Autism Linked to Increased Oncogene Mutations but Decreased Cancer Rate.
Autism Linked to Increased Oncogene Mutations but Decreased Cancer Rate.
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DOI：
10.1371/journal.pone.0149041
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Bassuk AG
中科院分区：
文献类型：
--
作者：
Darbro BW;Singh R;Zimmerman MB;Mahajan VB;Bassuk AG
自闭症谱系障碍（ASD）是许多单基因遗传性癌症综合征的一个表型方面。癌症基因对自闭症表型的多效性效应可能导致肿瘤药物的重新利用，以治疗这种目前没有治疗方法的日益普遍的神经发育疾病。为了探索这一假设，我们试图发现自闭症患者是否更经常在肿瘤抑制基因和癌基因中具有罕见的编码，单核苷酸变异，以及自闭症患者是否更经常被诊断为肿瘤。将来自ARRA自闭症测序协作组的外显子组测序数据与来自外显子组变体服务器数据库的对照组的数据进行比较，揭示了癌基因内的罕见编码变体在ARRA ASD组中富集（p<1.0x10-8）。相比之下，变体在肿瘤抑制基因中没有显著富集。从表型来看，患有ASD的儿童和成人表现出对癌症的保护作用，频率为1.3%比3.9%（p<0.001），但保护作用随着年龄的增长而减弱。ASD患者与对照组相比，肿瘤的优势比为0.06（95% CI：0.02，0.19; p<0.0001），0至14岁年龄组; 0.35（95% CI：0.14，0.87; p = 0.024），15 - 29岁年龄组; 0.41（95% CI：0.15，1.17; p = 0.095）; 55岁及以上人群为0.49（95% CI：0.14，1.74; p = 0.267）。雄性和雌性均表现出保护作用。这些发现表明，细胞增殖的缺陷和潜在的衰老可能会影响自闭症和肿瘤，并且已经批准的靶向致癌途径的药物也可能对治疗自闭症具有治疗价值。
Autism spectrum disorder (ASD) is one phenotypic aspect of many monogenic, hereditary cancer syndromes. Pleiotropic effects of cancer genes on the autism phenotype could lead to repurposing of oncology medications to treat this increasingly prevalent neurodevelopmental condition for which there is currently no treatment. To explore this hypothesis we sought to discover whether autistic patients more often have rare coding, single-nucleotide variants within tumor suppressor and oncogenes and whether autistic patients are more often diagnosed with neoplasms. Exome-sequencing data from the ARRA Autism Sequencing Collaboration was compared to that of a control cohort from the Exome Variant Server database revealing that rare, coding variants within oncogenes were enriched for in the ARRA ASD cohort (p<1.0x10-8). In contrast, variants were not significantly enriched in tumor suppressor genes. Phenotypically, children and adults with ASD exhibited a protective effect against cancer, with a frequency of 1.3% vs. 3.9% (p<0.001), but the protective effect decreased with age. The odds ratio of neoplasm for those with ASD relative to controls was 0.06 (95% CI: 0.02, 0.19; p<0.0001) in the 0 to 14 age group; 0.35 (95% CI: 0.14, 0.87; p = 0.024) in the 15 to 29 age group; 0.41 (95% CI: 0.15, 1.17; p = 0.095) in the 30 to 54 age group; and 0.49 (95% CI: 0.14, 1.74; p = 0.267) in those 55 and older. Both males and females demonstrated the protective effect. These findings suggest that defects in cellular proliferation, and potentially senescence, might influence both autism and neoplasm, and already approved drugs targeting oncogenic pathways might also have therapeutic value for treating autism.