Lyn D, Cherney B W, Lalande M, Berenson J R, Lichtenstein A, Lupold S, Bhatia K G, Smulson M
Department of Biochemistry and Molecular Biology, Georgetown University School of Medicine, Washington, DC 20007.
Am J Hum Genet. 1993 Jan;52(1):124-34.
The poly(ADP-ribose) polymerase (PADPRP) gene (13q33-qter) depicts a two-allele (A/B) polymorphism. In the noncancer population, the frequency of the B allele is higher among blacks than among whites. Since the incidence of multiple myeloma and prostate and lung cancer is higher in the U.S. black population, we have analyzed the B-allele frequency in germ-line DNA to determine whether the PADPRP gene correlates with a polymorphic susceptibility to these diseases. For multiple myeloma and prostate cancer, an increased frequency of the B allele appeared to be striking only in black patients. In contrast, the distribution of the B allele in germ-line DNA did not differ among white patients with these diseases, when compared with the control group. An elevated B-allele frequency was also found in germ-line DNA in blacks with colon cancer. These observations suggest that the PADPRP polymorphism may provide a valid marker for a predisposition to these cancers in black individuals. To determine the genomic structure of the polymorphic PADPRP sequences, a 2.68-kb HindIII clone was isolated and sequenced from a chromosome 13-enriched library. Sequence analysis of this clone (A allele) revealed a close sequence similarity (91.8%) to PADPRP cDNA (1q42) and an absence of introns, suggesting that the gene on 13q exists as a processed pseudogene. A 193-bp conserved duplicated region within the A allele was identified as the source of the polymorphism. The nucleotide differences between the PADPRP gene on chromosome 13 and related PADPRP genes were exploited to develop oligonucleotides that can detect the difference between the A/B genotypes in a PCR. This PCR assay offers the opportunity for analyzing additional black cancer patients, to determine how the PADPRP processed pseudogene or an unidentified gene that cosegregates with the PADPRP gene might be involved with the development of malignancy.
聚（ADP - 核糖）聚合酶（PADPRP）基因（13q33 - qter）呈现出双等位基因（A/B）多态性。在非癌症人群中，B等位基因的频率在黑人中高于白人。由于美国黑人人群中多发性骨髓瘤、前列腺癌和肺癌的发病率较高，我们分析了生殖系DNA中的B等位基因频率，以确定PADPRP基因是否与这些疾病的多态性易感性相关。对于多发性骨髓瘤和前列腺癌，B等位基因频率的增加似乎仅在黑人患者中显著。相比之下，与对照组相比，患有这些疾病的白人患者生殖系DNA中B等位基因的分布没有差异。在患有结肠癌的黑人的生殖系DNA中也发现了B等位基因频率升高。这些观察结果表明，PADPRP多态性可能为黑人个体中这些癌症的易感性提供一个有效的标志物。为了确定多态性PADPRP序列的基因组结构，从一个富含13号染色体的文库中分离并测序了一个2.68 kb的HindIII克隆。对该克隆（A等位基因）的序列分析显示，它与PADPRP cDNA（1q42）有密切的序列相似性（91.8%），并且没有内含子，这表明13q上的基因以加工假基因的形式存在。在A等位基因内一个19bp的保守重复区域被确定为多态性的来源。利用13号染色体上的PADPRP基因与相关PADPRP基因之间的核苷酸差异，开发了能够在PCR中检测A/B基因型差异的寡核苷酸。这种PCR检测方法为分析更多的黑人癌症患者提供了机会，以确定PADPRP加工假基因或与PADPRP基因共分离的未鉴定基因可能如何参与恶性肿瘤的发生发展。
