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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非恶性疾病中癌症基因的悖论：对精密医学的启示。

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相关分子特征的癌症中显示出显着的功效。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偶发的非恶性疾病中发现，其中一些具有可忽略的和/或低的转化为癌症的潜力。例如，在子宫内膜异位症和脑动静脉畸形中识别出激活的KRAS突变，使类风湿性关节炎滑膜中的TP53肿瘤抑制子突变以及阿尔茨海默氏病患者的大脑中的AKT，MAPK和AMPK途径基因改变失活。此外，这些类型的改变也可能表征遗传病，导致多种多样的残疾，并且与癌症发展的终生敏感性相关，从近乎普遍到无升高风险。最近，针对与这些基因组改变有关的非恶性疾病的靶向癌症药物的重新利用已获得治疗成功。例如，可以通过PIK3CA抑制剂alpelisib来改善CLOVES综合征的表型表现，该症状以组织过度生长和由PIK3CA突变的激活引起的复杂血管异常为特征，该抑制剂已经开发并被批准用于乳腺癌。在这篇评论中