Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland; Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland.
Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Am J Hum Genet. 2023 Mar 2;110(3):460-474. doi: 10.1016/j.ajhg.2023.01.009. Epub 2023 Feb 10.
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.
子宫肌瘤（ULs）是常见于绝经前妇女的良性平滑肌肿瘤。MED12、HMGA2、FH 等基因的体细胞改变，以及参与 Cullin 3-RING E3 连接酶 neddylation 的基因，是相互排斥的 UL 驱动基因。已确定的易感性基因仅部分解释了 UL 的估计遗传率。在这里，我们在一个由 233614 名白种欧洲女性组成的队列中检查了 18899 个基因的失活变体，揭示了编码 SRCAP 复合物亚基的四个基因（YEATS4、ZNHIT1、DMAP1 和 ACTL6A）中的变体与 ULs 有显著关联，并且 YEATS4 和 ZNHIT1 分别显著排名第一和第二。阳性突变状态也与诊断和子宫切除术时的年龄较小有关。中度外显率的 UL 风险主要归因于影响 SRCAP 复合物的罕见非同义突变。为了更仔细地研究这种疾病表型，我们着手在我们的芬兰 UL 患者（n=860）内部样本集中识别影响 SRCAP 复合物的遗传突变。我们在一名 ACTL6A 剪接位点突变个体、两名 YEATS4 错义突变个体和四名 DMAP1 突变个体中检测到：一名剪接位点、一名无义突变和两名错义突变。这些个体有大的和/或多个 ULs，通常在早期被诊断出来，许多人有 UL 的家族史。当发现体细胞第二次打击时，ACTL6A 和 DMAP1 在肿瘤中通过体细胞突变失活，YEATS4 通过启动子超甲基化失活。在肿瘤中观察到 H2A.Z 染色减少，为种系突变的致病性提供了进一步证据。我们的研究结果确定了编码 SRCAP 复合物亚基的基因失活是中度外显率 UL 易感性的核心因素。
