Gillanders Elizabeth M, Xu Jianfeng, Chang Bao-li, Lange Ethan M, Wiklund Fredrik, Bailey-Wilson Joan E, Baffoe-Bonnie Agnes, Jones MaryPat, Gildea Derek, Riedesel Erica, Albertus Julie, Isaacs Sarah D, Wiley Kathleen E, Mohai Caroline E, Matikainen Mika P, Tammela Teuvo L J, Zheng S Lilly, Brown W Mark, Rökman Annika, Carpten John D, Meyers Deborah A, Walsh Patrick C, Schleutker Johanna, Gronberg Henrik, Cooney Kathleen A, Isaacs William B, Trent Jeffrey M
National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
J Natl Cancer Inst. 2004 Aug 18;96(16):1240-7. doi: 10.1093/jnci/djh228.
Prostate cancer represents a substantial public health burden worldwide. It is the second leading cause of cancer death among men in the United States. A family history of the disease is among the most well-established risk factors for prostate cancer. Efforts to localize prostate cancer susceptibility alleles by using genetic linkage analysis methods have been hindered by genetic heterogeneity, incomplete penetrance, disease phenocopies, and the lack of DNA samples from parents of individuals with late-onset prostate cancer.
We performed a combined genome-wide linkage analysis among 426 families from four existing hereditary prostate cancer (HPC) study populations to systematically search for prostate cancer susceptibility genes. To decrease the degree of locus heterogeneity, we analyzed subsets of families with similar clinical and demographic characteristics. Nonparametric multipoint linkage was the primary method of analysis. Results are presented as allele-sharing logarithm of the odds (LOD) scores, and all reported P values are two-sided.
The strongest evidence for prostate cancer linkage was found at chromosome region 17q22 (nonparametric multipoint Kong and Cox allele-sharing LOD score = 3.16 at marker D17S787; P =.00007). Stratified analyses revealed several additional chromosomal regions that are likely to segregate prostate cancer susceptibility genes among specific subsets of HPC families, including 15q11 among families with late-onset disease (allele-sharing LOD = 5.57 at marker D15S128; P<.00001) and 4q35 among families with four or more affected family members (allele-sharing LOD = 3.10 at marker D4S1615; P =.00008).
Fine mapping studies to facilitate identification of prostate cancer susceptibility genes in these linked regions are warranted.
前列腺癌在全球范围内构成了重大的公共卫生负担。它是美国男性癌症死亡的第二大主要原因。该疾病的家族史是前列腺癌最确定的风险因素之一。利用遗传连锁分析方法定位前列腺癌易感等位基因的努力受到遗传异质性、不完全外显率、疾病表型模拟以及缺乏晚发性前列腺癌患者父母的DNA样本的阻碍。
我们对来自四个现有的遗传性前列腺癌（HPC）研究人群的426个家庭进行了全基因组联合连锁分析，以系统地寻找前列腺癌易感基因。为了降低基因座异质性的程度，我们分析了具有相似临床和人口统计学特征的家庭子集。非参数多点连锁分析是主要的分析方法。结果以等位基因共享优势对数（LOD）分数表示，所有报告的P值均为双侧。
在染色体区域17q22发现了前列腺癌连锁的最强证据（在标记D17S787处，非参数多点Kong和Cox等位基因共享LOD分数 = 3.16；P = 0.00007）。分层分析揭示了几个其他染色体区域，这些区域可能在HPC家庭的特定子集中分离前列腺癌易感基因，包括晚发性疾病家庭中的15q11（在标记D15S128处等位基因共享LOD = 5.57；P < 0.00001）和有四个或更多受影响家庭成员的家庭中的4q35（在标记D4S1615处等位基因共享LOD = 3.10；P = 0.00008）。
有必要进行精细定位研究，以促进在这些连锁区域中鉴定前列腺癌易感基因。
