Bhatia K G, Cherney B W, Huppi K, Magrath I T, Cossman J, Sausville E, Barriga F, Johnson B, Gause B, Bonney G
Department of Biochemistry, Georgetown University School of Medicine, Washington, DC 20007.
Cancer Res. 1990 Sep 1;50(17):5406-13.
The nuclear enzyme poly(ADP-ribose) polymerase (PADPRP) is thought to play a role in DNA recombination, replication, and repair. In view of the implication of these processes in tumorigenesis, and based on preliminary evidence which indicated the presence of an extraneous polymorphic restriction fragment for murine PADPRP loci in strains of mice susceptible to plasmacytomas, we investigated correlations between the restriction fragment length polymorphism of the PADPRP gene(s) and human Burkitt lymphoma. No increase in the frequency of polymorphisms on chromosome 1 (containing the active gene) or on chromosome 14 (a pseudogene) was observed. However, restriction fragment length polymorphism analysis of PADPRP sequences on chromosome 13 (either a processed pseudogene or a gene with extensive identity to PADPRP) revealed that of 19 DNA samples derived from endemic Burkitt lymphoma all contained at least one copy of a rare allele (B). Simple two-allele (A/B) polymorphisms in this PADPRP-like locus were identified by digestion with a number of restriction enzymes including HindIII, PstI, KpnI, and MspI. These restriction fragment length polymorphisms always segregated together, suggesting that they identify a deletion within or close to the PADPRP sequences on chromosome 13, which we mapped precisely to 13q33-qter. Based upon family studies the A and B alleles were shown to be transferred in a Mendelian codominant fashion. Subsequently, this probe was used as a linkage marker to study the frequency of this deletion in various tumors including B-cell follicular lymphomas, small cell lung carcinomas, breast carcinomas, and colorectal carcinomas. In noncancer control populations, the frequency of this deletion was 3-fold higher among Blacks as compared to Caucasians. When DNA from various tumors was compared to normal DNA from racially appropriate noncancer controls, the frequency of this deletion was still 2- to 3-fold higher in the tumor DNA. Matched samples provided instances of tumor-specific loss of heterozygosity but also revealed that the predominant source of this deletion is the germ line, suggesting that the chromosome 13 region neighboring the PADPRP locus may harbor a gene whose loss may predispose individuals to malignancy.
核酶聚（ADP - 核糖）聚合酶（PADPRP）被认为在DNA重组、复制和修复中发挥作用。鉴于这些过程在肿瘤发生中的作用，并基于初步证据表明在易患浆细胞瘤的小鼠品系中存在鼠PADPRP基因座的外来多态性限制性片段，我们研究了PADPRP基因的限制性片段长度多态性与人类伯基特淋巴瘤之间的相关性。未观察到1号染色体（包含活性基因）或14号染色体（假基因）上多态性频率增加。然而，对13号染色体上PADPRP序列的限制性片段长度多态性分析（13号染色体上要么是加工后的假基因，要么是与PADPRP具有广泛同源性的基因）显示，来自地方性伯基特淋巴瘤的19个DNA样本均至少含有一个罕见等位基因（B）的拷贝。通过用包括HindIII、PstI、KpnI和MspI在内的多种限制性酶消化，在这个类似PADPRP的基因座中鉴定出简单的双等位基因（A/B）多态性。这些限制性片段长度多态性总是一起分离，表明它们识别出13号染色体上PADPRP序列内或附近的一个缺失，我们将其精确定位到13q33 - qter。基于家系研究，A和B等位基因以孟德尔共显性方式传递。随后，该探针被用作连锁标记来研究这种缺失在包括B细胞滤泡性淋巴瘤、小细胞肺癌、乳腺癌和结直肠癌在内的各种肿瘤中的频率。在非癌症对照人群中，黑人中这种缺失的频率比白人高3倍。当将各种肿瘤的DNA与来自种族匹配的非癌症对照的正常DNA进行比较时，肿瘤DNA中这种缺失的频率仍然高2至3倍。匹配样本提供了肿瘤特异性杂合性缺失的实例，但也表明这种缺失的主要来源是种系，这表明与PADPRP基因座相邻的13号染色体区域可能含有一个基因，其缺失可能使个体易患恶性肿瘤。
