Alterations of p16-pRb pathway and chromosome locus 9p21-22 in sporadic invasive breast carcinomas
Alterations of p16-pRb pathway and chromosome locus 9p21-22 in sporadic invasive breast carcinomas
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DOI：
10.1007/bf03401773
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发表时间：
1998-12-01
影响因子：
5.7
通讯作者：
Kittas, C
中科院分区：
文献类型：
--
作者：
Gorgoulis, VG;Koutroumbi, EN;Kittas, C
p16-pRb通路代表了重要的细胞周期检查点。在本研究中，我们调查了一系列的55例乳腺癌的G1期蛋白通路的改变，采用免疫组化和分子生物学方法，并与患者的临床病理特征的结果。此外，我们通过缺失图谱分析研究了其与染色体区域9 p21 -22状态的关系，因为有迹象表明，除了CDKN 2和MTS 2/p15（INK 4 B）肿瘤抑制基因（TSG）外，该区域还含有其他TSG。在26例（47%）和16例（29%）癌中观察到p16和pRb的异常表达（Ab），分别一个统计学趋势指出，p16和pRb表达之间的反比关系被发现（p = 0.079）。通过缺失定位、基于PCR的甲基化分析和PCR-SSCP分析p16编码区，发现缺失和甲基化导致的转录沉默可能是乳腺癌中CDKN 2/p16（INK 4A）失活的主要机制。缺失定位结果还提示，在9 p21 -22区域，特别是D9 S162位点可能存在另一个TSG，该基因与CDKN 2/p16（INK 4A）共缺失可能在乳腺癌发生中起作用。此外，微卫星不稳定性（MI），一个复制错误表型（RER+）的标记，观察到的频率为16%，在该地区的检查，并与杂合性丢失（洛）呈负相关。有趣的是，大多数在编码p16区域的MI病例聚集在乳腺癌亚组中，没有其他明显的遗传和/或表观遗传CDKN 2/p16（INK 4A）改变。我们推测CDKN 2/p16（INK 4A）失活还有另外一种机制。p16蛋白水平pRb、状态、p16-pRb联合免疫谱和在9 p21 -22位点检测到的微卫星改变与患者临床病理参数的关系揭示了两个显著相关性：pRb正常表达与淋巴结受累之间的关系（p = 0.0263），另一个在微卫星改变之间（洛缺失和/或MI）和肿瘤大小（p = 9.2 × 10（-3））。鉴于乳腺癌的异质性，我们认为在相当大比例的乳腺癌中，p16-pRb通路的失调与9 p21 -22区域的另一个尚未鉴定的TSG相关，可能在启动或进行致癌过程中起作用，而在其他亚组中，替代分子可能起此作用。
The p16-pRb pathway represents a vital cell-cycle checkpoint. In the present study we investigated the alterations of this G1-phase protein pathway using immunohistochemical and molecular methods in a series of 55 breast carcinomas and correlated the findings with clinicopathological features of the patients. Furthermore, we examined its relationship with the status of the chromosomal region 9p21-22 performing a deletion map analysis because there are indications that, in addition to CDKN2 and MTS2/p15(INK4B) tumor suppressor genes (TSGs), this area harbors other TSG(s).Aberrant expression (Ab) of p16 and pRb was observed in 26 (47%) and 16 (29%) of the carcinomas, respectively. A statistical trend pointing out an inverse relationship between p16 and pRb expression was found (p = 0.079). Analysis of the region that encodes for p16 by deletion mapping, a PCR-based methylation assay and PCR-SSCP, revealed that deletions and transcriptional silencing by methylation might represent the main mechanisms of CDKN2/p16(INK4A) inactivation in breast carcinomas. The results of deletion mapping also suggest that another TSG(s) may reside at the 9p21-22 area particularly at the D9S162 loci and that co-deletion of this putative gene with CDKN2/p16(INK4A) may play a role in breast carcinogenesis. Ln addition, microsatellite instability (MI), a marker of replication error phenotype (RER+), was observed with a frequency of 16% in the area examined and was inversely related with loss of heterozygosity (LOH). Interestingly, most cases with MI at the region encoding for p16 were aggregated in a subgroup of breast carcinomas with no other obvious genetic and/or epigenetic CDKN2/p16(INK4A) alterations. We speculate that there is an additional mechanism of CDKN2/p16(INK4A) inactivation. The relationship of p16 protein level pRb, status, the p16-pRb combined immunoprofiles, and the microsatellite alterations detected at the 9p21-22 locus with the patients' clinicopathological parameters revealed two significant correlations: one between normal pRb expression and lymph node involvement (p = 0.0263), and the other between microsatellite alterations (LOH and or MI) and tumor size (p = 9.2 x 10(-3)).In view of the heterogenous nature of breast cancer, we suggest that in a significant proportion of breast carcinomas, deregulation of the p16-pRb pathway in association with another, as-yet unidentified, TSG(s) of the 9p21-22 region may play a role in initiating or progressing the oncogenic procedure, while in other subgroups, alternative molecules may play this role.