背景:胰腺腺癌是预后最差的癌症之一。目前基于联合化疗的治疗模式在过去十年中提高了生存率,但是这种疾病在大多数情况下仍然是致命的。需要利用对疾病分子病理学的日益理解的新疗法。尽管该疾病很少出现复发性分子改变,这些代表了开发靶向治疗的机会.然而,少数病例没有这些常见的改变。对胰腺腺癌这一子集的分子景观的描述可以揭示存在于其中的其他分子病变,这些病变可以作为治疗靶标。
方法:没有KRAS常见改变的胰腺癌亚组,TP53、CDKN2A和SMAD4已经从公开的和公开可用的胰腺癌队列中检查,以确定它们的临床和分子特征。cBioportal平台用于此评估,OncoKB知识库用于确定发现的突变的功能意义。
结果:大约5%至10%的胰腺腺癌存在,而没有作为疾病特征的常见分子改变。这些病例往往是基因组稳定的,微卫星或染色体不稳定性的患病率较低。在胰腺癌中观察到的分子改变的频率低于四种最普遍的改变。如DNA损伤反应和表观遗传修饰突变,在没有常见改变的子集中仍然观察到,并且可能是致病相关的。
结论:尽管在一组胰腺腺癌中没有最常见的胰腺癌改变,该子集具有与其他胰腺癌相似的其他频率改变.讨论了现有改变的推定靶向,可以作为靶向治疗开发的基础。
BACKGROUND: Pancreatic adenocarcinoma is one of the cancers with the worst prognosis. The current treatment paradigm based on combination chemotherapy has improved survival over the last decade, but the disease is still fatal in most cases. New therapies exploiting the increasing understanding of the molecular pathology of the disease are needed. Although the disease presents with few recurrent molecular alterations, these represent opportunities for targeted treatments to be developed. However, a minority of cases are devoid of these common alterations. A description of the molecular landscape of this sub-set of pancreatic adenocarcinoma could uncover other molecular lesions present in them that could serve as therapeutic targets.
METHODS: The sub-set of pancreatic cancers without the common alterations in KRAS, TP53, CDKN2A and SMAD4 has been examined from published and publicly available pancreatic cancer cohorts for determination of their clinical and molecular characteristics. The cBioportal platform was used for this evaluation and the OncoKB knowledgebase was used for determination of the functional significance of discovered mutations.
RESULTS: About 5% to 10% of pancreatic adenocarcinomas present without the usual molecular alterations that characterize the disease. These cases tend to be genomically stable and have low prevalence of microsatellite or chromosome instability. Molecular alterations that are observed in pancreatic cancers in lower frequencies than the four most prevalent alterations, such as DNA Damage Response and epigenetic modifier mutations, are still observed in the sub-set without the common alterations and may be pathogenically relevant.
CONCLUSIONS: Despite the absence of most frequent pancreatic cancer alterations in a sub-set of pancreatic adenocarcinomas, this sub-set possesses other alterations in frequencies similar to the rest of pancreatic cancers. Putative targeting of alterations present is discussed and can serve as the basis for targeted therapies development.