子宫平滑肌瘤(ULs)是良性平滑肌肿瘤,常见于绝经前妇女。MED12、HMGA2、FH、编码SRCAP复合体亚基的基因,与Cullin3-RINGE3连接酶neddylation相关的基因是互斥的UL驱动因素。已建立的易感基因仅部分解释了平滑肌瘤的估计遗传性。这里,我们在233,614名欧洲白人女性的队列中检查了18,899个基因的功能缺失变异,揭示了四个编码SRCAP复杂亚基(YEATS4,ZNHIT1,DMAP1和ACTL6A)的基因中的变异,与ULs具有显着关联,YEATS4和ZNHIT1惊人地排名第一和第二,分别。阳性突变状态也与诊断和子宫切除术时年龄较小有关。中度外显率UL风险主要归因于影响SRCAP复合物的罕见非同义突变。为了更仔细地检查这种疾病的表型,我们着手在我们的芬兰ULs个体的内部样本收集中鉴定影响SRCAP复合体的遗传突变(n=860).我们检测到一个具有ACTL6A剪接位点突变的个体,两个有YEATS4错义突变的个体,和四个有DMAP1突变的个体:一个剪接位点,一个废话,和两个错觉变体。这些人具有大的和/或多个UL,通常在很小的时候就被诊断出来,许多人都有ULS的家族史。当发现第二次身体撞击时,ACTL6A和DMAP1在肿瘤中通过体细胞突变沉默,YEATS4通过启动子超甲基化沉默。H2A减少。在肿瘤中观察到Z染色,为种系突变的致病性质提供了进一步的证据。我们的结果确定了编码SRCAP复杂亚基的基因的失活是中度外显率UL易感性的主要原因。
Uterine leiomyomas (ULs) are benign smooth muscle tumors that are common in premenopausal women. Somatic alterations in MED12, HMGA2, FH, genes encoding subunits of the SRCAP complex, and genes involved in Cullin 3-RING E3 ligase neddylation are mutually exclusive UL drivers. Established predisposition genes explain only partially the estimated heritability of leiomyomas. Here, we examined loss-of-function variants across 18,899 genes in a cohort of 233,614 White European women, revealing variants in four genes encoding SRCAP complex subunits (YEATS4, ZNHIT1, DMAP1, and ACTL6A) with a significant association to ULs, and YEATS4 and ZNHIT1 strikingly rank first and second, respectively. Positive mutation status was also associated with younger age at diagnosis and hysterectomy. Moderate-penetrance UL risk was largely attributed to rare non-synonymous mutations affecting the SRCAP complex. To examine this disease phenotype more closely, we set out to identify inherited mutations affecting the SRCAP complex in our in-house sample collection of Finnish individuals with ULs (n = 860). We detected one individual with an ACTL6A splice-site mutation, two individuals with a YEATS4 missense mutation, and four individuals with DMAP1 mutations: one splice-site, one nonsense, and two missense variants. These individuals had large and/or multiple ULs, were often diagnosed at an early age, and many had family history of ULs. When a somatic second hit was found, ACTL6A and DMAP1 were silenced in tumors by somatic mutation and YEATS4 by promoter hypermethylation. Decreased H2A.Z staining was observed in the tumors, providing further evidence for the pathogenic nature of the germline mutations. Our results establish inactivation of genes encoding SRCAP complex subunits as a central contributor to moderate-penetrance UL predisposition.