Qi Hongjian, Dong Chengliang, Chung Wendy K, Wang Kai, Shen Yufeng
Department of Applied Physics and Applied Mathematics, Columbia University, New York, New York.
Department of Systems Biology, Columbia University Medical Center, New York, New York.
Hum Mutat. 2016 Oct;37(10):1042-50. doi: 10.1002/humu.23040. Epub 2016 Aug 23.
Cancer and developmental disorders (DDs) share dysregulated cellular processes such as proliferation and differentiation. There are well-known genes implicated in both in cancer and DDs. In this study, we aim to quantify this genetic connection using publicly available data. We found that among DD patients, germline damaging de novo variants are more enriched in cancer driver genes than non-drivers. We estimate that cancer driver genes comprise about a third of DD risk genes. Additionally, de novo likely-gene-disrupting variants are more enriched in tumor suppressors, and about 40% of implicated de novo damaging missense variants are located in cancer somatic mutation hotspots, indicating that many genes have a similar mode of action in cancer and DDs. Our results suggest that we can view tumors as natural laboratories for assessing the deleterious effects of mutations that are applicable to germline variants and identification of causal genes and variants in DDs.
癌症和发育障碍（DDs）存在细胞增殖和分化等细胞过程失调的情况。有一些知名基因与癌症和发育障碍都有关联。在本研究中，我们旨在利用公开可用的数据量化这种遗传联系。我们发现，在发育障碍患者中，种系有害新生变异在癌症驱动基因中比在非驱动基因中更为富集。我们估计癌症驱动基因约占发育障碍风险基因的三分之一。此外，新生的可能破坏基因的变异在肿瘤抑制基因中更为富集，并且约40%的相关新生有害错义变异位于癌症体细胞突变热点区域，这表明许多基因在癌症和发育障碍中具有相似的作用模式。我们的结果表明，我们可以将肿瘤视为天然实验室，用于评估适用于种系变异的突变的有害影响，并识别发育障碍中的致病基因和变异。
