Hoovers J M, Kalikin L M, Johnson L A, Alders M, Redeker B, Law D J, Bliek J, Steenman M, Benedict M, Wiegant J, Lengauer C, Taillon-Miller P, Schlessinger D, Edwards M C, Elledge S J, Ivens A, Westerveld A, Little P, Mannens M, Feinberg A P
Institute of Human Genetics, University of Amsterdam Academic Medical Center, The Netherlands.
Proc Natl Acad Sci U S A. 1995 Dec 19;92(26):12456-60. doi: 10.1073/pnas.92.26.12456.
Beckwith-Wiedemann syndrome (BWS) involves fetal overgrowth and predisposition to a wide variety of embryonal tumors of childhood. We have previously found that BWS is genetically linked to 11p15 and that this same band shows loss of heterozygosity in the types of tumors to which children with BWS are susceptible. However, 11p15 contains > 20 megabases, and therefore, the BWS and tumor suppressor genes could be distinct. To determine the precise physical relationship between these loci, we isolated yeast artificial chromosomes, and cosmid libraries from them, within the region of loss of heterozygosity in embryonal tumors. Five germ-line balanced chromosomal rearrangement breakpoint sites from BWS patients, as well as a balanced chromosomal translocation breakpoint from a rhabdoid tumor, were isolated within a 295- to 320-kb cluster defined by a complete cosmid contig crossing these breakpoints. This breakpoint cluster terminated approximately 100 kb centromeric to the imprinted gene IGF2 and 100 kb telomeric to p57KIP2, an inhibitor of cyclin-dependent kinases, and was located within subchromosomal transferable fragments that suppressed the growth of embryonal tumor cells in genetic complementation experiments. We have identified 11 transcribed sequences in this BWS/tumor suppressor coincident region, one of which corresponded to p57KIP2. However, three additional BWS breakpoints were > 4 megabases centromeric to the other five breakpoints and were excluded from the tumor suppressor region defined by subchromosomal transferable fragments. Thus, multiple genetic loci define BWS and tumor suppression on 11p15.
贝克威思-维德曼综合征（BWS）表现为胎儿过度生长，并易患多种儿童期胚胎性肿瘤。我们之前发现BWS与11p15存在遗传连锁关系，并且在BWS患儿易患的肿瘤类型中，该条带显示杂合性缺失。然而，11p15包含超过20兆碱基，因此，BWS和肿瘤抑制基因可能是不同的。为了确定这些基因座之间的确切物理关系，我们在胚胎性肿瘤杂合性缺失区域内分离了酵母人工染色体及其黏粒文库。在一个由跨越这些断点的完整黏粒重叠群定义的295至320 kb簇内，分离出了来自BWS患者的5个种系平衡染色体重排断点位点，以及来自横纹肌样瘤的一个平衡染色体重排断点。这个断点簇在印记基因IGF2着丝粒方向约100 kb处终止，在细胞周期蛋白依赖性激酶抑制剂p57KIP2端粒方向约100 kb处终止，并且位于亚染色体可转移片段内，这些片段在遗传互补实验中抑制胚胎性肿瘤细胞的生长。我们在这个BWS/肿瘤抑制基因重合区域鉴定出了11个转录序列，其中一个与p57KIP2相对应。然而，另外三个BWS断点在其他五个断点的着丝粒方向超过4兆碱基，并且被排除在由亚染色体可转移片段定义的肿瘤抑制区域之外。因此，多个基因座在11p15上定义了BWS和肿瘤抑制。
