Pollack A, Czerniak B, Zagars G K, Hu S X, Wu C S, Dinney C P, Chyle V, Benedict W F
Department of Radiotherapy, The University of Texas M. D. Anderson Cancer Center, Houston, USA.
Int J Radiat Oncol Biol Phys. 1997 Oct 1;39(3):687-95. doi: 10.1016/s0360-3016(97)00147-8.
The retinoblastoma protein (pRB) is a key regulator of the G1 cell cycle checkpoint and has been implicated as having a role in G1 arrest and apoptosis induced by radiation damage. In this report we examine the association between pRB expression and radiation response in patients treated between 1960 and 1983 with preoperative radiotherapy (50 Gy in 25 fractions) followed 4-6 weeks later by radical cystectomy. The correlation of pRB to patient outcome and how this relationship is complimentary to that seen with p53 staining status is also described.
Immunohistochemical staining of pRB and p53 in paraffin-embedded tumor sections using WL-1 anti-RB and DO1 anti-p53 antibodies was considered adequate in 98 and 97 pretreatment tumor samples, respectively. There were 46 patients with clinical Stage T2, 28 with Stage T3a, and 24 with Stage T3b disease. The median age was 62 years and follow-up for those living was 85 months.
Staining for pRB was negative in 30% of the cases. Correlations were observed between pRB negativity and high pretreatment apoptosis level (p = 0.06), locally advanced clinical stage (p = 0.01), increased clinical-to-pathologic downstaging (p = 0.014), and more pathologic complete responses (Path-CRs; p = 0.019). Several other factors were tested and were not associated with pRB status, including p53 expression. RB status was the only pretreatment prognostic factor in the univariate analyses that correlated with downstaging and was independently associated with Path-CR using multivariate logistic regression. Despite these significant relationships, no correlations with patient outcome were observed when the entire cohort was analyzed. Restriction of the analyses to Stage T3b patients, however, revealed that pRB negativity predicted for enhanced distant metastasis freedom (p = 0.006, log rank) and overall survival (p = 0.02). The overexpression of p53 also correlated with distant metastasis freedom and overall survival in Stage T3b patients. Patient outcome was best when RB negative and p53 negative staining were seen.
Our results indicate that loss of RB function as measured by immunohistochemical staining is the strongest correlate of radiation response thus far recognized. Loss of RB expression also predicted for poor outcome in Stage T3b patients, which appeared to compliment the finding of normal p53 expression. While normal RB protein expression is usually associated with better patient outcome, other series have not examined patients treated with radiotherapy. The absence of pRB may be a useful marker for selecting patients for bladder preservation with radiotherapy, particularly when wild-type p53 is present.
视网膜母细胞瘤蛋白（pRB）是G1期细胞周期检查点的关键调节因子，并且被认为在辐射损伤诱导的G1期阻滞和细胞凋亡中发挥作用。在本报告中，我们研究了1960年至1983年间接受术前放疗（25次分割，共50 Gy）、4 - 6周后行根治性膀胱切除术的患者中pRB表达与放射反应之间的关联。还描述了pRB与患者预后的相关性，以及这种关系如何与p53染色状态的关系互补。
分别使用WL - 1抗RB抗体和DO1抗p53抗体对石蜡包埋的肿瘤切片进行pRB和p53的免疫组织化学染色，在98例和97例预处理肿瘤样本中被认为是充分的。有46例临床T2期患者，28例T3a期患者和24例T3b期患者。中位年龄为62岁，存活患者的随访时间为85个月。
30%的病例中pRB染色为阴性。观察到pRB阴性与预处理时高细胞凋亡水平（p = 0.06）、局部晚期临床分期（p = 0.01）、临床 - 病理降期增加（p = 0.014）以及更多的病理完全缓解（Path - CR；p = 0.019）之间存在相关性。还测试了其他几个因素，它们与pRB状态无关，包括p53表达。在单变量分析中，RB状态是与降期相关的唯一预处理预后因素，并且使用多变量逻辑回归与Path - CR独立相关。尽管存在这些显著关系，但在分析整个队列时未观察到与患者预后的相关性。然而，将分析限制在T3b期患者中发现，pRB阴性预测远处转移自由度增加（p = 0.006，对数秩检验）和总生存期延长（p = 0.02）。p53的过表达在T3b期患者中也与远处转移自由度和总生存期相关。当RB阴性和p53阴性染色同时出现时患者预后最佳。
我们的结果表明，通过免疫组织化学染色测量的RB功能丧失是迄今为止所认识到的与放射反应最强的相关性。RB表达的丧失也预测T3b期患者预后不良，这似乎补充了p53表达正常的发现。虽然正常RB蛋白表达通常与更好的患者预后相关，但其他系列研究未对接受放疗的患者进行检查。pRB的缺失可能是选择接受放疗以保留膀胱的患者的有用标志物，特别是当存在野生型p53时。
