A Dominantly Inherited 5' UTR Variant Causing Methylation-Associated Silencing of BRCA1 as a Cause of Breast and Ovarian Cancer.
A Dominantly Inherited 5' UTR Variant Causing Methylation-Associated Silencing of BRCA1 as a Cause of Breast and Ovarian Cancer.
复制标题
DOI：
10.1016/j.ajhg.2018.07.002
复制
发表时间：
2018-08-02
影响因子：
9.8
通讯作者：
Newman WG
中科院分区：
文献类型：
--
作者：
Evans DGR;van Veen EM;Byers HJ;Wallace AJ;Ellingford JM;Beaman G;Santoyo-Lopez J;Aitman TJ;Eccles DM;Lalloo FI;Smith MJ;Newman WG
在有多个个体受到早发性乳腺癌和/或卵巢癌影响的家庭中，有20%的∼发现了BRCA1或BRCA2的致病变异。对额外的高渗透性基因或改变BRCA1或BRCA2的替代突变机制的广泛搜索无法解释缺失的遗传性。在这里，我们报告了一个显性遗传的5‘非编码区变异与表观遗传的BRCA1沉默相关，这是由于乳腺癌和卵巢癌患者的两个家族中的启动子高甲基化所致。用焦磷酸测序和克隆性亚硫酸氢盐测序的方法研究了乳腺癌和/或卵巢癌家系中无BRCA1或BRCA2致病变异的10个CpG二核苷酸的BRCA1启动子甲基化。对来自淋巴细胞的BRCA1进行RNA和DNA测序，以确定等位基因的表达和生殖系变异的存在。BRCA1启动子高甲基化在49个家系中有2个被鉴定出来，在这些家系中，多名女性受到3级乳腺癌或高级别浆液性卵巢癌的影响。在血液、颊粘膜和毛囊中证实了BRCA1启动子高甲基化。焦磷酸测序显示∼50%甲基化，与克隆亚硫酸氢盐测序证实的1个等位基因沉默一致。测序结果显示BRCA1基因在两个家系中均有表达缺失，并且这种表达缺失与BRCA1 5‘端非编码区杂合突变c.−107A和gt；T分离。我们的结果建立了一种机制，即家族性乳腺癌和卵巢癌是由两个独立家族中的顺式5‘非编码区变异与BRCA1启动子的表观遗传沉默相关。我们建议进行甲基化分析，以确定在没有BRCA1或BRCA2致病变异的早发性乳腺癌和/或卵巢癌患者家庭中这一机制的频率。
Pathogenic variants in BRCA1 or BRCA2 are identified in ∼20% of families with multiple individuals affected by early-onset breast and/or ovarian cancer. Extensive searches for additional highly penetrant genes or alternative mutational mechanisms altering BRCA1 or BRCA2 have not explained the missing heritability. Here, we report a dominantly inherited 5′ UTR variant associated with epigenetic BRCA1 silencing due to promoter hypermethylation in two families affected by breast and ovarian cancer. BRCA1 promoter methylation of ten CpG dinucleotides in families who are affected by breast and/or ovarian cancer but do not have germline BRCA1 or BRCA2 pathogenic variants was assessed by pyrosequencing and clonal bisulfite sequencing. RNA and DNA sequencing of BRCA1 from lymphocytes was undertaken to establish allelic expression and the presence of germline variants. BRCA1 promoter hypermethylation was identified in 2 of 49 families in which multiple women are affected by grade 3 breast cancer or high-grade serous ovarian cancer. Soma-wide BRCA1 promoter hypermethylation was confirmed in blood, buccal mucosa, and hair follicles. Pyrosequencing showed that DNA was ∼50% methylated, consistent with the silencing of one allele, which was confirmed by clonal bisulfite sequencing. RNA sequencing revealed the allelic loss of BRCA1 expression in both families and that this loss of expression segregated with the heterozygous variant c.−107A>T in the BRCA1 5′ UTR. Our results establish a mechanism whereby familial breast and ovarian cancer is caused by an in cis 5′ UTR variant associated with epigenetic silencing of the BRCA1 promoter in two independent families. We propose that methylation analyses be undertaken to establish the frequency of this mechanism in families affected by early-onset breast and/or ovarian cancer without a BRCA1 or BRCA2 pathogenic variant.
登录
查看更多内容
BRCA1表观遗传失活预测了乳腺癌和卵巢癌中基于铂的化学疗法的敏感性。
影响因子：
3.7
作者：
Stefansson OA;Villanueva A;Vidal A;Martí L;Esteller M
通讯作者：
Esteller M
DOI：
10.1089/gte.2006.0518
发表时间：
2007-09-01
期刊：
GENETIC TESTING
影响因子：
--
作者：
Frosk, Patrick;Burgess, Susan;Spriggs, Elizabeth L.
通讯作者：
Spriggs, Elizabeth L.
影响因子：
4
作者：
Morak, Monika;Ibisler, Ayseguel;Holinski-Feder, Elke
通讯作者：
Holinski-Feder, Elke
影响因子：
10.3
作者：
Esteller, M;Silva, JM;Herman, JG
通讯作者：
Herman, JG
影响因子：
4
作者：
Evans, DGR;Eccles, DM;Lalloo, F
通讯作者：
Lalloo, F