Habuchi T, Kinoshita H, Yamada H, Kakehi Y, Ogawa O, Wu W J, Takahashi R, Sugiyama T, Yoshida O
Department of Urology, Faculty of Medicine, Kyoto University, Japan.
J Natl Cancer Inst. 1994 Sep 7;86(17):1331-5. doi: 10.1093/jnci/86.17.1331.
Previously, p53 (also known as TP53) gene mutations have been shown to be frequently detected in highly malignant urothelial cancers. Evidence has been accumulating that the disruption of the normal function of p53 may lead to genomic instability, including predisposition to gene amplification. Furthermore, the normal function of p53 may be abrogated by MDM2 (murine double minute-2) gene amplification in some human tumors.
Our purpose was to investigate the relationship between protooncogene amplification and p53 alteration in urothelial cancers by examining the existence of amplification of MDM2 and 14 other protooncogenes in 50 urothelial tumors in which p53 gene status was known.
We analyzed gene amplification by Southern-blot analysis in 50 urothelial cancer specimens. These tumors were previously examined for p53 mutations by polymerase chain reaction-single-strand conformation analysis, and 17 tumors contained p53 mutations.
Two high-grade advanced tumors (4%) without p53 mutation harbored MDM2 amplification with concurrent int-2 gene amplification. As for other genes, amplification was detected for int-2 (also known as WNT2) (seven [14%] of 50), erbB-2 (also known as ERBB2) (three [6%] of 50), N-ras (also known as NRAS) (one [2%] of 50), L-myc (also known as MYCL1) (one [2%] of 50), and raf-1 (also known as RAF1) (one [2%] of 50). The amplification of at least one gene examined was observed in 11 (22%) of 50 tumors. The presence of p53 mutations was not significantly associated with the occurrence of gene amplification, since the amplification was detected in six (35%) of 17 tumors with p53 mutations and in five (15%) of 33 tumors without p53 mutations. However, eight (73%) of 11 tumors with proto-oncogene amplification harbored p53 mutations or MDM2 amplification.
A subset of advanced urothelial cancers without p53 mutations may harbor MDM2 amplification. This finding should be taken into account when adopting p53 alteration as a marker of aggressiveness in urothelial cancers. Although the abrogation of normal p53 function may be one of the key steps to protooncogene amplification, the data further indicate that the predisposition to gene amplification in urothelial cancers was not determined by the presence of p53 alteration alone.
此前研究表明，在高恶性尿路上皮癌中经常检测到p53（也称为TP53）基因突变。越来越多的证据表明，p53正常功能的破坏可能导致基因组不稳定，包括基因扩增倾向。此外，在一些人类肿瘤中，MDM2（小鼠双微体-2）基因扩增可能会废除p53的正常功能。
我们的目的是通过检测50例已知p53基因状态的尿路上皮肿瘤中MDM2和其他14种原癌基因的扩增情况，来研究尿路上皮癌中原癌基因扩增与p53改变之间的关系。
我们通过Southern印迹分析对50例尿路上皮癌标本进行基因扩增分析。这些肿瘤之前通过聚合酶链反应-单链构象分析检测过p53突变，其中17例肿瘤含有p53突变。
2例无p53突变的高级别进展期肿瘤（4%）存在MDM2扩增并伴有int-2基因扩增。至于其他基因，检测到int-2（也称为WNT2）扩增（50例中有7例[14%]）、erbB-2（也称为ERBB2）扩增（50例中有3例[6%]）、N-ras（也称为NRAS）扩增（50例中有1例[2%]）、L-myc（也称为MYCL1）扩增（50例中有1例[2%]）和raf-1（也称为RAF1）扩增（50例中有1例[2%]）。50例肿瘤中有11例（22%）观察到至少一种检测基因的扩增。p53突变的存在与基因扩增的发生无显著相关性，因为在17例有p53突变的肿瘤中有6例（35%）检测到扩增，在33例无p53突变的肿瘤中有5例（15%）检测到扩增。然而，11例有原癌基因扩增的肿瘤中有8例（73%）存在p53突变或MDM2扩增。
一部分无p53突变的进展期尿路上皮癌可能存在MDM2扩增。在将p53改变作为尿路上皮癌侵袭性标志物时应考虑这一发现。虽然p53正常功能的废除可能是原癌基因扩增的关键步骤之一，但数据进一步表明，尿路上皮癌中基因扩增的倾向并非仅由p53改变决定。
