Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Department of Nutrition, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
HGG Adv. 2023 Apr 24;4(3):100199. doi: 10.1016/j.xhgg.2023.100199. eCollection 2023 Jul 13.
Cancer and autism spectrum disorder/developmental delay (ASD/DD) are two common clinical phenotypes in individuals with germline variants ( hamartoma tumor syndrome, PHTS). Burgeoning studies have shown that genomic and metabolomic factors may act as modifiers of ASD/DD versus cancer in PHTS. Recently, we showed copy number variations to be associated with ASD/DD versus cancer in these PHTS individuals. We also found that mitochondrial complex II variants occurring in 10% of PHTS individuals modify breast cancer risk and thyroid cancer histology. These studies suggest that mitochondrial pathways could act as important factors in PHTS phenotype development. However, the mitochondrial genome (mtDNA) has never been systematically studied in PHTS. We therefore investigated the mtDNA landscape extracted from whole-genome sequencing data from 498 PHTS individuals, including 164 with ASD/DD (PHTS-onlyASD/DD), 184 with cancer (PHTS-onlyCancer), 132 with neither ASD/DD nor cancer (PHTS-neither), and 18 with both ASD/DD and cancer (PHTS-ASDCancer). We demonstrate that PHTS-onlyASD/DD has significantly higher mtDNA copy number than PHTS-onlyCancer group (p = 9.2 × 10 in all samples; p = 4.2 × 10 in the H haplogroup). PHTS-neither group has significantly higher mtDNA variant burden than PHTS-ASDCancer group (p = 4.6 × 10); the PHTS-noCancer group (PHTS-onlyASD/DD and PHTS-neither groups) also shows higher variant burden than the PHTS-Cancer group (PHTS-onlyCancer and PHTS-ASD/Cancer groups; p = 3.3 × 10). Our study implicates the mtDNA as a modifier of ASD/DD versus cancer phenotype development in PHTS.
癌症和自闭症谱系障碍/发育迟缓（ASD/DD）是具有种系变异（错构瘤肿瘤综合征，PHTS）个体的两种常见临床表型。越来越多的研究表明，基因组和代谢组学因素可能是 PHTS 中 ASD/DD 与癌症的修饰因子。最近，我们发现 PHTS 个体中的拷贝数变异与 ASD/DD 与癌症有关。我们还发现，10%的 PHTS 个体中存在的线粒体复合物 II 变异可改变乳腺癌风险和甲状腺癌组织学。这些研究表明，线粒体途径可能是 PHTS 表型发育的重要因素。然而，线粒体基因组（mtDNA）从未在 PHTS 中进行过系统研究。因此，我们从 498 名 PHTS 个体的全基因组测序数据中提取 mtDNA 图谱进行研究，其中包括 164 名患有 ASD/DD（PHTS-onlyASD/DD）、184 名患有癌症（PHTS-onlyCancer）、132 名既没有 ASD/DD 也没有癌症（PHTS-neither）和 18 名同时患有 ASD/DD 和癌症（PHTS-ASDCancer）。我们证明，与 PHTS-onlyCancer 组相比，PHTS-onlyASD/DD 组的 mtDNA 拷贝数显著更高（所有样本中 p = 9.2×10；H 单倍群中 p = 4.2×10）。与 PHTS-ASDCancer 组相比，PHTS-neither 组的 mtDNA 变异负担显著更高（p = 4.6×10）；与 PHTS-Cancer 组相比，PHTS-noCancer 组（PHTS-onlyASD/DD 和 PHTS-neither 组）也显示出更高的变异负担（p = 3.3×10）。我们的研究表明，mtDNA 是 PHTS 中 ASD/DD 与癌症表型发育的修饰因子。
