Inserm UMR 1037- University of Toulouse III, Cancer Research Center of Toulouse (CRCT), BP 84225, CHU Rangeuil, Toulouse 31432, Cedex 4, France.
Curr Genomics. 2011 Mar;12(1):15-24. doi: 10.2174/138920211794520132.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide. Despite significant progresses in the last decades, the origin of this cancer remains unclear and no efficient therapy exists. PDAC does not arise de novo: three remarkable different types of pancreatic lesions can evolve towards pancreatic cancer. These precursor lesions include: Pancreatic intraepithelial neoplasia (PanIN) that are microscopic lesions of the pancreas, Intraductal Papillary Mucinous Neoplasms (IPMN) and Mucinous Cystic Neoplasms (MCN) that are both macroscopic lesions. However, the cellular origin of these lesions is still a matter of debate. Classically, neoplasm initiation or progression is driven by several genetic and epigenetic alterations. The aim of this review is to assemble the current information on genetic mutations and epigenetic disorders that affect genes during pancreatic carcinogenesis. We will further discuss the interest of the genetic and epigenetic alterations for the diagnosis and prognosis of PDAC. Large genetic alterations (chromosomal deletion/amplification) and single point mutations are well described for carcinogenesis inducers. Mutations classically occur within key regions of the genome. Consequences are various and include activation of mitogenic pathways or silencing of apoptotic processes. Alterations of K-RAS, P16 and DPC4 genes are frequently observed in PDAC samples and have been described to arise gradually during carcinogenesis. DNA methylation is an epigenetic process involved in imprinting and X chromosome inactivation. Alteration of DNA methylation patterns leads to deregulation of gene expression, in the absence of mutation. Both genetic and epigenetic events influence genes and non-coding RNA expression, with dramatic effects on proliferation, survival and invasion. Besides improvement in our fundamental understanding of PDAC development, highlighting the molecular alterations that occur in pancreatic carcinogenesis could provide new clinical tools for early diagnosis of PDAC and the molecular basis for the development of new effective therapies.
胰腺导管腺癌 (PDAC) 是全球最致命的癌症之一。尽管在过去几十年中取得了重大进展，但这种癌症的起源仍不清楚，也没有有效的治疗方法。PDAC 并非全新出现：三种不同类型的胰腺病变可发展为胰腺癌。这些前体病变包括：胰腺上皮内瘤变 (PanIN)，这是胰腺的微观病变；导管内乳头状黏液性肿瘤 (IPMN) 和黏液性囊腺瘤 (MCN)，这两者都是宏观病变。然而，这些病变的细胞起源仍存在争议。传统上，肿瘤的发生或进展是由几种遗传和表观遗传改变驱动的。本综述的目的是汇集目前关于影响胰腺癌变过程中基因的遗传突变和表观遗传紊乱的信息。我们将进一步讨论遗传和表观遗传改变对 PDAC 的诊断和预后的意义。大的遗传改变（染色体缺失/扩增）和单点突变已被很好地描述为致癌剂诱导的改变。突变通常发生在基因组的关键区域内。其后果多种多样，包括激活有丝分裂途径或沉默凋亡过程。K-RAS、P16 和 DPC4 基因的突变在 PDAC 样本中经常观察到，并已被描述为在癌变过程中逐渐出现。DNA 甲基化是一种参与印迹和 X 染色体失活的表观遗传过程。DNA 甲基化模式的改变导致基因表达的失调，而没有突变。遗传和表观遗传事件都影响基因和非编码 RNA 的表达，对增殖、存活和侵袭有巨大影响。除了提高我们对 PDAC 发展的基本理解外，强调胰腺癌变过程中发生的分子改变可能为 PDAC 的早期诊断提供新的临床工具，并为开发新的有效治疗方法提供分子基础。
