ALTERATION OF THE P53 TUMOR-SUPPRESSOR GENE OCCURS INDEPENDENTLY OF K-RAS ACTIVATION AND MORE FREQUENTLY IN SEROUS ADENOCARCINOMAS THAN IN OTHER COMMON EPITHELIAL TUMORS OF THE HUMAN OVARY
ALTERATION OF THE P53 TUMOR-SUPPRESSOR GENE OCCURS INDEPENDENTLY OF K-RAS ACTIVATION AND MORE FREQUENTLY IN SEROUS ADENOCARCINOMAS THAN IN OTHER COMMON EPITHELIAL TUMORS OF THE HUMAN OVARY
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DOI：
10.1111/j.1349-7006.1994.tb02937.x
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发表时间：
1994-12-01
期刊：
影响因子：
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通讯作者：
NOMURA, T
中科院分区：
文献类型：
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作者：
FUJITA, M;ENOMOTO, T;NOMURA, T
为了阐明p53肿瘤抑制基因在人卵巢上皮性肿瘤发生发展中的作用，并研究p53改变与K-ras激活的关系，我们对来自日本的70例常见卵巢上皮性肿瘤进行了研究。其中浆液性腺癌31例，黏液性腺癌12例，交界性恶性黏液性肿瘤5例，子宫内膜样腺癌13例，透明细胞癌9例。通过限制性内切片段长度多态性分析和聚合酶链反应（PCR）扩增DNA片段的单链构象多态性（SSCP）分析，36例患者中有14例（39%）检测到p53基因密码子72多态性位点的等位基因缺失。通过pcr扩增片段的SSCP分析，检测到了p53基因高度保守区域的突变。70例卵巢肿瘤中有22例（31%）存在突变，其中5例交界性恶性粘液瘤中有1例存在突变。突变随后通过直接测序进行表征。在13例卵巢癌和1例交界性恶性黏液性肿瘤中检测到单义碱基替换。8例出现1 ~ 8 bp的短缺失和插入。p53基因突变在浆液性腺癌中的发生率（14/31,45%）高于所有非浆液性恶性上皮肿瘤的总和（7/34,21%；P=0.032）。通过pcr扩增片段与突变特异性寡核苷酸的点杂交分析和直接测序，鉴定了K-ras的点突变。K-ras突变的总频率为19/70（27%）。17例黏液性肿瘤中有12例（71%）存在K-ras突变（8/12黏液性癌[67%]和4/5交界性恶性黏液性肿瘤[80%]），其发生率高于浆液性癌（4/ 31,13%，P=0.00009）或所有非黏液性卵巢上皮性肿瘤的发生率（7/ 53,13%，P=0.00002）。这些数据表明，癌基因和/或抑癌基因的不同组合可能参与了组织学上不同类型的人类卵巢常见上皮肿瘤的发生和发展。
To clarify the role of the p53 tumor suppressor gene in the development of human ovarian epithelial tumors and to study the association of p53 alterations with K-ras activation, a series of 70 common epithelial ovarian tumors from Japanese patients was studied. These included 31 serous adenocarcinomas, 12 mucinous adenocarcinomas, 5 mucinous tumors of borderline malignancy, 13 endometrioid adenocarcinomas, and 9 clear cell carcinomas. Allelic loss, recognized at the polymorphic site in codon 72 of the p53 gene, was detected in 14 of 36 (39%) informative cases by restriction fragment length polymorphism analysis and by single-strand conformation polymorphism (SSCP) analysis of polymerase chain reaction(PCR)-amplified DNA fragments. Mutations in the highly conserved regions of the p53 gene were detected by SSCP analysis of PCR-amplified fragments. Mutations were found in 22 of 70 (31%) ovarian tumors, including 1 of 5 mucinous tumors of borderline malignancy. Mutations were subsequently characterized by direct sequencing. Single missense base substitutions were detected in 13 ovarian carcinomas and in one case of mucinous tumor of borderline malignancy. Short (1-8 bp) deletions and insertions were found in 8 cases. Mutations in the p53 gene occurred more frequently in serous adenocarcinomas (14/31, 45%) than in all nonserous types of malignant epithelial tumors combined (7/34, 21%; P=0.032). Point mutations in K-ras were identified by dot blot hybridization analysis of PCR-amplified fragments with mutation-specific oligonucleotides and by direct sequencing. The overall frequency of K-ras mutations was 19/70 (27%). K-ras mutations were found in 12 of 17 (71%) mucinous tumors (8/12 mucinous carcinomas [67%] and 4/5 mucinous tumors of borderline malignancy [80%]), and occurred more frequently than in serous carcinomas (4/31, 13%; P=0.00009) or in all nonmucinous types of ovarian epithelial tumors combined (7/53, 13%; P=0.00002). These data suggest that different combinations of oncogenes and/or tumor suppresser genes may be involved in the genesis and development of histologically distinct categories of common epithelial tumors of the human ovary.