Founding BRCA1 mutations in hereditary breast and ovarian cancer in southern Sweden.
Founding BRCA1 mutations in hereditary breast and ovarian cancer in southern Sweden.
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发表时间：
1996-03
影响因子：
9.8
通讯作者：
O. Johannsson;E. A. Ostermeyer;Sara Håkansson;L. Friedman;U. Johansson;G. Sellberg;K. Brøndum‐Nielsen;V. Sele;Hampus Olsson;M. King;Å. Borg
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文献类型：
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作者：
O. Johannsson;E. A. Ostermeyer;Sara Håkansson;L. Friedman;U. Johansson;G. Sellberg;K. Brøndum‐Nielsen;V. Sele;Hampus Olsson;M. King;Å. Borg
通过对所有外显子和侧翼内含子区域的SSCP和异源双链分析，以及外显子11的蛋白质截断测试和直接测序，在瑞典南部47个家系中的15个家庭中发现了BRCA1乳腺癌和卵巢癌易感基因的9种不同的胚系突变。除一个突变外，所有突变都被预测会导致提前翻译终止，包括7个移码插入或缺失、1个无义突变和1个剪接受体位点突变。剩下的突变是锌结合基序中的错义突变(Cys61Gly)。在5个家系中发现2595位核苷酸缺失A，3个家系中发现C 1806 T无义突变，3个家系中发现3166个插入TGAGA突变，2个家系中发现1201位缺失11位核苷酸。对D17S855基因内多态的分析支持突变的共同来源。显示BRCA1突变的15个家系中有11个是乳腺癌-卵巢癌家族，其中几个具有主要的卵巢癌表型。在32个未检测到BRCA1改变的家系中，包括1个乳腺癌-卵巢癌家族，表现出与BRCA1区域明显的连锁和相关肿瘤中野生型染色体的丢失。在BRCA1突变/单倍型携带者中发现的其他肿瘤类型包括前列腺癌、胰腺癌、皮肤癌和肺癌、恶性黑色素瘤、少突胶质瘤和癌肉瘤。总体而言，显示BRCA1突变或连锁的16个家系中有12个家系患有卵巢癌，而其余31个家系中只有6个家系患有卵巢癌(P<；.001)。本研究证实BRCA1参与了通常以卵巢癌为特征的遗传性乳腺癌家族的疾病易感性。
Nine different germ-line mutations in the BRCA1 breast and ovarian cancer susceptibility gene were identified in 15 of 47 kindreds from southern Sweden, by use of SSCP and heteroduplex analysis of all exons and flanking intron region and by a protein-truncation test for exon 11, followed by direct sequencing. All but one of the mutations are predicted to give rise to premature translation termination and include seven frameshift insertions or deletions, a nonsense mutation, and a splice acceptor site mutation. The remaining mutation is a missense mutation (Cys61Gly) in the zinc-binding motif. Four novel Swedish founding mutations were identified: the nucleotide 2595 deletion A was found in five families, the C 1806 T nonsense mutation in three families, the 3166 insertion TGAGA in three families, and the nucleotide 1201 deletion 11 in two families. Analysis of the intragenic polymorphism D17S855 supports common origins of the mutations. Eleven of the 15 kindreds manifesting BRCA1 mutations were breast-ovarian cancer families, several of them with a predominant ovarian cancer phenotype. The set of 32 families in which no BRCA1 alterations were detected included 1 breast-ovarian cancer kindred manifesting clear linkage to the BRCA1 region and loss of the wild-type chromosome in associated tumors. Other tumor types found in BRCA1 mutation/haplotype carriers included prostatic, pancreas, skin, and lung cancer, a malignant melanoma, an oligodendroglioma, and a carcinosarcoma. In all, 12 of 16 kindreds manifesting BRCA1 mutation or linkage contained ovarian cancer, as compared with only 6 of the remaining 31 families (P<.001). The present study confirms the involvement of BRCA1 in disease predisposition for a subset of hereditary breast cancer families often characterized by ovarian cancers.