Common variants upstream of MLF1 at 3q25 and within CPZ at 4p16 associated with neuroblastoma.
Common variants upstream of MLF1 at 3q25 and within CPZ at 4p16 associated with neuroblastoma.
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DOI：
10.1371/journal.pgen.1006787
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发表时间：
2017-05
期刊：
影响因子：
4.5
通讯作者：
Diskin SJ
中科院分区：
文献类型：
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作者：
McDaniel LD;Conkrite KL;Chang X;Capasso M;Vaksman Z;Oldridge DA;Zachariou A;Horn M;Diamond M;Hou C;Iolascon A;Hakonarson H;Rahman N;Devoto M;Diskin SJ
神经母细胞瘤是一种发展中的交感神经系统的癌症，最常见于幼儿，约占儿科肿瘤死亡的12%。在这里，我们报告了一项全基因组关联研究（GWAS），该研究在一个发现队列或2，101例病例和4，202例欧洲血统对照中进行。我们在3q 25和4p 16上发现了两个新的关联信号，在包括1,163例病例和4,396例对照的多个独立队列中得到了稳健的复制（3q 25：rs6441201组合P = 1.2x10-11，比值比1.23，95%CI：1.16-1.31; 4p 16：rs3796727组合P = 1.26x10-12，比值比1.30，95%CI：1.21-1.40）。4p 16信号映射在羧肽酶Z（CPZ）基因内。3q 25信号位于富含精氨酸/丝氨酸的卷曲螺旋1（RSRC 1）基因和髓性白血病因子1（MLF 1）基因的上游。在rs6441201风险等位基因纯合子的神经母细胞瘤细胞中观察到MLF 1表达增加（P = 0.02），并且在神经母细胞瘤细胞中在MLF 1耗尽后观察到显著的生长抑制（P < 0.0001）。总之，我们发现CPZ内4p 16和MLF 1上游3q 25的常见DNA变异影响神经母细胞瘤的易感性，MLF 1可能在神经母细胞瘤的发生中起重要作用。神经母细胞瘤是一种发育中的交感神经系统的胚胎性肿瘤，占儿童癌症死亡的12%。大约1-2%的病例以常染色体显性方式遗传。这些家族性病例通常在ALK或PHOX 2B中携带种系突变。然而，绝大多数神经母细胞瘤似乎是偶发性的。我们正在通过一项正在进行的全基因组关联研究（GWAS）来研究散发性神经母细胞瘤。迄今为止，这项工作已经鉴定了CASC 15和CASC 14、BARD 1、LMO 1、DUSP 12、HSD 17 B12、DDX 4/IL 31 RA、HACE 1、LIN 28 B和TP 53内或上游的单核苷酸多态性（SNP），沿着染色体1q21.1处NBPF 23内的共同拷贝数变异（CNV），每种都与神经母细胞瘤高度相关。在这里，我们报告了包括3，264名神经母细胞瘤患者和8，598名对照受试者的全基因组关联研究（GWAS）。我们在3q 25和4p 16发现了两个新的关联信号（3q 25：rs6441201组合P = 1.2x10-11，比值比1.23，95%CI：1.16-1.31; 4p 16：rs3796727组合P = 1.26x10-12，比值比1.30，95%CI：1.21-1.40）。3q 25信号位于MLF 1基因的上游，4p 16信号定位于CPZ基因。我们进一步证明，在3q 25的风险等位基因纯合的神经母细胞瘤细胞表达更高水平的MLF 1和MLF 1在神经母细胞瘤细胞中的沉默导致显着的生长抑制。
Neuroblastoma is a cancer of the developing sympathetic nervous system that most commonly presents in young children and accounts for approximately 12% of pediatric oncology deaths. Here, we report on a genome-wide association study (GWAS) in a discovery cohort or 2,101 cases and 4,202 controls of European ancestry. We identify two new association signals at 3q25 and 4p16 that replicated robustly in multiple independent cohorts comprising 1,163 cases and 4,396 controls (3q25: rs6441201 combined P = 1.2x10-11, Odds Ratio 1.23, 95% CI:1.16–1.31; 4p16: rs3796727 combined P = 1.26x10-12, Odds Ratio 1.30, 95% CI: 1.21–1.40). The 4p16 signal maps within the carboxypeptidase Z (CPZ) gene. The 3q25 signal resides within the arginine/serine-rich coiled-coil 1 (RSRC1) gene and upstream of the myeloid leukemia factor 1 (MLF1) gene. Increased expression of MLF1 was observed in neuroblastoma cells homozygous for the rs6441201 risk allele (P = 0.02), and significant growth inhibition was observed upon depletion of MLF1 (P < 0.0001) in neuroblastoma cells. Taken together, we show that common DNA variants within CPZ at 4p16 and upstream of MLF1 at 3q25 influence neuroblastoma susceptibility and MLF1 likely plays an important role in neuroblastoma tumorigenesis. Neuroblastoma is an embryonal tumor of the developing sympathetic nervous system that accounts for 12% of childhood cancer deaths. Approximately 1–2% of cases are inherited in an autosomal dominant fashion. These familial cases often harbor germline mutations in ALK or PHOX2B. However, the vast majority of neuroblastomas appear to arise sporadically. We are studying sporadic neuroblastoma through an ongoing genome-wide association study (GWAS). To date, this effort has identified single nucleotide polymorphisms (SNPs) within or upstream of CASC15 and CASC14, BARD1, LMO1, DUSP12, HSD17B12, DDX4/IL31RA, HACE1, LIN28B, and TP53, along with a common copy number variation (CNV) within NBPF23 at chromosome 1q21.1, each being highly associated with neuroblastoma. Here, we report on genome-wide association study (GWAS) comprising 3,264 neuroblastoma patients and 8,598 control subjects. We identify two new association signals at 3q25 and 4p16 (3q25: rs6441201 combined P = 1.2x10-11, Odds Ratio 1.23, 95% CI:1.16–1.31; 4p16: rs3796727 combined P = 1.26x10-12, Odds Ratio 1.30, 95% CI: 1.21–1.40). The 3q25 signal resides upstream of the MLF1 gene and the 4p16 signal maps to the CPZ gene. We further demonstrate that neuroblastoma cells homozygous for the risk allele at 3q25 express higher levels of MLF1 and that silencing of MLF1 in neuroblastoma cells results in significant growth inhibition.