Haplotype and phenotype analysis of nine recurrent BRCA2 mutations in 111 families:: Results of an international study
Haplotype and phenotype analysis of nine recurrent BRCA2 mutations in 111 families:: Results of an international study
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DOI：
10.1086/301885
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发表时间：
1998-06-01
影响因子：
9.8
通讯作者：
Goldgar, D
中科院分区：
文献类型：
--
作者：
Neuhausen, SL;Godwin, AK;Goldgar, D
几种BRCA2突变被发现发生在不同地理位置的乳腺癌和卵巢癌家族中。为了研究BRCA2引起的突变起源和突变特异性表型，我们在111个乳腺癌或乳腺癌/卵巢癌家族中选择了9个复发性BRCA2突变之一，构建了BRCA2位点两侧10个多态短串联重复（STR）标记的单倍型。据估计，其中6个突变发生在400- 2000年前。特别是6174delT突变，在大约1%的德系犹太人祖先中发现，估计在29代以前出现（1-LOD支持区间22-38）。这比我们对BRCA1突变的类似研究得出的BRCA1 185delAG突变的估计年龄（46代）要近得多。总的来说，没有证据表明相同的BRCA2突变有多个起源。我们的研究数据与之前的报道一致，即在第11外显子3.3 kb区域（卵巢癌簇区[OCCR]）突变的家庭中卵巢癌发病率较高（P = .10）；但这种较高的发病率在统计上并不显著。有显著证据表明，乳腺癌的诊断年龄因突变而异（P < 0.001），尽管只有8%的诊断年龄差异可以用特定突变来解释，并且没有证据表明存在家族特异性影响。当通过OCCR检查乳腺癌病例的诊断年龄时，与OCCR突变相关的病例的平均诊断年龄明显大于该区域以外的患者（48岁对42岁；P = 0.0005）。
Several BRCA2 mutations are found to occur in geographically diverse breast and ovarian cancer families. To investigate both mutation origin and mutation-specific phenotypes due to BRCA2, we constructed a haplotype of 10 polymorphic short tandem-repeat (STR) markers flanking the BRCA2 locus, in a set of 111 breast or breast/ovarian cancer families selected for having one of nine recurrent BRCA2 mutations. Six of the individual mutations are estimated to have arisen 400-2,000 years ago. In particular, the 6174delT mutation, found in similar to 1% of individuals of Ashkenazi Jewish ancestry, was estimated to have arisen 29 generations ago (1-LOD support interval 22-38). This is substantially more recent than the estimated age of the BRCA1 185delAG mutation (46 generations), derived from our analogous study of BRCA1 mutations. In general, there was no evidence of multiple origins of identical BRCA2 mutations. Our study data were consistent with the previous report of a higher incidence of ovarian cancer in families with mutations in a 3.3-kb region of exon 11 (the ovarian cancer cluster region [OCCR]) (P = .10); but that higher incidence was not statistically significant. There was significant evidence that age at diagnosis of breast cancer varied by mutation (P < .001), although only 8% of the variance in age at diagnosis could be explained by the specific mutation, and there was no evidence of family-specific effects. When the age at diagnosis of the breast cancer cases was examined by OCCR, cases associated with mutations in the OCCR had a significantly older mean age at diagnosis than was seen in those outside this region (48 years vs. 42 years; P = .0005).