Molecular aspects of gastrinoma

与大多数常见的腺癌（胰腺、胃、结肠等）相反，常见的癌基因（ras、c-fos、myc等）或常见的肿瘤抑制基因（视网膜母细胞瘤、p53等）在大多数胰腺内分泌肿瘤的发病机制或进展中不起显著作用。因此，其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的常规组织学特征不能预测其生物学行为。由于这些原因，这些患者的长期管理是困难的，因为缺乏预后工具。此外，这些肿瘤具有非内分泌肿瘤所不具备的功能特征，并且对其分子决定因素知之甚少。胃泌素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良好模型，因为长期随访允许识别患有追求侵袭性过程的肿瘤的患者，允许分子临床相关性，否则由于这些肿瘤中的一些肿瘤的缓慢生长模式而难以实现。 我们以前的研究已经证明了MEN 1基因，p16 INK 4a和HER 2/neu的频繁异常，但这些异常要么不能预测攻击行为，要么预测能力很弱。这项研究证明了所有胃泌素瘤上都存在分泌素受体，并评估了它们的表达水平以及一种分泌素受体变体，据报道该变体具有显性负突变的功能，并且据报道其在胰腺癌中的表达与恶性行为相关。我们的分析表明，该变异体存在于所有肿瘤中，但其表达水平与促胰液素激发试验结果的相关性没有提供证据表明其在这些胃泌素瘤中以显性阴性模式发挥作用，也没有证据表明其存在可能解释了先前由其他人提出的阴性促胰液素试验。此外，它的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，对变异体或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.