Valeri A, Berthon P, Fournier G, Buzzi J C, Briollais L, Meria P, Blanche H, Bellanne-Chantelot C, Teillac P, Demenais F, Mangin P, Cohen N, Le Duc A, Cussenot O
Département d'Urologie, Hôpital Saint-Louis, Paris.
Prog Urol. 1996 Apr;6(2):226-35.
To initiate a genetic linkage study in order to localize one or several predisposition gene(s) for hereditary prostatic cancer (PC), as various epidemiological studies have demonstrated a possible family aggregation in about 25% of cases. A family segregation study [14] has also shown that a genetic predisposition, with autosomal dominant transmission and high penetrance (88% at 85 years) could be responsible for 9% of all PC.
A national collection of families with at least 2 cases of PC allowed: 1) identification of families with hereditary forms of PC, 2) creation of a constitutional DNA bank after collecting blood samples from subjects belonging to these families, and 3) a simulation study of genetic linkage analysis prior to microsatellite genotyping.
From July 1994 to September 1995, we included 67 families (180 cases of PC). Another 45 families are currently being included. 24 of these 67 families (89 PC, 54 survivors) satisfied at least one of the criteria defined in the study by CARTER et al. for hereditary forms of familial PC. Two families were also included as the 3 patients with PC were second degree relatives. A total of 26 families therefore presented a hereditary form, 18 of which (73 PC, 46 survivors) were considered to be informative for a genetic linkage study (lod score = 4 for theta = 0.001 with an 8 allele marker). The constitutional DNA of 271 individuals of these informative families was extracted from circulating cells obtained from blood samples, immortalized lymphocytes, and the genotyping was initiated for 216 microsatellite markers distributed throughout the genome, an average of every 20 cM.
Although the recruitment allowed us to identify many informative families for an inherited risk of PC, the predictive study suggested a high probability for localization of a predisposition gene by genetic linkage analysis. It would therefore be possible to identify, within the families concerned, the subjects carrying the genetic anomaly and consequently at high-risk of PC. Finally, the demonstration of the locus would allow cloning and identification of the gene (s) involved.
开展一项基因连锁研究，以定位遗传性前列腺癌（PC）的一个或多个易感基因，因为多项流行病学研究表明，约25%的病例可能存在家族聚集性。一项家族分离研究[14]还表明，具有常染色体显性遗传和高外显率（85岁时为88%）的遗传易感性可能导致所有前列腺癌的9%。
在全国范围内收集至少有2例前列腺癌病例的家族，这使得：1）识别出具有遗传性前列腺癌形式的家族；2）在从这些家族的受试者采集血样后建立一个基因组DNA库；3）在进行微卫星基因分型之前对基因连锁分析进行模拟研究。
从1994年7月到1995年9月，我们纳入了67个家族（180例前列腺癌病例）。目前正在纳入另外45个家族。这67个家族中的24个（89例前列腺癌，54例存活者）至少满足卡特等人在研究中定义的遗传性家族性前列腺癌形式的标准之一。另外两个家族也被纳入，因为这3例前列腺癌患者是二级亲属。因此，共有26个家族呈现出遗传形式，其中18个（73例前列腺癌，46例存活者）被认为对基因连锁研究具有信息价值（对于一个有8个等位基因的标记，θ = 0.001时的对数优势比 = 4）。从这些有信息价值的家族的271名个体的循环细胞、永生化淋巴细胞中提取基因组DNA，并开始对分布在整个基因组中的216个微卫星标记进行基因分型，平均每20厘摩一个标记。
尽管招募工作使我们能够识别出许多具有前列腺癌遗传风险的有信息价值的家族，但预测性研究表明通过基因连锁分析定位易感基因的可能性很大。因此，有可能在相关家族中识别出携带遗传异常并因此处于前列腺癌高风险的个体。最后，该基因座的证明将有助于克隆和鉴定相关基因。
