肾母细胞瘤是最常见的儿童肾癌,具有遗传异质性。虽然已经确定了几个Wilms肿瘤易感性基因,有强有力的证据表明可能存在进一步的易感基因。我们的研究目的是确定Wilms肿瘤的新易感基因。
在这项外显子组测序研究中,我们分析了890例Wilms肿瘤患者的淋巴细胞DNA,包括来自49个家族性Wilms肿瘤谱系的91个受影响的个体。我们使用蛋白质截断变体优先排序方法来优先考虑潜在的疾病相关基因以进行进一步评估。我们评估了我们在334名患有其他27种儿童癌症的个体中产生的外显子组测序数据中的新易感基因,以及来自7632名患有28种成人癌症的个体的癌症基因组图谱的外显子组数据。
我们在33名儿童癌症患者中确定了宪法性癌症易感突变。在蛋白质截短变体优先级分析中具有最强信号的三个鉴定的基因是TRIM28、FBXW7和NYNRIN。33个个体中有21个在TRIM28中突变;有强烈的亲源效应,所有十种遗传突变均通过母体传播(p=0·00098)。我们还发现与罕见的Wilms肿瘤上皮亚型密切相关,16个肿瘤中有14个是上皮或上皮占优势。在患有其他儿童或成人癌症的个体中没有TRIM28突变。我们在四个患有Wilms肿瘤的个体中确定了截短的FBXW7突变,在患有横纹肌样肿瘤的儿童中确定了从头非同义的FBXW7突变。在三个患有Wilms肿瘤的个体中鉴定出NYNRIN的双等位基因截断突变,这不太可能是偶然发生的(p<0·0001)。最后,我们确定了两个从头KDM3B突变,支持KDM3B作为儿童癌症易感性基因的作用。
确定了四个新的Wilms肿瘤易感性基因-TRIM28,FBXW7,NYNRIN,和KDM3B-参与不同的生物过程,连同其他17个已知的Wilms肿瘤易感性基因,约占Wilms肿瘤病例的10%。这21个组成突变的易感基因和20个在Wilms肿瘤中体细胞突变的基因之间的重叠是有限的,由四个基因组成。我们建议所有患有Wilms肿瘤的人都应该进行基因检测,特别是,那些与上皮肾母细胞瘤应提供TRIM28基因检测。我们分析的家族性Wilms肿瘤中只有三分之一归因于已知基因,表明进一步的Wilms肿瘤易感性因素有待发现。
惠康信托基金。
Wilms tumour is the most common childhood renal cancer and is genetically heterogeneous. While several Wilms tumour predisposition genes have been identified, there is strong evidence that further predisposition genes are likely to exist. Our
study aim was to identify new predisposition genes for Wilms tumour.
In this exome sequencing
study, we analysed lymphocyte DNA from 890 individuals with Wilms tumour, including 91 affected individuals from 49 familial Wilms tumour pedigrees. We used the protein-truncating variant prioritisation method to prioritise potential disease-associated genes for further assessment. We evaluated new predisposition genes in exome sequencing data that we generated in 334 individuals with 27 other childhood cancers and in exome data from The Cancer Genome Atlas obtained from 7632 individuals with 28 adult cancers.
We identified constitutional cancer-predisposing mutations in 33 individuals with childhood cancer. The three identified genes with the strongest signal in the protein-truncating variant prioritisation analyses were TRIM28, FBXW7, and NYNRIN. 21 of 33 individuals had a mutation in TRIM28; there was a strong parent-of-origin effect, with all ten inherited mutations being maternally transmitted (p=0·00098). We also found a strong association with the rare epithelial subtype of Wilms tumour, with 14 of 16 tumours being epithelial or epithelial predominant. There were no TRIM28 mutations in individuals with other childhood or adult cancers. We identified truncating FBXW7 mutations in four individuals with Wilms tumour and a de-novo non-synonymous FBXW7 mutation in a child with a rhabdoid tumour. Biallelic truncating mutations in NYNRIN were identified in three individuals with Wilms tumour, which is highly unlikely to have occurred by chance (p<0·0001). Finally, we identified two de-novo KDM3B mutations, supporting the role of KDM3B as a childhood cancer predisposition gene.
The four new Wilms tumour predisposition genes identified-TRIM28, FBXW7, NYNRIN, and KDM3B-are involved in diverse biological processes and, together with the other 17 known Wilms tumour predisposition genes, account for about 10% of Wilms tumour cases. The overlap between these 21 constitutionally mutated predisposition genes and 20 genes somatically mutated in Wilms tumour is limited, consisting of only four genes. We recommend that all individuals with Wilms tumour should be offered genetic testing and particularly, those with epithelial Wilms tumour should be offered TRIM28 genetic testing. Only a third of the familial Wilms tumour clusters we analysed were attributable to known genes, indicating that further Wilms tumour predisposition factors await discovery.
Wellcome Trust.