Genome-wide scanning for linkage in Finnish breast cancer families
Genome-wide scanning for linkage in Finnish breast cancer families
复制标题
DOI：
10.1038/sj.ejhg.5201091
复制
发表时间：
2004-02-01
影响因子：
5.2
通讯作者：
Kallioniemi, OP
中科院分区：
文献类型：
--
作者：
Huusko, P;Juo, SHH;Kallioniemi, OP
只有一部分乳腺癌家族在BRCA 1或BRCA 2基因中存在生殖系突变，这表明存在其他易感基因。由于疾病的遗传异质性、表型相似性和突变的不完全突变，通过连锁分析发现这些基因已经被证明是困难的。隔离的人群可能有助于降低遗传异质性的水平，并为进一步的遗传分析提供有用的起点。在这里，我们报告了来自芬兰的14个高风险乳腺癌家族的全基因组连锁分析结果。这些家庭测试阴性BRCA 1和BRCA 2生殖系突变，并显示没有连锁的13 q21区域，最近提出作为一个额外的易感基因座。在标记D2 S364（2 q32）处观察到暗示性连锁，参数两点LOD评分为1.61（θ = 0），非参数分析中LOD评分为2.49。在BAC RP 11 - 67 G7中，对目标区域周围的40 cM染色体区域进行额外的基因分型，在D2 S2262处获得的最大参数两点LOD评分为1.80（θ = 0），在相邻的新标记物11291 M1处获得的非参数LOD评分为3.11。在显性遗传假设下，在11291 M1处观察到非参数多点LOD评分为3.20。虽然没有提供连锁的证据，考虑到家庭数量少，大量的实验室和统计分析进行，这些结果值得进一步研究的2 q32染色体区域作为一个候选人的乳腺癌易感基因座。连锁和关联研究可能是有用的，特别是在其他孤立的人群。
Only a proportion of breast cancer families has germline mutations in the BRCA1 or BRCA2 genes, suggesting the presence of additional susceptibility genes. Finding such genes by linkage analysis has turned out to be difficult due to the genetic heterogeneity of the disease, phenocopies and incomplete penetrance of the mutations. Isolated populations may be helpful in reducing the level of genetic heterogeneity and in providing useful starting points for further genetic analyses. Here, we report results from a genome-wide linkage analysis of 14 high-risk breast cancer families from Finland. These families tested negative for BRCA1 and BRCA2 germline mutations and showed no linkage to the 13q21 region, recently proposed as an additional susceptibility locus. Suggestive linkage was seen at marker D2S364 (2q32) with a parametric two-point LOD score of 1.61 (theta = 0), and an LOD score of 2.49 in nonparametric analyses. Additional genotyping of a 40 cM chromosomal region surrounding the region of interest yielded a maximum parametric two-point LOD score of 1.80 ( theta = 0) at D2S2262 and a nonparametric LOD score of 3.11 at an adjacent novel marker 11291M1 in BAC RP11-67G7. A nonparametric multipoint LOD score of 3.20 was seen at 11291M1 under the assumption of dominant inheritance. While not providing proof of linkage considering the small number of families and large number of laboratory and statistical analyses performed, these results warrant further studies of the 2q32 chromosomal region as a candidate breast cancer susceptibility locus. Both linkage and association studies are likely to be useful, particularly in other isolated populations.