Somatic deletions in hereditary breast cancers implicate 13q21 as a putative novel breast cancer susceptibility locus
Somatic deletions in hereditary breast cancers implicate 13q21 as a putative novel breast cancer susceptibility locus
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DOI：
10.1073/pnas.97.17.9603
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发表时间：
2000-08-15
影响因子：
11.1
通讯作者：
Nevanlinna, H
中科院分区：
文献类型：
--
作者：
Kainu, T;Juo, SHH;Nevanlinna, H
很大一部分家族性乳腺癌无法用BRCA 1或BRCA 2基因突变来解释。我们应用了一种策略，通过使用数学模型识别肿瘤组织中的早期体细胞遗传缺失，然后进行靶向连锁分析，来识别乳腺癌的易感基因位点。采用比较基因组杂交研究了来自37个乳腺癌家族的61个乳腺肿瘤，这些乳腺肿瘤没有发现BRCA 1或BRCA 2突变。分支和系统发育树模型预测，13 q的丢失是遗传性癌症中最早的遗传事件之一。在一个有5例乳腺癌病例的瑞典家族中，所有分析的肿瘤均显示出明显的13 q缺失，13 q21-q22缺失的区域最小。基因分型揭示了一个共享的13 q21生殖系单倍型的家庭隔离。在一组77个芬兰、冰岛和瑞典乳腺癌家族中进行了有针对性的连锁分析，这些家族没有检测到BRCA 1和BRCA 2突变。在13 q21（D13 S1308，θ = 0.10）的标记获得的最大参数两点对数的优势得分为2.76。异质性条件下的多点对数优势值为3.46。通过模拟进一步评价结果，以评估获得有利于偶然连锁的显著证据的概率，并考虑位于新基因座重组分数为0.25处的BRCA 2基因座的可能影响。模拟结果证实了D13 S1308位点的连锁性（P < 0.0017）。这些结果保证了在其他人群中对这一假定的乳腺癌易感基因座的研究。
A significant proportion of familial breast cancers cannot be explained by mutations in the BRCA1 or BRCA2 genes. We applied a strategy to identify predisposition loci for breast cancer by using mathematical models to identify early somatic genetic deletions in tumor tissues followed by targeted linkage analysis. Comparative genomic hybridization was used to study 61 breast tumors from 37 breast cancer families with no identified BRCA1 or BRCA2 mutations. Branching and phylogenetic tree models predicted that loss of 13q was one of the earliest genetic events in hereditary cancers. In a Swedish family with five breast cancer cases, all analyzed tumors showed distinct 13q deletions, with the minimal region of loss at 13q21-q22. Genotyping revealed segregation of a shared 13q21 germ-line haplotype in the family. Targeted linkage analysis was carried out in a set of 77 Finnish, Icelandic, and Swedish breast cancer families with no detected BRCA1 and BRCA2 mutations. A maximum parametric two-point logarithm of odds score of 2.76 was obtained for a marker at 13q21 (D13S1308, theta = 0.10). The multipoint logarithm of odds score under heterogeneity was 3.46. The results were further evaluated by simulation to assess the probability of obtaining significant evidence in favor of linkage by chance as well as to take into account the possible influence of the BRCA2 locus, located at a recombination fraction of 0.25 from the new locus. The simulation substantiated the evidence of linkage at D13S1308 (P < 0.0017). The results warrant studies of this putative breast cancer predisposition locus in other populations.