Molecular aspects of gastrinoma

与大多数常见的腺癌（胰腺、胃、结肠等）相比，常见的致癌基因（ras、c-fos、myc等）或常见的抑癌基因（视网膜母细胞瘤、p53等）在大多数胰腺内分泌肿瘤的发病或进展中并不起突出作用。因此，它们的分子发病机制在很大程度上是未知的。此外，与大多数常见肿瘤相比，pet的常规组织学特征并不能预测其生物学行为。由于这些原因，由于缺乏预后工具，这些患者的长期管理是困难的。此外，这些肿瘤具有非内分泌肿瘤所不具备的功能特征，对这些特征的分子决定因素所知甚少。胃原质瘤患者的长期前瞻性研究是研究和开发可能的预后分子参数的一个很好的模型，因为长期随访可以识别具有侵袭性病程的肿瘤患者，从而允许分子临床相关性，否则由于某些肿瘤的缓慢生长模式而难以实现。我们之前的研究表明MEN1基因、p16INK4a和HER2/neu经常出现异常，但这些异常要么不能预测攻击行为，要么预测能力较弱。我们最近又进行了一项与肿瘤生物活性相关的研究。本研究证实了分泌素受体存在于所有胃泌素瘤中，并评估了它们的表达水平，以及一种分泌素受体变异，该变异被报道为显性阴性突变，其在胰腺癌中的表达被报道与恶性行为相关。我们的分析表明，该变异存在于所有肿瘤中，但其表达水平与分泌素激发试验结果的相关性没有提供证据表明它在这些胃泌素瘤中以显性阴性模式发挥作用，也没有证据表明它的存在可能解释了其他人先前提出的分泌素试验阴性。此外，其表达水平和分泌素受体本身都与恶性行为无关。这些研究表明，无论是变异还是分泌素受体的评估都不是一个有用的预测因素。

In contrast to most common adenocarcinonomas (pancreas, gastric, colon, etc), common oncogenes (ras, c-fos, myc, etc) or common tumor suppressor genes (retinoblastoma, p53, etc) do not play a prominent role in the pathogenesis or progression of most pancreatic endocrine tumors. Therefore their molecular pathogenesis is largely unknown. Furthermore, routine histological features of PETs, in contrast to most common tumors, are not predictive of their biological behavior. For these reason the long term management of these patients is difficult because of lack of prognostic tools. In addition these tumors have functional features that nonendocrine tumors do not possess and little is known of the molecular determinants of these. The longterm prospective study of gastrinoma patients is a good model to study and develop possible prognostic molecular parameters because the long term follow-up allows the identification of patients with tumors that pursue an aggressive course allowing molecular clinical correlations that are otherwise difficult because of the slow growth patterns of some of these tumors. Previous studies by us have demonstrated frequent abnormalities in the MEN1 gene, p16INK4a and HER2/neu but these abnormalities were either not predictive of aggressive behavior or weakly predictive.We have performed one additional recent study related to tumoral biological ativity. This study demonstrated the presence of secretin receptors on all gastrinomas and assessed the level of their expression as well as a secretin receptor variant that is reported to function as a dominant negative mutant and its expression in pancreatic cancers is reported to correlate with malignant behavior. Our analysis demonstrated the variant was present in all tumors but correlation of its level of expression with results of the secretin provocative test provided no evidence it was functioning in a dominant negative pattern in these gastrinomas, nor that its presence might account for a negative secretin test as previous proposed by others. Furthermore, neither its level of expression nor of the secretin receptor itself correlated with malignant behavior.These studies showed the assessment of neither the variant or the secretin receptor would be a useful predictive factor.