion.
    UNASSIGNED: We identified a novel pathogenic variant in APC, namely, p.V677Sfs*3. The process of carcinogenesis in FAP-CRC supports the classical cancerization model, where an initial APC mutation leads to the activation of the WNT signaling pathway and CIN. Subsequently, additional mutations occur in other putative CIN genes (e.g., DNA repair, chromatin remodeling), ultimately leading to the development of microsatellite stable (MSS) tumors. Our study provides a comprehensive understanding of the genomic landscapes that underlie the transition from adenoma to carcinoma.
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  • 文章类型: Journal Article
    肿瘤进化模型认为,恶性转化之前是癌症基因中随机分布的驱动突变,导致表型正常组织中的克隆扩增。尽管克隆扩增可以重塑整个组织1-3,但导致少数克隆转化为恶性肿瘤的机制仍然未知。在这里,我们开发了一种体内单细胞CRISPR策略,以系统地研究150个最常见突变的鳞状细胞癌基因的全组织克隆动力学。我们在子宫内进行超声引导的慢病毒显微注射,单细胞RNA测序和引导捕获,以纵向监测克隆扩增,并以单细胞转录组分辨率记录其基础基因程序。我们发现了肿瘤坏死因子(TNF)信号模块,它依赖于TNF受体1并涉及巨噬细胞,它是上皮组织克隆扩张的普遍驱动因素。相反,在肿瘤发生过程中,TNF信号传导模块下调。相反,我们确定了一个侵袭性癌细胞亚群,其转换为与上皮-间质转化相关的自分泌TNF基因程序.最后,我们提供了体内证据,证明自分泌TNF基因程序足以介导侵袭特性,并表明TNF特征与鳞状细胞癌患者的总生存期缩短相关.总的来说,我们的研究证明了将体内单细胞CRISPR筛选应用于哺乳动物组织的力量,揭示了肿瘤进化中不同的TNF程序,并强调了理解上皮克隆性扩张与肿瘤发生之间关系的重要性。
    The tumour evolution model posits that malignant transformation is preceded by randomly distributed driver mutations in cancer genes, which cause clonal expansions in phenotypically normal tissues. Although clonal expansions can remodel entire tissues1-3, the mechanisms that result in only a small number of clones transforming into malignant tumours remain unknown. Here we develop an in vivo single-cell CRISPR strategy to systematically investigate tissue-wide clonal dynamics of the 150 most frequently mutated squamous cell carcinoma genes. We couple ultrasound-guided in utero lentiviral microinjections, single-cell RNA sequencing and guide capture to longitudinally monitor clonal expansions and document their underlying gene programmes at single-cell transcriptomic resolution. We uncover a tumour necrosis factor (TNF) signalling module, which is dependent on TNF receptor 1 and involving macrophages, that acts as a generalizable driver of clonal expansions in epithelial tissues. Conversely, during tumorigenesis, the TNF signalling module is downregulated. Instead, we identify a subpopulation of invasive cancer cells that switch to an autocrine TNF gene programme associated with epithelial-mesenchymal transition. Finally, we provide in vivo evidence that the autocrine TNF gene programme is sufficient to mediate invasive properties and show that the TNF signature correlates with shorter overall survival of patients with squamous cell carcinoma. Collectively, our study demonstrates the power of applying in vivo single-cell CRISPR screening to mammalian tissues, unveils distinct TNF programmes in tumour evolution and highlights the importance of understanding the relationship between clonal expansions in epithelia and tumorigenesis.
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  • 文章类型: Journal Article
    膀胱癌是一种普遍的全球恶性肿瘤,在发病率和预后方面均表现出明显的性别差异。尽管治疗方法取得了长足的进步,强大的耐药性挑战依然存在.膀胱癌的基因组景观,以复杂的克隆异质性为特征,成为促进这种抵抗的关键决定因素。克隆演化,随着时间的推移,封装肿瘤细胞亚群内的动态转化,与耐药性状的出现有关。在这次审查中,我们阐明了克隆进化在膀胱癌中的作用,阐明其作为肿瘤启动驱动因素的影响,疾病进展,以及治疗抵抗的巨大障碍。
    Bladder cancer stands as a prevalent global malignancy, exhibiting notable sex-based variations in both incidence and prognosis. Despite substantial strides in therapeutic approaches, the formidable challenge of drug resistance persists. The genomic landscape of bladder cancer, characterized by intricate clonal heterogeneity, emerges as a pivotal determinant in fostering this resistance. Clonal evolution, encapsulating the dynamic transformations within subpopulations of tumor cells over time, is implicated in the emergence of drug-resistant traits. Within this review, we illuminate contemporary insights into the role of clonal evolution in bladder cancer, elucidating its influence as a driver in tumor initiation, disease progression, and the formidable obstacle of therapy resistance.
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  • 文章类型: Journal Article
    肿瘤可能含有数十亿个细胞,包括不同的恶性克隆和非恶性细胞类型。澄清进化史,患病率,确定这些细胞的分子特征对于改善临床结果至关重要,因为肿瘤内异质性为获得对靶向治疗的抵抗提供了燃料。在这里,我们提出了一种基于统计学的策略,通过对连续肿瘤切片(MOMA)的多体和多尺度分析来解构肿瘤内异质性。通过将IDH突变型星形细胞瘤的深度采样与单核苷酸变体的整合分析相结合,拷贝数变体,和基因表达,我们重建和验证系统发育,空间分布,和不同恶性克隆的转录谱。通过对单核RNA-seq分析的核进行基因分型,我们进一步表明,从单细胞转录组识别癌细胞的常用算法可能不准确。我们还证明,将大量样品中的基因表达与肿瘤纯度相关联可以揭示恶性细胞的最佳标志物,并使用这种方法来鉴定星形细胞瘤躯干克隆一致表达的一组核心基因。包括AKR1C3,其表达与几种癌症的不良预后相关。总之,MOMA提供了一种强大而灵活的策略,可以精确地解构肿瘤内异质性,并阐明实体瘤中不同细胞群的核心分子特性。
    Tumors may contain billions of cells, including distinct malignant clones and nonmalignant cell types. Clarifying the evolutionary histories, prevalence, and defining molecular features of these cells is essential for improving clinical outcomes, since intratumoral heterogeneity provides fuel for acquired resistance to targeted therapies. Here we present a statistically motivated strategy for deconstructing intratumoral heterogeneity through multiomic and multiscale analysis of serial tumor sections (MOMA). By combining deep sampling of IDH-mutant astrocytomas with integrative analysis of single-nucleotide variants, copy-number variants, and gene expression, we reconstruct and validate the phylogenies, spatial distributions, and transcriptional profiles of distinct malignant clones. By genotyping nuclei analyzed by single-nucleus RNA-seq for truncal mutations, we further show that commonly used algorithms for identifying cancer cells from single-cell transcriptomes may be inaccurate. We also demonstrate that correlating gene expression with tumor purity in bulk samples can reveal optimal markers of malignant cells and use this approach to identify a core set of genes that are consistently expressed by astrocytoma truncal clones, including AKR1C3, whose expression is associated with poor outcomes in several types of cancer. In summary, MOMA provides a robust and flexible strategy for precisely deconstructing intratumoral heterogeneity and clarifying the core molecular properties of distinct cellular populations in solid tumors.
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  • 文章类型: Journal Article
    大多数原发性血小板增多症(ET)患者的克隆在JAK2,CALR,或MPL基因,这些克隆在转化为急性髓细胞性白血病(AML)时通常会获得额外的突变。然而,有时在AML转化时观察到三阴性克隆的增殖.为了阐明ET向AML的克隆进化,我们分析了8例患者ET和AML转化时的配对样本.我们确定了JAK2未突变的AML克隆在AML转化时在三名患者中增殖,其中JAK2突变的克隆在ET上占优势。在两个病人中,TET2突变,但不是JAK2突变的,克隆可能是ET和转化的AML的常见起始克隆。在患有JAK2突变的ET的患者中,SMARCC2、UBR4和ZNF143而不是JAK2突变的克隆在AML转化时增殖。使用单细胞分选的CD34+/CD38-级分的精确分析表明,具有JAK2突变的ET克隆和具有TP53突变的AML克隆源自具有这些突变的常见克隆。尽管需要进一步的研究来阐明SMARCC2,UBR4和ZNF143突变在ET和AML转化的疾病进展中的生物学意义,目前的结果证明了一个共同的初始克隆参与ET和转化的AML的可能性.
    Most of essential thrombocythemia (ET) patients have the clone harboring a mutation in one of the JAK2, CALR, or MPL gene, and these clones generally acquire additional mutations at transformation to acute myeloid leukemia (AML). However, the proliferation of triple-negative clones has sometimes been observed at AML transformation. To clarify the clonal evolution of ET to AML, we analyzed paired samples at ET and AML transformation in eight patients. We identified that JAK2-unmutated AML clones proliferated at AML transformation in three patients in whom the JAK2-mutated clone was dominant at ET. In two patients, TET2-mutated, but not JAK2-mutated, clones might be common initiating clones for ET and transformed AML. In a patient with JAK2-mutated ET, SMARCC2, UBR4, and ZNF143, but not JAK2, -mutated clones proliferated at AML transformation. Precise analysis using single-cell sorted CD34+/CD38- fractions suggested that ET clone with JAK2-mutated and AML clone with TP53 mutation was derived from the common clone with these mutations. Although further study is required to clarify the biological significance of SMARCC2, UBR4, and ZNF143 mutations during disease progression of ET and AML transformation, the present results demonstrate the possibility of a common initial clone involved in both ET and transformed AML.
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  • 文章类型: Journal Article
    卵巢癌(OC)表现为以患者间和患者内异质性为特征的复杂疾病。尽管生物和遗传见解得到了增强,OC仍然是一种顽固性恶性肿瘤,生存改善最小。基于多部位采样和多谱系患者来源的异种移植物(PDX)建立策略,我们在此介绍了从组织学和分子异质性OC患者中建立的全面PDX生物样本库。匹配的PDX和患者样品的综合分析证明PDX紧密地概括了亲本肿瘤。通过利用多血统模型,我们发现,先前报道的PDX的基因组差异可能主要归因于患者内部空间异质性,而不是实质性的模型无关的基因组进化.此外,DNA损伤应答途径抑制剂(DDRi)筛选揭示了跨模型的异质性应答。在最初敏感的模型中,长时间的迭代药物暴露概括了获得性耐药性。同时,对诱导耐药(IDR)模型的询问表明,抑制的干扰素(IFN)反应和激活的Wnt/β-catenin信号传导有助于获得性DDRi耐药性。
    Ovarian cancer (OC) manifests as a complex disease characterized by inter- and intra-patient heterogeneity. Despite enhanced biological and genetic insights, OC remains a recalcitrant malignancy with minimal survival improvement. Based on multi-site sampling and a multi-lineage patient-derived xenograft (PDX) establishment strategy, we present herein the establishment of a comprehensive PDX biobank from histologically and molecularly heterogeneous OC patients. Comprehensive profiling of matched PDX and patient samples demonstrates that PDXs closely recapitulate parental tumors. By leveraging multi-lineage models, we reveal that the previously reported genomic disparities of PDX could be mainly attributed to intra-patient spatial heterogeneity instead of substantial model-independent genomic evolution. Moreover, DNA damage response pathway inhibitor (DDRi) screening uncovers heterogeneous responses across models. Prolonged iterative drug exposure recapitulates acquired drug resistance in initially sensitive models. Meanwhile, interrogation of induced drug-resistant (IDR) models reveals that suppressed interferon (IFN) response and activated Wnt/β-catenin signaling contribute to acquired DDRi drug resistance.
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  • 文章类型: Journal Article
    胰腺癌是最致命的恶性肿瘤之一,然而,关于它的前体是如何发展的,还有很多有待学习的东西。在最近的《自然》杂志上,布拉克斯顿和基曼等人。发现正常的,成人胰腺有成百上千个通过各种途径进化的胰腺癌前体。
    Pancreatic cancer is one of the most lethal malignancies, yet much remains to be learned regarding how its precursors develop. In a recent Nature publication, Braxton and Kiemen et al. found that the normal, adult pancreas harbors hundreds to thousands of pancreatic cancer precursors evolving by a variety of routes.
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