ONCOGENE PROTEIN COEXPRESSION - VALUE OF HA-RAS, C-MYC, C-FOS, AND P53 AS PROGNOSTIC DISCRIMINANTS FOR BREAST-CARCINOMA
ONCOGENE PROTEIN COEXPRESSION - VALUE OF HA-RAS, C-MYC, C-FOS, AND P53 AS PROGNOSTIC DISCRIMINANTS FOR BREAST-CARCINOMA
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DOI：
10.1097/00000658-199506000-00010
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发表时间：
1995-06-01
影响因子：
9
通讯作者：
WANEBO, HJ
中科院分区：
文献类型：
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作者：
BLAND, KI;KONSTADOULAKIS, MM;WANEBO, HJ
使用传统的病理学标记物与癌基因蛋白、酶和激素因子结合，对预后变量进行改进，可能会提高预测乳腺癌患者复发或生存的能力。方法应用抗人乳腺癌基因蛋白的单克隆抗体cS93.1、9E1.0、F235-1.7.1和PAb 1801，应用抗生物素蛋白-生物素复合物免疫过氧化物酶法，对c-fos、c-myc、Ha-ras、p53、p54、p55、p56、p57、p58、p59、p p53分别。对85例乳腺癌患者（I期、IIA期和IIB期）的存档病理组织进行了分析。40名患者（47%）出现疾病复发; 45名患者在平均48个月（范围6-180个月）的随访时仍无局部区域或远处疾病。将分子生物学数据与临床病理人口统计学数据合并，1）确定该患者人群中癌基因的单一或共表达频率，2）评估这些分子蛋白标志物预测复发概率的价值; 3）确定所研究的癌基因与传统临床病理参数和总生存率相关的价值。结果在这项研究中，癌基因表达与复发有统计学相关性，共表达增加：一个癌基因17.2%，两个癌基因56.3%，三个或四个癌基因100%（p = 0.001）。癌基因或共癌基因表达增加与无病生存期和总生存期的统计学显著降低相关;无癌基因表达时，无病生存期为30（SE +/- 5.7）个月，总生存期为56.4（SE +/- 4.57）个月。在三种癌基因表达的情况下，无病生存期为12（SE +/- 1.23）个月（p = 0.0018），总生存期为23.4（SE +/- 3.38）个月（p = 0.0025）。在单变量Wilcoxon分析中，癌基因表达是确定生存期的最重要变量（p = 0.035）;在多变量分析中，年龄和癌基因共表达均成为总生存期的最重要变量。对于比例风险回归模型，癌基因共表达是显著的（p = 0.0104，风险比1.914），并与年龄和肿瘤大小作为显著变量相关。Ha-ras和c-fos都是影响生存率的重要癌基因蛋白（分别为p = 0.0925，风险比3.517和p = 0.025，风险比4.214）。原癌基因c-myc和抗肿瘤抑制基因p53作为单个癌基因对生存率没有显着影响。结论本分析中大约五分之一的乳腺癌患者（无病和复发）仅表达一种癌基因标记物（c-fos、c-myc、Ha-ras或p53）;四分之一的复发性疾病患者仅表达一种癌基因蛋白。单个癌基因的表达对预测复发没有独立的预后意义。此外，p53突变并不作为预后的独立相关因素。研究的原癌基因（c-myc，Ha-ras）和核转录蛋白（c-fos）的共同表达作为一个强有力的预后相关的复发和生存;单个癌基因预测生存的效果是最大的Ha-ras和c-fos。三种癌基因蛋白在肿瘤转化中的即时或早期共表达赋予浸润性癌细胞侵袭性表型。这种侵袭性表型在一小部分研究人群（11%）中是明显的，并预测了不良的无病生存率和总生存率。这些研究结果表明，癌基因共表达具有显着的预后和潜在的治疗价值，将这种分子技术纳入未来的前瞻性随机试验是可取的。
ObjectiveA refinement of prognostic variables using traditional pathologic markers integrated with oncogene proteins, enzymes, and hormonal factors may enhance the ability to predict for recurrence or survival in patients with mammary carcinoma. Although various oncogenes and oncogene products have been identified in human breast carcinoma, their relationship to disease outcome remains controversial.MethodsUsing the monoclonal antibodies cS93.1, 9E1.0, F235-1.7.1, and PAb 1801 against each oncogene protein studied, the avidin-biotin complex immunoperoxidase method provided immunohistochemical staining of bound oncogene protein for c-fos, c-myc, Ha-ras, and p53, respectively. Analyses were made on archival pathology tissues of 85 breast cancer patients (stages I, IIA, and IIB). Forty patients (47%) had recurrence of disease; 45 remained free of local-regional or distant disease at mean follow-up of 48 months (range 6-180 months). Molecular biological data were merged with clinicopathologic demographics 1) to determine the frequency of single or co-expression of oncogenes in this patient population, 2) to evaluate the Value of these molecular protein markers to predict probability of recurrence; and 3) to determine worth of the studied oncogenes to correlate with traditional clinical pathologic parameters and overall survival.ResultsIn this study, oncogene expression had statistical correlation for recurrence with increasing coexpression: one oncogene 17.2%, two oncogenes 56.3%, three or four oncogenes, 100% (p = 0.001). Increasing oncogene or co-oncogene expression correlated with statistically significant reduction in disease-free and overall survival; with no expression of oncogenes, disease-free survival was 30 (SE +/- 5.7) months and overall survival was 56.4 (SE +/- 4.57) months. With expression of three oncogenes, disease-free survival was 12 (SE +/- 1.23) months (p = 0.0018) and overall survival was 23.4 (SE +/- 3.38) months (p = 0.0025). In univariate Wilcoxon analysis, oncogene expression was the most significant variable to determine survival (p = 0.035); in multivariate analysis, age and oncogene co-expression each emerged as the most significant variables for overall survival. For the proportional hazards regression model, oncogene coexpression was significant (p = 0.0104, risk-ratio 1.914) and correlated with age and tumor size as significant variables. Ha-ras and c-fos both emerged as important individual oncogene proteins to affect survival (p = 0.0925, risk-ratio 3.517 and p = 0.025, risk-ratio 4.214, respectively). The proto-oncogene c-myc and the antitumor suppressor gene p53 did not have significant effects as individual oncogenes to influence survival.ConclusionsApproximately one fifth of the breast cancer patients in this analysis (disease-free and recurrent) expressed only a single oncogene marker (c-fos, c-myc, Ha-ras, or p53); one quarter of patients with recurrent disease expressed only one oncogene protein. Single oncogene expression did not possess independent prognostic significance for prediction of recurrence. Further, p53 mutations did not function as independent correlates for prognosis. The co-expression of the studied protooncogenes (c-myc, Ha-ras) and the nuclear transcriptional protein (c-fos) functioned as a strong prognostic correlate for recurrence and survival; the effect of individual oncogenes to predict survival was greatest for Ha-ras and c-fos. Immediate or early co-expression of three oncogene proteins in neoplastic transformation endowed cells of invasive carcinoma with an aggressive phenotype. This aggressive phenotype was evident in a small percentage of the studied population (11%) and predicted adverse disease-free and overall survival. These findings suggest that oncogene co-expression possesses significant prognostic and potential therapeutic value; incorporation of this molecular technology into future prospective randomized trials is advisable.