Schultz D C, Vanderveer L, Buetow K H, Boente M P, Ozols R F, Hamilton T C, Godwin A K
Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Cancer Res. 1995 May 15;55(10):2150-7.
We have examined 41 forms of ovarian cancer for genetic alterations on chromosome 9 using a combination of five RFLP DNA probes and 15 simple tandem repeat polymorphisms. Genetic imbalance (i.e., loss of heterozygosity, microsatellite instability, amplification) for 1 or more informative markers on chromosome 9 was observed in 66% (27 of 41) of our tumor panel. Genetic imbalance was observed on 9q in 59% (24 of 41) of tumors informative for at least one locus. In contrast, only 13% (5 of 40) of informative tumors demonstrated a genetic alteration involving 9p. Furthermore, allelic loss on 9q was more common in late stage tumors (63%, 17 of 27) and poorly differentiated tumors (75%, 15 of 20) as compared to benign and early stage tumors (30%, 3 of 10). Evaluation of 15 tumors showing limited regions of genetic imbalance has identified 2 candidate tumor suppressor regions on 9q and 1 on 9p. Interestingly, the regions defined to 9p21-p24, 9q31, and 9q32-q34 all overlap with several known disease loci. In this aspect, the potential role of the CDKN2 gene at 9p21-p22 in ovarian carcinogenesis was assessed in an extended panel of ovarian tumors, 11 human ovarian carcinoma cell lines, and 1 cervical tumor cell line. With the use of comparative multiplex PCR, homozygous deletions were detected in 16 of 115 (14%) fresh tumors and 3 of 12 cancer cell lines. For those tumors demonstrating allelic loss for markers on 9p no somatic mutations were observed in the retained allele of CDKN2, as determined by single-strand conformation polymorphism analysis, but a mutation was observed in an additional cell line. Furthermore, CDKN2 mRNA levels were similar in the 9 cancer cell lines that retain CDKN2, as compared to normal human ovarian surface epithelial cell lines. Overall, our results suggest the potential involvement of a gene or genes on chromosome 9q and de-emphasize a significant role for the CDKN2 gene on 9p in the initiation and progression of ovarian cancer.
我们使用5种限制性片段长度多态性（RFLP）DNA探针和15种简单串联重复多态性，对41种卵巢癌形式进行了9号染色体基因改变检测。在我们的肿瘤样本中，66%（41例中的27例）观察到9号染色体上1个或更多信息性标记的基因失衡（即杂合性缺失、微卫星不稳定性、扩增）。在至少一个位点有信息的41例肿瘤中，59%（24例）在9q上观察到基因失衡。相比之下，在有信息的肿瘤中，只有13%（40例中的5例）显示涉及9p的基因改变。此外，与良性和早期肿瘤（30%，10例中的3例）相比，9q上等位基因缺失在晚期肿瘤（63%，27例中的17例）和低分化肿瘤（75%，20例中的15例）中更常见。对15例显示有限基因失衡区域的肿瘤进行评估，在9q上确定了2个候选肿瘤抑制区域，在9p上确定了1个。有趣的是，定位于9p21 - p24、9q31和9q32 - q34的区域都与几个已知疾病位点重叠。在这方面，在一组扩大的卵巢肿瘤、11个人卵巢癌细胞系和1个宫颈肿瘤细胞系中评估了9p21 - p22处CDKN2基因在卵巢癌发生中的潜在作用。使用比较多重PCR，在115例新鲜肿瘤中的16例（14%）和12例癌细胞系中的3例检测到纯合缺失。对于那些显示9p上标记等位基因缺失的肿瘤，通过单链构象多态性分析确定，在保留的CDKN2等位基因中未观察到体细胞突变，但在另一个细胞系中观察到了1个突变。此外，与正常人卵巢表面上皮细胞系相比，保留CDKN2的9个癌细胞系中CDKN2 mRNA水平相似。总体而言，我们的结果表明9号染色体q臂上一个或多个基因可能参与其中，而9p上的CDKN2基因在卵巢癌的发生和发展中不发挥重要作用。
