Mutations in BRIP1 confer high risk of ovarian cancer
Mutations in BRIP1 confer high risk of ovarian cancer
复制标题
DOI：
10.1038/ng.955
复制
发表时间：
2011-11-01
期刊：
影响因子：
30.8
通讯作者：
Stefansson, Kari
中科院分区：
文献类型：
--
作者：
Rafnar, Thorunn;Gudbjartsson, Daniel F.;Stefansson, Kari
在发达国家，卵巢癌比任何其他妇科恶性肿瘤导致更多的死亡。通过对457名冰岛人进行全基因组测序，确定了1600万个序列变异，并使用SNP芯片对41，675名冰岛人及其亲属进行了基因分型。检测序列变异与卵巢癌的相关性（受影响个体的N = 656）。我们在BRIP 1（FANCJ）基因中发现了一种罕见的（0.41%等位基因频率）移码突变c.2040_2041insTT，该突变导致卵巢癌风险增加（比值比（OR）= 8.13，P = 2.8 x 10（-14））。这种突变也与癌症风险增加有关，并使寿命缩短3.6年。在西班牙人群中，144名卵巢癌受试者中有2名和1，780名对照受试者中有1名出现BRIP 1的另一个移码突变c.1702_1703del（P = 0.016）。该等位基因也与乳腺癌相关（见于6/927例; P = 0.0079）。来自冰岛突变的杂合子携带者的卵巢肿瘤显示野生型等位基因的丢失，表明BRIP 1在卵巢癌中表现得像经典的肿瘤抑制基因。
Ovarian cancer causes more deaths than any other gynecologic malignancy in developed countries. Sixteen million sequence variants, identified through whole-genome sequencing of 457 Icelanders, were imputed to 41,675 Icelanders genotyped using SNP chips, as well as to their relatives. Sequence variants were tested for association with ovarian cancer (N of affected individuals = 656). We discovered a rare (0.41% allelic frequency) frameshift mutation, c.2040_2041insTT, in the BRIP1 (FANCJ) gene that confers an increase in ovarian cancer risk (odds ratio (OR) = 8.13, P = 2.8 x 10(-14)). The mutation was also associated with increased risk of cancer in general and reduced lifespan by 3.6 years. In a Spanish population, another frameshift mutation in BRIP1, c.1702_1703del, was seen in 2 out of 144 subjects with ovarian cancer and 1 out of 1,780 control subjects (P = 0.016). This allele was also associated with breast cancer (seen in 6/927 cases; P = 0.0079). Ovarian tumors from heterozygous carriers of the Icelandic mutation show loss of the wild-type allele, indicating that BRIP1 behaves like a classical tumor suppressor gene in ovarian cancer.