Background:Pancreatic cancer is frequently identified as the cancer type with the shortest probable survival time after diagnosis, and efforts to develop successful treatments have had a very limited impact in the clinic. One reason for the limited therapeutic options is the lack of appealing drug targets. The great majority of pancreatic cancers are classified as Pancreatic Ductal Adenocarcinoma (PDAC), in which the genetic landscape is dominated by four genes:KRAS,TP53,CDKN2A, andSMAD4. However, despite extensive knowledge of these genetic drivers, the development of effective therapies has seen only very limited success.Methods: Existing evidence indicates that mutations in the tumour suppressor genePTENare uncommon in PDAC (<10% cases). However, the loss of PTEN function through non-genetic mechanisms may be much more common and have a strong impact. We therefore summarise and review a large body of immunohistochemical studies that address the loss of PTEN in PDAC as well as a smaller number of studies addressing other implicated proteins, including KDM6A and ARID1A.Results: These studies show some loss of PTEN protein in more than half of PDAC cases. Furthermore, although genetic changes in genes including KDM6A/UTX and ARID1A are also uncommon, reduced expression of their encoded proteins is observed in many, perhaps most, cases of PDAC.Conclusions: These analyses, which go beyond genetics, highlight the broader set of cellular functions that are dysregulated in many pancreatic cancers and provide broader opportunities for treatment strategies. This review highlights the emerging importance of other drivers in PDAC, which are less well-studied in this context.
背景：胰腺癌常被认定为诊断后预期生存期最短的癌症类型，开发有效治疗方法的努力在临床上影响甚微。治疗选择有限的原因之一是缺乏有吸引力的药物靶点。绝大多数胰腺癌被归类为胰腺导管腺癌（PDAC），其遗传图谱主要由四个基因主导：KRAS、TP53、CDKN2A和SMAD4。然而，尽管对这些遗传驱动因素有广泛了解，有效疗法的开发却收效甚微。 方法：现有证据表明，肿瘤抑制基因PTEN的突变在PDAC中并不常见（<10%的病例）。然而，通过非遗传机制导致PTEN功能丧失的情况可能更为普遍，且影响重大。因此，我们总结并回顾了大量关于PDAC中PTEN缺失的免疫组织化学研究，以及少量涉及其他相关蛋白（包括KDM6A和ARID1A）的研究。 结果：这些研究表明，超过一半的PDAC病例中存在PTEN蛋白的部分缺失。此外，尽管包括KDM6A/UTX和ARID1A在内的基因遗传变化也不常见，但在许多（可能是大多数）PDAC病例中观察到其编码蛋白的表达降低。 结论：这些超越遗传学范畴的分析，突显了在许多胰腺癌中失调的更广泛的细胞功能，并为治疗策略提供了更广阔的机会。本综述强调了PDAC中其他驱动因素日益凸显的重要性，这些因素在此背景下研究较少。
肿瘤(癌症)患者之家