Rökman Annika, Baffoe-Bonnie Agnes B, Gillanders Elizabeth, Fredriksson Henna, Autio Ville, Ikonen Tarja, Gibbs Kenneth D, Jones Marypat, Gildea Derek, Freas-Lutz Diane, Markey Carol, Matikainen Mika P, Koivisto Pasi A, Tammela Teuvo L J, Kallioniemi Olli P, Trent Jeffrey, Bailey-Wilson Joan E, Schleutker Johanna
Laboratory of Cancer Genetics, Institute of Medical Technology, University of Tampere and Tampere University Hospital, Tampere 33014, Finland.
Hum Genet. 2005 Jan;116(1-2):43-50. doi: 10.1007/s00439-004-1214-7. Epub 2004 Nov 11.
In a recent genome-wide linkage (GWL) analysis of Finnish families at high risk for prostate cancer, we found two novel putative susceptibility loci at 3p25-p26 and 11q14. Here, we report the fine-mapping of these two critical regions at high resolution with 39 microsatellite markers in 16 families, including multiplex families that were not used in the GWL scan. The maximum multipoint HLOD was 3.39 at 3p26 and 1.42 at 11q14. The highest LOD scores were seen around markers D3S1270 and D3S4559 (alpha=0.89), covering approximately two megabases. The two known genes in this region CHL1 (cell adhesion molecule with homology to L1CAM) and CNTN6 (contactin 6) were screened for exonic mutations in the families showing the strongest linkage, but no disease-segregating sequence variants were observed. The recombination map pointed to a region proximal to the area of best linkage, suggesting that more genes may need to be investigated as candidates. These results provide strong evidence for the existence of a prostate cancer susceptibility gene at 3p26 in Finnish prostate cancer families. This locus has not been strongly linked with hereditary prostate cancer in other populations. However, the mildly positive 3p LOD scores in a recent GWL analysis of patients from the United States suggest that the locus may also be important in other populations.
在最近一项针对前列腺癌高危芬兰家族的全基因组连锁（GWL）分析中，我们在3p25 - p26和11q14发现了两个新的假定易感基因座。在此，我们报告了利用39个微卫星标记对这两个关键区域进行的高分辨率精细定位，研究对象为16个家族，包括未用于GWL扫描的多重家族。在3p26处最大多点HLOD为3.39，在11q14处为1.42。在标记D3S1270和D3S4559（α = 0.89）附近观察到最高LOD分数，覆盖约两百万碱基对。对该区域的两个已知基因CHL1（与L1CAM具有同源性的细胞粘附分子）和CNTN6（接触蛋白6）进行了外显子突变筛查，这些突变来自显示最强连锁的家族，但未观察到疾病分离序列变异。重组图谱指向最佳连锁区域近端的一个区域，这表明可能需要研究更多基因作为候选基因。这些结果为芬兰前列腺癌家族中3p26存在前列腺癌易感基因提供了有力证据。该基因座在其他人群中与遗传性前列腺癌的关联并不强。然而，最近一项对美国患者的GWL分析中3p的轻度阳性LOD分数表明，该基因座在其他人群中可能也很重要。
