The use of ancestral Haplotypes in the molecular diagnosis of familial breast cancer
The use of ancestral Haplotypes in the molecular diagnosis of familial breast cancer
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DOI：
10.1089/gte.2006.0518
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发表时间：
2007-09-01
期刊：
影响因子：
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通讯作者：
Spriggs, Elizabeth L.
中科院分区：
文献类型：
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作者：
Frosk, Patrick;Burgess, Susan;Spriggs, Elizabeth L.
BRCA1和BRCA2基因突变约占乳腺癌和/或卵巢癌遗传易感性家庭的40%。对这两个基因的突变分析已经成为有强烈遗传易感性的家庭的标准护理。筛查的方法各不相同，但最受欢迎的技术之一是dHPLC，因为它结合了高灵敏度和低成本。这两个BRCA基因中存在大量的多态，这使得dHPLC分析变得复杂，常常导致复杂的洗脱图谱。有人担心，多态杂合子样本产生的模式可能与同一扩增子内唯一突变杂合子样本产生的模式非常相似。通常需要进一步的分子分析来确定任何给定的突变是由于多态还是致病突变所致。探讨了祖先单倍型的使用，以此作为将进一步分析的必要性降至最低的一种手段。对86例患者进行了12个BRCA1或20个BRCA2基因分型。对于BRCA1，确定了8种不同的单倍型，它们主要是两个主要谱系的衍生品。对于BRCA2，鉴定出17种不同的单倍型，导致了更复杂的多态图谱。有了这些知识，我们已经定义了一个系统来确定哪些患者需要进一步的检查。该方法可用于对位于NF1、CFTR、MLH1或MSH2等强连锁不平衡区域的其他大基因的全面筛选方法的补充。
Mutations in BRCA1 and BRCA2 account for about 40% of families with an inherited susceptibility to breast and/or ovarian cancer. Mutational analysis of these two genes has become the standard of care for families with a strong suggestion of inherited susceptibility. Methodologies for screening vary, but one of the more popular techniques is dHPLC, due to its combination of high sensitivity and low cost. The presence of a large number of polymorphisms in the two BRCA genes complicates dHPLC analysis, often leading to complex elution profiles. There are concerns that a pattern produced by a sample heterozygous for a polymorphism may be very similar to that produced by a sample heterozygous for a unique mutation within the same amplicon. Further molecular analysis is often required to resolve whether any given shift is due to a polymorphism or a disease-causing mutation. The use of ancestral haplotypes was explored as a means to minimize the need for further analysis. Groups of 86 patients were genotyped for 12 BRCA1 polymorphisms or 20 BRCA2 polymorphisms. For BRCA1, eight distinct haplotypes were identified, which are largely derivatives of two main lineages. For BRCA2, 17 distinct haplotypes were identified, leading to a much more complex polymorphic pattern. With this knowledge, we have defined a system to determine which patients, if any, require further investigations. This method could be used to supplement any comprehensive screening methodology for other large genes that lie within strong regions of linkage disequilibrium such as NF1, CFTR, MLH1, or MSH2.