Next-generation sequencing has enabled patient selection for targeted drugs, some of which have shown remarkable efficacy in cancers that have the cognate molecular signatures. Intriguingly, rapidly emerging data indicate that altered genes representing oncogenic drivers can also be found in sporadic non-malignant conditions, some of which have negligible and/or low potential for transformation to cancer. For instance, activating KRAS mutations are discerned in endometriosis and in brain arteriovenous malformations, inactivating TP53 tumor suppressor mutations in rheumatoid arthritis synovium, and AKT, MAPK, and AMPK pathway gene alterations in the brains of Alzheimer's disease patients. Furthermore, these types of alterations may also characterize hereditary conditions that result in diverse disabilities and that are associated with a range of lifetime susceptibility to the development of cancer, varying from near universal to no elevated risk. Very recently, the repurposing of targeted cancer drugs for non-malignant conditions that are associated with these genomic alterations has yielded therapeutic successes. For instance, the phenotypic manifestations of CLOVES syndrome, which is characterized by tissue overgrowth and complex vascular anomalies that result from the activation of PIK3CA mutations, can be ameliorated by the PIK3CA inhibitor alpelisib, which was developed and approved for breast cancer. In this review, we discuss the profound implications of finding molecular alterations in non-malignant conditions that are indistinguishable from those driving cancers, with respect to our understanding of the genomic basis of medicine, the potential confounding effects in early cancer detection that relies on sensitive blood tests for oncogenic mutations, and the possibility of reverse repurposing drugs that are used in oncology in order to ameliorate non-malignant illnesses and/or to prevent the emergence of cancer.

中文翻译：

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非恶性条件下癌症基因的悖论：对精准医学的影响。


下一代测序使患者能够选择靶向药物，其中一些药物在具有同源分子特征的癌症中显示出显着的疗效。有趣的是，迅速出现的数据表明，代表致癌驱动因素的改变基因也可以在散发的非恶性疾病中发现，其中一些转化为癌症的可能性可以忽略不计和/或很低。例如，在子宫内膜异位症和脑动静脉畸形中发现激活的 KRAS 突变，在类风湿性关节炎滑膜中发现失活的 TP53 肿瘤抑制突变，以及在阿尔茨海默病患者的大脑中发现 AKT、MAPK 和 AMPK 通路基因改变。此外，这些类型的改变也可能是导致多种残疾的遗传性疾病的特征，并且与终生罹患癌症的一系列易感性相关，从几乎普遍存在到不增加风险。最近，针对与这些基因组改变相关的非恶性疾病的靶向癌症药物的重新利用已经取得了治疗成功。例如，CLOVES 综合征的表型表现是由于 PIK3CA 突变激活导致的组织过度生长和复杂的血管异常，可以通过 PIK3CA 抑制剂 alpelisib 得到改善，该抑制剂是为乳腺癌开发和批准的。 在这篇综述中，我们讨论了在非恶性疾病中发现与癌症驱动因素无法区分的分子改变的深远影响，这涉及我们对医学基因组基础的理解，依赖于敏感的早期癌症检测的潜在混杂效应。血液检测致癌突变，以及逆转肿瘤学中使用的药物的可能性，以改善非恶性疾病和/或预防癌症的出现。