Genome-wide search for breast cancer linkage in large Icelandic non-BRCA1/2 families.
Genome-wide search for breast cancer linkage in large Icelandic non-BRCA1/2 families.
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DOI：
10.1186/bcr2608
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发表时间：
2010
期刊：
影响因子：
--
通讯作者：
Barkardottir RB
中科院分区：
文献类型：
--
作者：
Arason A;Gunnarsson H;Johannesdottir G;Jonasson K;Bendahl PO;Gillanders EM;Agnarsson BA;Jönsson G;Pylkäs K;Mustonen A;Heikkinen T;Aittomäki K;Blomqvist C;Melin B;Johannsson OT;Møller P;Winqvist R;Nevanlinna H;Borg A;Barkardottir RB
很大一部分高危乳腺癌家族不能用已知基因的突变来解释。最近的全基因组搜索（GWS）没有发现任何单一的主要位点让人联想到BRCA 1和BRCA 2，这表明仍然不明的基因可能解释相对较少的家庭，每个或相互作用的方式模糊的连锁分析。这引起了人们对研究遗传异质性可能减少的种群的可能益处的关注。因此，我们进行了一个GWS的连锁9冰岛多例非BRCA 1/2家庭的理想大小映射高渗透位点。为了跟踪提示位点，对来自其他北欧国家的另外13个家庭进行了选定标记的基因分型。使用811个微卫星标记进行GWS，提供约5厘摩（cM）分辨率。使用参数和非参数方法计算多点比值对数（LOD）评分。对于选定的标记物和病例，将肿瘤组织与正常组织进行比较，以寻找指示肿瘤抑制基因的等位基因缺失。最高信号的三个染色体位于染色体6 q、2 p和14 q。一个家庭在所有这些地区提供了提示性LOD评分（LOD 2.63至3.03，显性模型），没有一致的肿瘤抑制基因的证据。在9个受影响的家庭成员的单倍型定位到2p23.2到p21，6q14.2到q23.2和14q21.3到q24.3的基因座。没有证据表明，一个高度外显位点被发现在其余的家庭。在6 q、2 p和14 q位点上的异质性检测限（HLOD）分别为3.27、1.66和1.24。13个北欧家庭的子集在染色体6 q上显示支持性HLODs（根据国家子集，范围从0.34到1.37）。2 p和14 q基因座与以前GWS乳腺癌研究中大家族所指示的区域重叠。染色体2 p、6 q和14 q是共同导致乳腺癌高风险的基因的候选位点。多基因模型得到支持，表明基因的联合作用在非BRCA 1/2家族中对乳腺癌风险的贡献相当普遍。对于遗传咨询来说，解决遗传相互作用的模式似乎很重要。
A significant proportion of high-risk breast cancer families are not explained by mutations in known genes. Recent genome-wide searches (GWS) have not revealed any single major locus reminiscent of BRCA1 and BRCA2, indicating that still unidentified genes may explain relatively few families each or interact in a way obscure to linkage analyses. This has drawn attention to possible benefits of studying populations where genetic heterogeneity might be reduced. We thus performed a GWS for linkage on nine Icelandic multiple-case non-BRCA1/2 families of desirable size for mapping highly penetrant loci. To follow up suggestive loci, an additional 13 families from other Nordic countries were genotyped for selected markers. GWS was performed using 811 microsatellite markers providing about five centiMorgan (cM) resolution. Multipoint logarithm of odds (LOD) scores were calculated using parametric and nonparametric methods. For selected markers and cases, tumour tissue was compared to normal tissue to look for allelic loss indicative of a tumour suppressor gene. The three highest signals were located at chromosomes 6q, 2p and 14q. One family contributed suggestive LOD scores (LOD 2.63 to 3.03, dominant model) at all these regions, without consistent evidence of a tumour suppressor gene. Haplotypes in nine affected family members mapped the loci to 2p23.2 to p21, 6q14.2 to q23.2 and 14q21.3 to q24.3. No evidence of a highly penetrant locus was found among the remaining families. The heterogeneity LOD (HLOD) at the 6q, 2p and 14q loci in all families was 3.27, 1.66 and 1.24, respectively. The subset of 13 Nordic families showed supportive HLODs at chromosome 6q (ranging from 0.34 to 1.37 by country subset). The 2p and 14q loci overlap with regions indicated by large families in previous GWS studies of breast cancer. Chromosomes 2p, 6q and 14q are candidate sites for genes contributing together to high breast cancer risk. A polygenic model is supported, suggesting the joint effect of genes in contributing to breast cancer risk to be rather common in non-BRCA1/2 families. For genetic counselling it would seem important to resolve the mode of genetic interaction.
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DOI：
10.1073/pnas.97.17.9603
发表时间：
2000-08-15
影响因子：
11.1
作者：
Kainu, T;Juo, SHH;Nevanlinna, H
通讯作者：
Nevanlinna, H
影响因子：
5.2
作者：
Huusko, P;Juo, SHH;Kallioniemi, OP
通讯作者：
Kallioniemi, OP
DOI：
10.1093/jnci/91.11.943
发表时间：
1999-06-02
期刊：
JOURNAL OF THE NATIONAL CANCER INSTITUTE
影响因子：
--
作者：
Peto, J;Collins, N;Stratton, MR
通讯作者：
Stratton, MR
影响因子：
4
作者：
Arason, A;Jonasdottir, A;Egilsson, V
通讯作者：
Egilsson, V
影响因子：
3.7
作者：
Smith, Paula;McGuffog, Lesley;Easton, Douglas F;Mann, Graham J;Pupo, Gulietta M;Newman, Beth;Chenevix-Trench, Georgia;Szabo, Csilla;Southey, Melissa;Renard, Helene;Odefrey, Fabrice;Lynch, Henry;Stoppa-Lyonnet, Dominique;Couch, Fergus;Hopper, John L;Giles, Graham G;McCredie, Margaret R E;Buys, Saundra;Andrulis, Irene;Senie, Ruby;Goldgar, David E;Oldenburg, Rogier;Kroeze-Jansema, Karin;Kraan, Jaennelle;Meijers-Heijboer, Hanne;Klijn, Jan G M;van Asperen, Christi;van Leeuwen, Inge;Vasen, Hans F A;Cornelisse, Cees J;Devilee, Peter;Baskcomb, Linda;Seal, Sheila;Barfoot, Rita;Mangion, Jon;Hall, Anita;Edkins, Sarah;Rapley, Elizabeth;Wooster, Richard;Chang-Claude, Jenny;Eccles, Diana;Evans, D Gareth;Futreal, P Andrew;Nathanson, Katherine L;Weber, Barbara L;Rahman, Nazneen;Stratton, Michael R
通讯作者：
Stratton, Michael R