Cooney K A, McCarthy J D, Lange E, Huang L, Miesfeldt S, Montie J E, Oesterling J E, Sandler H M, Lange K
Department of Internal Medicine, University of Michigan Medical School, and Ann Arbor Veterans Affairs Medical Center, USA.
J Natl Cancer Inst. 1997 Jul 2;89(13):955-9. doi: 10.1093/jnci/89.13.955.
Recent recognition that a predisposition to prostate cancer can be inherited has led to a search for specific genes associated with the disease. Through a study of families with three or more affected first-degree relatives, a region on the long arm of chromosome 1 (i.e., 1q24-25) has been tentatively identified as containing a gene, HPC1, involved in the development of hereditary prostate cancer. Confirmation of this finding is needed, however, before attempts are made to isolate and characterize the putative HPC1 gene.
To confirm that chromosome 1q24-25 contains a gene relevant to hereditary prostate cancer, we analyzed an independent set of families, each with two or more affected individuals.
Fifty-nine unrelated families were selected for analysis on the sole criterion that more than one living family member was affected by prostate cancer. DNA samples were subsequently isolated from 130 individuals with the disease. These samples were genotyped at six polymorphic marker sequences (D1S215, D1S2883, D1S466, D1S158, D1S518, and D1S2757) covering the chromosomal region proposed to contain HPC1. The resulting data were analyzed by nonparametric multipoint linkage (NPL) methods, yielding NPL Z scores and corresponding one-sided P values.
When the entire set of 59 families was considered, the occurrence of prostate cancer (and, presumably, the HPC1 gene) was most tightly linked to marker D1S466 (NPL Z score = 1.58; P = .0574). Analysis of the 20 families (51 affected individuals) fulfilling one or more of the proposed clinical criteria for hereditary prostate cancer (i.e., three or more affected individuals within one nuclear family; affected individuals in three successive generations [maternal or paternal lineage]; and/or clustering of two or more individuals affected before the age of 55 years) revealed more convincing evidence of disease linkage to chromosome 1q24-25 (maximum NPL Z score [at marker D1S466] = 1.72; P = .0451). The 39 families (79 affected individuals) that did not meet the clinical criteria for hereditary prostate cancer exhibited no significant evidence of disease linkage to DNA sequences at chromosome 1q24-25 (maximum NPL Z score [at marker D1S466] = 0.809; P = .208). The six African-American families in our study contributed disproportionately to the observation of linkage, with a maximum NPL Z score at marker D1S158 of 1.39 (P = .0848) for these families.
Our data confirm that chromosome 1q24-25 is likely to contain a prostate cancer susceptibility gene. Future efforts at positional cloning of the HPC1 gene should focus on families who meet the proposed clinical criteria for hereditary prostate cancer.
最近认识到前列腺癌易感性可能是可遗传的，这促使人们寻找与该疾病相关的特定基因。通过对有三个或更多受影响的一级亲属的家族进行研究，1号染色体长臂上的一个区域（即1q24 - 25）已被初步确定含有一个与遗传性前列腺癌发生相关的基因HPC1。然而，在尝试分离和鉴定假定的HPC1基因之前，需要对这一发现进行确认。
为了确认1号染色体q24 - 25区域含有与遗传性前列腺癌相关的基因，我们分析了另一组独立的家族，每个家族有两个或更多受影响的个体。
仅根据有不止一名在世家族成员患前列腺癌这一标准，选择了59个无亲缘关系的家族进行分析。随后从130名患有该疾病的个体中分离出DNA样本。这些样本在覆盖提议包含HPC1的染色体区域的六个多态性标记序列（D1S215、D1S2883、D1S466、D1S!58、D1S518和D1S2757）上进行基因分型。通过非参数多点连锁（NPL）方法分析所得数据，得出NPL Z分数和相应的单侧P值。
当考虑整个59个家族的集合时，前列腺癌（以及推测的HPC1基因）的发生与标记D1S466的联系最为紧密（NPL Z分数 = 1.58；P = 0.0574）。对满足一项或多项提议的遗传性前列腺癌临床标准的20个家族（51名受影响个体）进行分析（即一个核心家庭中有三个或更多受影响个体；三代连续（母系或父系谱系）中有受影响个体；和/或两名或更多个体在55岁之前受影响的聚集情况），发现了更令人信服的疾病与1号染色体q24 - 25区域连锁的证据（在标记D1S466处的最大NPL Z分数 = 1.72；P = 0.0451）。不符合遗传性前列腺癌临床标准的39个家族（79名受影响个体）没有显示出疾病与1号染色体q24 - 25区域DNA序列连锁的显著证据（在标记D1S466处的最大NPL Z分数 = 0.809；P = 0.208）。我们研究中的六个非裔美国家族对连锁观察的贡献不成比例，这些家族在标记D1S158处的最大NPL Z分数为1.39（P = 0.0848）。
我们的数据证实1号染色体q24 - 25区域可能含有一个前列腺癌易感基因。未来对HPC1基因进行定位克隆的工作应集中在符合提议的遗传性前列腺癌临床标准的家族上。
