PO.TB09.02 · 肿瘤生物学
从正常前列腺上皮经高级别PIN到癌的克隆进化的遗传学见解
Genetic insights into clonal evolution from normal prostate epithelium to cancer via HighGradePIN
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景 前列腺癌（PC）是发达国家最常见的癌症之一，其发病率仍在上升。大多数PC被认为起源于高级别前列腺上皮内瘤变（HGPIN），这是一种公认的前驱病变。然而，HGPIN的遗传学图谱及其与正常前列腺上皮（NPE）和PC的关系仍有待充分探索。为阐明PC发生所依赖的早期遗传事件和克隆动态，我们对NPE、HGPIN和PC进行了全面的基因组分析。
方法 我们采用激光捕获显微切割（LMD）获取PC（n = 49）、HGPIN（n = 77）和NPE（n = 393）样本，并进行全外显子组测序（WES）。我们使用高精度测序平台Nanoseq测量了5例患者正常前列腺上皮的全基因组突变负荷。
结果 在NanoSeq中，393个NPE样本中共检出10,047个SNV和插入缺失，据此估计NPE的突变累积率为0.205个突变/年/外显子。若干突变在NPE与HGPIN之间以及HGPIN与PC之间共享，提示存在共同的克隆起源。致病性FOXA1突变在HGPIN和PC中均频繁检出。尽管在NPE中也发现致病性FOXA1突变，但它们与HGPIN或PC中的突变不重叠，因此可能代表独立的突变事件。在一个病例中，空间上不同的多灶性癌表现出多个FOXA1突变，每个突变均与相应的邻近HGPIN共享。在另外的病例中，12个突变在PCa、HGPIN和NPE样本中共享，尽管其中未检出已知的驱动突变。这些发现提示PCa可能起源于组织学上表现正常的克隆，这些克隆经HGPIN进展为PC。对这些样本的系统发育分析显示，PC和HGPIN大约在45年前从一个共同的正常祖先分化而来。
结论 我们成功刻画了组织学上表现正常的前列腺上皮中的体细胞突变和CNV，在某些病例中这些突变与HGPIN和邻近PC共享。共享体细胞突变的存在支持从正常上皮到前驱病变再到浸润性癌的克隆连续体。这些见解增进了我们对前列腺癌早期发生的理解，并凸显了早期检测和干预的潜在途径。
查看英文原文 English abstract
Background Prostate cancer (PC) is one of the most prevalent cancers in the developed world, where its incidence is still increasing. Most PCs are thought to arise from high-grade prostatic intraepithelial neoplasia (HGPIN), a well-recognized precursor lesion. However, the genetic landscape of HGPIN and its relationship with normal prostate epithelium (NPE) and PC remains to be fully explored. To clarify the early genetic events and clonal dynamics underlying PC development, we performed comprehensive genomic profiling of NPE, HGPIN, and PC.
Methods We performed laser-capture microdissection (LMD) to obtain samples from PC (n = 49), HGPIN (n = 77), and NEP (n =393), which were subjected to whole-exome sequencing (WES). We measured genome-wide mutation burdens in normal prostate epithelium from 5 patients using a highly accurate sequencing platform, Nanoseq.
Results In NanoSeq, a total of 10,047 SNVs & indels were detected across 393 NPE samples, based on which the mutation accumulation rate in NPE was estimated to be 0.205 mutations/year/exon. Several mutations were shared between NPE and HGPIN as well as between HGPIN and PC, suggesting a common clonal origin. Pathogenic FOXA1 mutations were frequently detected in both HGPIN and PC. Although pathogenic FOXA1 mutations were also found in NPE, they did not overlapped with those in HGPIN or PC and therefore, likely represent independent mutational events. In one case, spatially distinct multifocal cancers exhibited multiple FOXA1 mutations, each of which was shared with corresponding adjacent HGPIN. In additional cases, 12 mutations were shared across PCa, HGPIN, and NPE samples, although no known driver mutations were detected therein. These findings suggest that PCa may arise from clones with apparently normal histology, which progress through HGPIN to PC. Phylogenetic analysis of these samples revealed that PC and HGPIN diverged from a common normal ancestor approximately 45 years earlier.
Conclusions We successfully characterized somatic mutations and CNVs in apparently normal prostate epithelium, which were shared between HGPIN and adjacent PC in some cases. The presence of shared somatic mutations supports a clonal continuum from normal epithelium to precursor lesions and invasive carcinoma. These insights enhance our understanding of early prostate carcinogenesis and highlight potential avenues for early detection and intervention.
利益披露 Disclosure
K. Hishiki, None.