Pancreatic Ductal Adenocarcinoma (PDAC) belongs to the types of cancer with the highest lethality. It is also remarkably chemoresistant to the few available cytotoxic therapeutic options. PDAC is characterized by limited mutational heterogeneity of the known driver genes, KRAS, CDKN2A, TP53, and SMAD4, observed in both early-stage and advanced tumors. In this review, we summarize the two proposed models of genetic evolution of pancreatic cancer. The gradual or stepwise accumulated mutations model has been widely studied. On the contrary, less evidence exists on the more recent simultaneous model, according to which rapid tumor evolution is driven by the concurrent accumulation of genetic alterations. In both models, oncogenic KRAS mutations are the main initiating event. Here, we analyze the emerging topic of KRAS allelic imbalances and how it arises during tumor evolution, as it is often detected in advanced and metastatic PDAC. We also summarize recent evidence on how it affects tumor biology, metastasis, and response to therapy. To this extent, we highlight the necessity to include studies of KRAS allelic frequencies in the design of future therapeutic strategies against pancreatic cancer.
胰腺导管腺癌（PDAC）属于致死率最高的癌症类型之一，且对现有有限的细胞毒性治疗方案表现出显著的耐药性。该癌症的特征在于已知驱动基因KRAS、CDKN2A、TP53和SMAD4的突变异质性较低，这一现象在早期和晚期肿瘤中均有体现。本文综述了目前提出的两种胰腺癌基因进化模型。其中逐步累积突变模型已被广泛研究，而近期提出的同步进化模型——即基因改变同时积累驱动肿瘤快速演化——则证据相对不足。两种模型均以致癌性KRAS突变为主要起始事件。本文重点分析了KRAS等位基因失衡这一新兴议题，探讨其在肿瘤演化过程中的产生机制（常见于晚期及转移性PDAC），并综述了其对肿瘤生物学特性、转移及治疗反应影响的最新证据。在此基础上，我们强调在未来胰腺癌治疗策略设计中纳入KRAS等位基因频率研究的必要性。
Unlocking the Genetic Secrets of Pancreatic Cancer:KRASAllelic Imbalances in Tumor Evolution
肿瘤(癌症)患者之家