National Clinical Research Center for Geriatric Disorders, Department of Geriatrics, Xiangya Hospital, Central South University, 87 #, Xiangya Road, Changsha, 410008, Hunan, China.
Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
J Mol Med (Berl). 2020 Dec;98(12):1701-1712. doi: 10.1007/s00109-020-01991-y. Epub 2020 Oct 12.
Epidemiological studies have shown an increased prevalence of cancer in some patients with neurodevelopmental disorder (NDD); however, the genetic mechanisms regarding how cancer-related genes (CRGs) contribute to NDD remain unclear. We performed bioinformatic analyses on 219 CRGs from OMIM and de novo mutations (DNMs) from 16,498 patients with different NDDs and 3391 controls. Our results showed that autism spectrum disorder, undiagnosed neurodevelopmental disorder, congenital heart disease and intellectual disability, but not epileptic encephalopathy and schizophrenia, harboured significantly more putative functional DNMs in CRGs, compared with controls, providing genetic evidence supporting previous epidemiological surveys. We further detected 26 CRGs with recurrent putative functional DNMs that showed high expression in the human brain during the prenatal stage and in non-brain organs in adults. The proteins coded by the 26 CRGs and known NDD candidate genes formed a functional network that is involved in brain development and tumorigenesis. Overall, we proposed 39 cancer-targeting drugs that could be investigated for treating patients with NDD, which would be potentially cost-effective. In conclusion, DNMs contribute to specific NDDs and there may be a shared genetic basis between NDDs and cancer, highlighting the importance of considering cancer-targeting drugs with potential curative effects in patients with NDDs. KEY MESSAGES: • The contribution of DNMs in NDD is consistent with epidemiological surveys. • We highlighted 26 CRGs, including nine genes with more than five functional DNMs. • Specific expression patterns underlie the genetic mechanism of CRGs in NDD. • Specific functional networks underlie the genetic mechanism of CRGs in NDD. • The shared genetic aetiology suggests potential mutual treatment strategies.
流行病学研究表明，一些神经发育障碍（NDD）患者的癌症患病率增加；然而，癌症相关基因（CRGs）如何导致 NDD 的遗传机制尚不清楚。我们对 OMIM 中的 219 个 CRGs 和来自 16498 名不同 NDD 患者和 3391 名对照的新生突变（DNMs）进行了生物信息学分析。我们的结果表明，自闭症谱系障碍、未确诊的神经发育障碍、先天性心脏病和智力障碍，但不是癫痫性脑病和精神分裂症，与对照相比，CRGs 中存在更多潜在的功能性 DNMs，这为先前的流行病学调查提供了遗传证据。我们进一步检测到 26 个具有高表达的 CRGs，这些基因在人类大脑的产前阶段和成人的非脑器官中都有表达。由 26 个 CRGs 和已知的 NDD 候选基因编码的蛋白质形成了一个功能网络，该网络参与大脑发育和肿瘤发生。总体而言，我们提出了 39 种可能针对癌症的靶向药物，可用于治疗 NDD 患者，这可能具有成本效益。总之，DNMs 导致特定的 NDD，NDD 和癌症之间可能存在共同的遗传基础，这强调了在 NDD 患者中考虑具有潜在疗效的癌症靶向药物的重要性。关键信息：
DNM 在 NDD 中的作用与流行病学调查一致。
我们强调了 26 个 CRGs，包括 9 个具有超过 5 个功能性 DNM 的基因。
特定的表达模式为 CRGs 在 NDD 中的遗传机制提供了基础。
特定的功能网络为 CRGs 在 NDD 中的遗传机制提供了基础。
共同的遗传病因学表明可能存在相互治疗策略。
