Unidad de Cáncer Familiar, Servicio de Oncología Médica, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Hospital Universitario Central de Asturias (HUCA), Calle de Celestino Villamil, Oviedo 33006, Spain.
BMC Cancer. 2013 May 17;13:243. doi: 10.1186/1471-2407-13-243.
The prevalence of BRCA1 and BRCA2 mutations in Spain is heterogeneous and varies according to geographical origin of studied families. The contribution of these mutations to hereditary breast and ovarian cancer has not been previously investigated in Asturian populations (Northern Spain).
In the present work, 256 unrelated high-risk probands with breast and/or ovarian cancer from families living in Asturias were analyzed for the presence of a BRCA1 or BRCA2 gene mutation from October 2007 to May 2012. The entire coding sequences and each intron/exon boundaries of BRCA1/2 genes were screened both by direct sequencing and Multiplex Ligation-dependent Probe Amplification (MLPA).
A total of 59 families (23%) were found to carry a pathogenic germ line mutation, 39 in BRCA1 and 20 in BRCA2. Twenty nine additional families (12%) carried an unknown significance variant. We detected 28 distinct pathogenic mutations (16 in BRCA1 and 12 in BRCA2), of which 3 mutations in BRCA1 (c.1674delA, c.1965C>A and c.2900_2901dupCT) and 5 in BRCA2 (c.262_263delCT, c.2095C>T, c.3263dupC, c.4030_4035delinsC, c.8042_8043delCA) had not been previously described.The novel mutations c.2900_2901dupCT in BRCA1 and c.4030_4035delinsC in BRCA2 occurred in 8 and 6 families respectively and clustered in two separated small geographically isolated areas suggesting a founder effect. These 2 mutations, together with the Galician BRCA1 mutation c.211A>G (9 families), and the common BRCA1 mutation c.3331_3334delCAAG (6 families), account for approximately 50% of all affected families. By contrast, very frequent mutations in other Spanish series such as the BRCA1 Ashkenazi founder mutation c.68_69delAG, was found in only one family.
In this study we report the BRCA1 and BRCA2 spectrum of mutations and their geographical distribution in Asturias, which largely differ from other areas of Spain. Our findings may help design a first step recurrent mutation panel for screening high-risk breast and/or ovarian cancer families from this specific area.
BRCA1 和 BRCA2 突变在西班牙的流行情况存在异质性，且根据研究家族的原籍地而有所不同。这些突变在阿斯图里亚斯人群（西班牙北部）中的遗传性乳腺癌和/或卵巢癌中的作用尚未被研究过。
在本研究中，我们分析了 2007 年 10 月至 2012 年 5 月期间来自阿斯图里亚斯的 256 个有乳腺癌和/或卵巢癌的高风险无关先证者家族中 BRCA1 或 BRCA2 基因的突变情况。通过直接测序和多重连接依赖性探针扩增（MLPA）筛查 BRCA1/2 基因的整个编码序列和每个内含子/外显子边界。
共发现 59 个家族（23%）携带致病性种系突变，其中 39 个为 BRCA1 突变，20 个为 BRCA2 突变。另外 29 个家族（12%）携带意义不明的变异。我们检测到 28 个不同的致病性突变（BRCA1 中有 16 个，BRCA2 中有 12 个），其中 BRCA1 中的 3 个突变（c.1674delA、c.1965C>A 和 c.2900_2901dupCT）和 BRCA2 中的 5 个突变（c.262_263delCT、c.2095C>T、c.3263dupC、c.4030_4035delinsC 和 c.8042_8043delCA）此前尚未描述过。BRCA1 中的新突变 c.2900_2901dupCT 和 BRCA2 中的 c.4030_4035delinsC 分别发生在 8 个和 6 个家族中，聚集在两个分隔的小地理隔离区域，提示存在一个奠基者效应。这 2 个突变与加利西亚的 BRCA1 突变 c.211A>G（9 个家族）和常见的 BRCA1 突变 c.3331_3334delCAAG（6 个家族）一起，约占所有受影响家族的 50%。相比之下，在其他西班牙系列中非常常见的突变，如 BRCA1 阿什肯纳兹突变 c.68_69delAG，仅在一个家族中发现。
在这项研究中，我们报告了 BRCA1 和 BRCA2 突变谱及其在阿斯图里亚斯的地理分布情况，与西班牙其他地区有很大的不同。我们的发现可能有助于为该特定地区的高危乳腺癌和/或卵巢癌家族设计首个常见突变筛查面板。
