The relationship of clinical classification to ras p21 expression in human non-small cell lung cancer

The relationship of tumor size, status of disease in the TNM classification, and stage of disease to ras oncogene expression was studied in human non-small cell lung cancer materials immunohistochemically using monoclonal antibody rp-35 against ras 21. Materials of adenocarcinoma and squamous cell carcinoma obtained from primary sites larger than 30 mm in diameter exhibited intensely positive reactions with rp-35 significantly more frequently than those with primary sites, 30 mm in diameter or smaller (p less than 0.01). Furthermore in the TNM classification, cases with T2 (with primary sites larger than 30 mm in diameter) or T3 (with direct extension to adjacent structures) showed significantly higher reaction with rp-35 than those with T1 (with primary sites 30 mm in diameter or smaller) (p less than 0.01), although N and M status did not correlate with ras p21 expression. These results suggest that ras oncogene may play a significant role in growth or tumorigenesis at the primary site in human non-small cell lung cancer.     

Establishment of four mouse hybridoma cell lines producing monoclonal antibodies reactive with ras oncogene product p21

With the use of proteins derived from Escherichia coli cells expressing the v-H-ras gene product as immunogens and an enzyme-linked immunosorbent assay with whole cells for a screening method, 4 BALB/c mouse hybridoma cell lines (rp-12, rp-28, rp-35, and rp-38) were isolated that produced monoclonal antibodies (MoAbs) showing higher reactivity with murine ras gene-activated cell lines than with normal cell lines. All the MoAbs complexed p21ras from the ras gene-activated cell lines in Western immunoblot analysis and demonstrated a binding property of p21ras to guanine nucleotides. The indirect immunofluorescence assay revealed that MoAbs rp-12 and rp-28 stained the murine and human H- or K-ras-activated cell lines, and MoAbs rp-35 and rp-38 not only stained these cell lines but also weakly stained a human N-ras-activated cell line. All these MoAbs stained the murine fibroblast lines with lower intensity, but they did not stain a human fibroblast line. Further, positive reactions with MoAb rp-12 were seen against human melanomas, but there was no reaction against nevi. The rp-12, rp-28, rp-35, and rp-38 antibodies are useful additions to the MoAbs reacting with p21ras reported previously.     

Ras and p53 expression in non-small-cell lung-cancer patients - p53 over-expression correlates with a poor prognosis

Expression of the tumor suppressor gene p53 and the ras oncogene were examined in 46 tumor and nodal specimens of non-small cell lung cancer (NSCLC) using the antibodies p53 pAb 240 and ras Y13-259 respectively. p53 expression was elevated in 46% and ras p21 was over-expressed in 85% of the tumor specimens analyzed. Fifteen cases of benign lessions were also assessed for both ras p21 and p53 expression; all were found to have negative staining. p53 over-expression was found to correlate with a poor prognosis in both the tumor specimens (p<0.05) and in the nodal tissues (p<0.005). Ras p21 over-expression was found to be associated with survival (p<0.1) in both the tumor and the nodal specimens. Stage of the disease correlated with survival; similarly both p53 and ras p21 over-expression correlated with stage. No correlations were found with the pathological grade of the tumors nor with a history of smoking or duration of smoking. No K-ras mutations at codon 12 were observed in a further 15 NSCLC specimens analyzed. These results indicate that the p53 gene in particular plays a role in the stages of NSCLC.     

Immunohistochemical study of ras p21 expression in human gastric cancers and benign lesions

Expression of ras p21 in human gastric cancers, benign lesions and normal tissues was immunohistochemically evaluated by the avidin-biotin peroxidase complex (ABC) method with anti-ras p21 monoclonal antibody rp-28. Positive p21 immunoreactivity was shown in 23 (77%) of 30 gastric cancers, in 13 (48%) of 27 benign lesions and in 10 (22%) of 46 normal mucosa cases. Among them, strong staining was demonstrated only in 11 (37%) of 30 gastric cancers, but not in benign lesions and normal tissues. Cases showing more than 20% positive cell ratio were observed in 22 (73%) gastric cancers, in 11 (41%) benign lesions and 6 (13%) normal mucosa cases. Further, intracellular distribution of ras p21 is heterogeneous in gastric cancers, while it is homogeneous in benign lesions or normal tissues. The ABC method with rp-28 could be helpful for clinical differential diagnosis between gastric cancers and benign lesions by investigating three factors: staining intensity, positive cell ratio and intracellular distribution of ras p21.     

Histologic demonstration of antigens reactive with anti-p21 ras monoclonal antibody (RAP-5) in human stomach cancers

The immunohistochemical reactivity of RAP-5, a monoclonal antibody (MoAb) raised against a synthetic peptide corresponding to positions 10-17 of the ras gene product from T24 bladder carcinoma, was studied in 96 surgically resected stomach cancers of humans. The cytoplasm of cancer cells in 65 cases (68%) was positively stained with MoAb RAP-5, although the staining was heterogeneous among cancer cells. There was no definite correlation between depth of tumor invasion and reactivity to MoAb RAP-5. Cancer cells of poorly differentiated tumors showed a tendency to react less frequently and less intensely to MoAb RAP-5. In nontumorous gastric mucosa, parietal cells and some portions of intestinal metaplasia were stained with MoAb RAP-5. These findings suggest an increased expression of the ras gene product (p21) in about two-thirds of gastric adenocarcinomas and in some nonneoplastic gastric epithelial cells.     

Five-year follow-up study of independent clinical and flow cytometric prognostic factors for the survival of patients with non-small cell lung carcinoma

Fresh surgical specimens of tumors of 187 patients with previously untreated non-small cell lung carcinomas were investigated by means of flow cytometry. The aim of the study was to look for cellular prognostic indicators for survival times of these patients in addition to the well-known clinical prognostic factors. All patients had a minimum of 5 years follow-up. Patients with aneuploid tumors had significantly shorter survival times than did those with diploid tumors (P less than or equal to 0.001). Identical results are obtained when the analysis is restricted to just those patients with T3 tumors or to patients with metastatic tumors at time of surgery or who were classified as Stage III (P less than or equal to 0.01). These data indicate that DNA ploidy is a strong and independent prognostic factor in patients with non-small cell lung carcinoma. Patients having tumors with a high proliferative activity died significantly (P less than 0.05) earlier than patients having tumors with lower proliferative activity. As with tumor ploidy, survival time in patients with high or low proliferative tumor activities was independent of whether the patients had T3-tumors, metastases, or were in Stage III. Univariate and multivariate analyses of the data in this study demonstrate two groups of independent prognostic factors for the survival of patients with non-small cell lung carcinoma: a group of clinical factors and a group of flow cytometric factors.     

Prognostic value of k-ras 12 genotypes in patients with advanced nonsmall cell lung-cancer receiving Carboplatin with either intravenous or chronic oral dose Etoposide

Despite the knowledge of strong prognostic factors such as stage and performance status, the outcome of individual patients with non-small cell lung cancer is not yet predictable, although it has been observed that patients whose tumors contain K-ras gene mutations at codon 12 have a shortened survival. We compared response rate, toxicity and survival of patients with non-small cell lung cancer receiving carboplatin 325 mg/m2 on day 1 with either intravenous etoposide (100 mg/m2 days 1-3) or oral etoposide (50 mg/m2/day) for 21 consecutive days. Secondly, we sought to find whether K-ras mutations or their genotypes could help to distinguish tumor types with clinical implications on prognosis. 180 patients were entered in this randomized study. Tumor specimens obtained at the time of bronchoscopy were available in 71 cases. 167 patients were assessable for response. We obtained 24 objective responses out of 88 patients (27%) in the intravenous etoposide plus carboplatin arm and 14 out of 79 patients (18%) in the oral etoposide plus carboplatin arm. Neither the objective response rate nor the survival time showed a significant difference between the two groups. Toxicity consisted mainly of myelosuppression. We detected 20 ras gene mutations in the 71 (28%) tumors analyzed. None of the 7 patients with aspartic and serine ras mutations had objective response as compared with 2 of 13 patients (15%) whose tumors contained cysteine, valine and arginine mutations and 16 of the 51 patients (31%) who had no ras mutations. Patients whose tumors had aspartic and serine mutations had a median survival time of 18 weeks in contrast with 36 weeks for the remainder (P=0.04). This study highlights the fact that K-ras genotypes may be an important prognostic variable in patients with advanced non-small cell lung cancer.     

Ⅰ期非小细胞肺癌预后因素的探讨

目的 探讨脂肪酸合成酶(FASE)、HER-2／neu、bcl-2和p63在Ⅰ期非小细胞肺癌(NSCLC)中的表达及其预后意义。方法 采用免疫组织化学法,对84例Ⅰ期肺癌手术标本进行FASE、HER-2／neu、bcl-2和p63蛋白的检测,分析各标志物与多种临床因素及预后的关系。结果 FASE、HER-2／neu、bcl-2和p63在Ⅰ期NSCLC中的阳性表达率分别为29.8％、40．5％、33．3％和39．3％。FASE阳性和阴性患者的术后局部复发率分别为28．0％和10．2％,差异有显著性(P=0．050);骨转移率分别为61．5％和23．9％,差异有极显著性(P=0．007)。HER-2／neu阳性和阴性患者的5年生存率分别为37．7％和67．7％(P=0．008),FASE阳性和阴性患者的5年生存率分别为35．1％和66．1％,差异均有极显著性(P均=0．008),表明HER-2／neu和FASE的表达与预后明显相关。HER-2／neu和FASE均为阴性的患者5年生存率为78．2％,均为阳性的患者5年生存率为36．3％,差异有极显著性(P=0．002)。然而,bcl-2和p63未发现有临床预后意义。结论 HER-2／neu和FASE是Ⅰ期非小细胞肺癌的独立预后因素,HER-2／neu和FASE阳性患者的预后差。     

DNA polymerase-alpha as a putative early relapse marker in non-small cell lung cancer. An immunohistochemical study.

The authors examined 72 fresh frozen sections of primary lung cancer using a monoclonal antibody for DNA polymerase-alpha (POL-alpha). The percentage of POL-alpha-positive cells was 17.3%. The tumors were divided into two groups. In one group, more than 5% of the POL-alpha-positive cells were designed POL-alpha-positive, and in the other group less than 5% were POL-alpha-negative. The incidence of POL-alpha-positive in men was statistically higher than that in women (P less than 0.05). The incidence correlated with the T (tumor) status, with a significance. Based on data on 43 patients with non-small cell lung cancer and who underwent a complete resection, the 3-year disease-free survival rates of POL-alpha-positive and POL-alpha-negative cells were 42% and 81%, respectively (P less than 0.05). When the patients were restricted to the class of N0 disease or Stage I, all the patients diagnosed as a cases of a relapse of lung cancer were POL-alpha positive. The 3-year disease-free survival rate of patients with POL-alpha negative was 100%. Our data suggest that in cases of non-small cell lung cancer, POL-alpha expression is associated with the extent of malignancy and a recurrence. Thus POL-alpha may prove to be a pertinent marker of an early relapse.     

Expression of ras oncogene p21 protein in esophageal squamous cell carcinoma

In order to investigate the value of ras oncogene expression as a prognostic indicator in esophageal squamous cell carcinoma, we evaluated the level of ras oncogene protein product (p21) in 52 specimens resected between 1977 and 1986. All patients were followed until death or for at least 2 years. Pathology slides and archival paraffin blocks were retrieved for confirmation of the original diagnosis, study of histopathologic features, and measurement of p21 content. P21 titers were obtained using the RAP-5 monoclonal antibody in a semiquantitative immunohistochemical assay. Titer was expressed as the highest dilution of antibody giving definitive staining using the avidin-biotin peroxidase method. Ras oncogene was expressed in 88.5% of the specimens. We did not find a significant correlation between ras expression and any of a variety of clinical and histopathologic prognostic parameters. Although patients' median survival after resection of specimens with ras oncogene expression was less than half the median survival after removal of tumors without such expression, this difference was not statistically significant. Further prospective investigations are needed to assess the role of ras oncogene evaluation in clinical practice.     

Prognostic significance of p27KIP1 protein and ki-67 growth fraction in non-small cell lung cancers.

We immunohistochemically examined specimens of 215 surgically resected non-small cell lung cancers (NSCLCs) for p27KIP1 protein (p27) expression and the growth fraction determined by the Ki-67 labeling index (LI). The NSCLCs analyzed showed considerable heterogeneity in both p27 and Ki-67 LIs; 25 of 207 (13%) lacked p27 expression (p27 LI < 5%), and 116 of 215 (54%) showed a high Ki-67 LI (>30%). The p27 LI was not significantly associated with the Ki-67 LI. A chi2 test showed that loss of p27 expression was inversely correlated with smoking (P = 0.01) and that a high Ki-67 LI was significantly associated with male gender, squamous cell carcinoma histology, and smoking (P < 0.0001 each). Prognostic values of p27 and Ki-67 expression were evaluated in 109 tumors of postsurgical pathological stages I and II. Patients with tumors lacking p27 expression survived for a significantly shorter time than patients with tumors expressing p27 (5-year survival rates, 38% and 68%, respectively; P = 0.02). Patients with tumors having a high Ki-67 LI survived for a significantly shorter time than patients with tumors having a low Ki-67 LI (5-year survival rates, 48% and 78%, respectively; P = 0.005). Multivariate analysis showed that loss of p27 expression tended to be an unfavorable prognostic factor (P = 0.054), whereas a high Ki-67 LI was a significant and independent unfavorable prognostic factor (P = 0.004). When analyzed by cell types, loss of p27 expression was a significant and independent unfavorable prognostic factor in squamous cell carcinomas (P = 0.01), whereas a high Ki-67 LI was a significant and independent unfavorable prognostic factor in nonsquamous cell carcinomas (P = 0.007). We further evaluated the importance of p27 expression in clinical outcome in combination with the Ki-67 LI and ras p21 protein (ras) expression, which we previously reported as an important prognostic factor in NSCLCs. Patients with tumors lacking p27 expression and having a high Ki-67 LI survived for a significantly shorter time than those with tumors expressing p27 and having a high Ki-67 LI (5-year survival rates, 17% and 52%, respectively; P = 0.003). Patients with p27-negative and ras-positive tumors survived for a significantly shorter time than those with both p27- and ras-positive tumors (5-year survival rates, 0% and 38%, respectively; P < 0.0001). These results indicate the pivotal roles of p27 and Ki-67 expression in the clinical outcome of NSCLCs.     

Low levels of ras p21 oncogene expression correlates with clinical outcome in head and neck squamous cell carcinoma.

We have previously demonstrated that the Ha-ras and the Ki-ras oncogenes are overexpressed in squamous cell carcinoma of the head and neck. In this study we have used the Y13-259 monoclonal antibody to p21 ras to determine if expression of the ras oncoprotein correlates with any of the clinico-pathological parameters or with survival in 69 patients with squamous cell carcinoma of the head and neck. Forty-four specimens were from patients with previously untreated tumours and 25 from patients with previously treated disease. We have found a correlation between low levels of ras expression and the disease-free survival period in patients with previously untreated tumours. Three per cent of the patients with ras negative staining were alive 60 months after diagnosis, whereas 54 per cent of the patients with positive staining were still alive after the same time period (P less than 0.05).     

In vitro analysis of the cellular proliferative response to 17-beta-estradiol of human breast cancer

In human breast cancer the proliferating cells appear to differ from those containing estrogen receptors (ER) as shown by studies on isolated cellular subpopulations. In this paper the in vitro effect of 17-beta-estradiol on cell proliferation in 30 primary breast tumors was studied. The effect of several estradiol concentrations was assayed, and the influence of diethylstilbestrol, tamoxifen, and nafoxidine was also tested. The response to these compounds was measured through the thymidine labeling index (TLI). When exposed to 10(-9) mol/l and 10(-8) mol/l estradiol, 14 of 19 ER-positive tumors and six of 11 ER-negative tumors were induced to further proliferate. The TLI increase over the control was 219% (P less than 0.05) at 10(-9) mol/l E2 and 258% (P less than 0.05) at 10(-8) mol/l E2 for ER-positive tumors, and 233% (0.1 less than P less than 0.2) at 10(-9) mol/l E2 and 321% (0.1 less than P less than 0.2) at 10(-8) mol/l E2 for ER-negative tumors. The addition of diethylstilbestrol and antiestrogens in vitro inhibited, to varying degrees, the estradiol-induced increase in the TLI irrespective of the ER-status. The response to E2 was correlated with the expression of the ras p21 protein and carcinoembryonic antigen. It was found that the ras p21 protein is preferentially expressed in ER-negative tumors, the opposite being true for carcinoembryonic antigen. The ras p21 protein is preferentially expressed in those ER-positive tumors that do not respond to estradiol with an increase in the TLI.     

肺癌淋巴结微转移灶检测的分子生物学意义

目的 通过免疫组化的方法检测非小细胞肺癌患者术后常规病理检查阴性的淋巴结的微转移灶，研究其分子生物学意义。方法 以行肺癌根治性手术的39名患者为对象，用免疫组化角蛋白(CK)染色的方法检测术后常规病理学检查阴性的90枚淋巴结中的微转移灶，同时也用免疫组化的方法检测相应患者原发肺癌病灶中的p53、p21^ras和Ki67的表达。结果 22个患者(56．4％)的26枚淋巴结(28．89％)检出微转移移灶。原发肺癌灶中有p53、p21^ras和Ki67表达的患者的淋巴结微转移灶检出率显著高于无这些蛋白表达的患者。肿瘤直径大于3cm的患者和肿瘤直径小于3cm的患者的淋巴结微转移灶的检出率分别为55．6‰和58．3％，两者的差别无统计学意义(P=1．000)。结论 原发肺癌病灶中p53、p21^ras和Ki67的表达和淋巴结微转移灶的存在有一定的关系。     

p53 null mutations undetected by immunohistochemical staining predict a poor outcome with early-stage non-small cell lung carcinomas.

The importance of p53 mutations in the pathogenesis of human lung carcinoma is well established, but it is still controversial whether the presence of p53 mutations or overexpression of p53 protein adversely affects an individual patient's chances of survival. The controversy may be partially due to the methodological differences in examination for p53 alterations: gene analysis or immunohistochemical staining. Furthermore, recent studies have suggested that different types of mutations of the p53 tumor suppressor gene confer different biological properties. To clarify the relationship between immunohistochemical staining and prognosis, we investigated mutations using single-strand conformation polymorphism followed by sequencing for exons 4-8 and 10 in 144 surgically treated non-small cell lung carcinoma patients with intensive clinical follow-up. Of 144 cases, 107 adenocarcinomas were examined for immunohistochemical staining with RSP53 antibody. p53 gene mutations were observed in 65 tumors (45%), including 44 missense and 21 null mutations, the latter comprising 7 nonsense mutations, 8 deletions, 2 insertions, and 4 splicing junction mutations. Presence of p53 mutations was an independent prognostic factor with a statistical trend (P = 0.14) in stage I patients but not in all cases. When examined by mutational pattern, null mutation was a significant indicator of poor outcome by multivariate analysis (P = 0.03) in stage I patients, whereas cases with missense mutations and without mutations did not differ (P = 0.76). Forty (37%) tumors demonstrated overexpression of the p53 protein but without any survival difference. Most tumors (76%) with missense mutations were immunopositive, but those with null mutations with one exception (93%) were not, and the concordance between the mutations and immunohistochemical staining was rather low at 65%. These data suggest that the type of p53 mutation is important for prediction of outcome in early-stage non-small cell lung carcinoma patients, whereas immunohistochemical staining for abnormal p53 gene products is nonpredictive. Furthermore, null mutations causing loss of function of the gene product may play more important roles than missense mutations in tumor progression.     

p21^WAF1和VEGF在非小细胞肺癌中的表达及临床相关性研究

目的 研究p21WAFI和血管内皮生长因子的表达和肿瘤内微血管密度测定在非小细胞肺癌中的意义。方法用免疫组化方法对45例非小细胞肺癌患者经纤支镜活检、经皮肺活检取得的标本检测p21WAFI和VEGF的表达,并用CD31抗体标记癌组织血管内皮细胞,计算MVD。结果 p21WAFI和VEGF阳性表达率分别为68.9％和77.8％;二者的表达和MVD均与性别、病理类型无关(P>0.05),与临床分期、癌组织MVD呈正相关(P<0.05);p21WAFI阳性、VEGF阴性组的中位生存期(14个月)与p21WAFI阴性、VEGF阳性组的中位生存期(11个月)相比,差异无显著性(P>0.05);p21WAFI阳性、VEGF阳性组的中位生存期(10个月)与p21WAFI阴性、VEGF阴性组的中位生存期(15个月)相比,差异无显著性(P>0.05)。结论p21WAFI和VEGF在非小细胞肺癌的发生和发展中起着重要作用,可反映非小细胞肺癌的恶性程度和进展情况。作为预后指标,p21WAFI作用的发挥是通过上调VEGF的表达水平来实现的,VEGF的表达对肿瘤血管形成、转移起重要作用。     

The expression of proliferating cell nuclear antigen in paraffin sections of peripheral, node-negative non-small cell lung cancer.

Cell proliferation of 40 peripheral, node-negative non-small cell lung cancers (NSCLC) treated with surgery alone was investigated by immunohistochemical analysis with the monoclonal antibody (MoAb) PC10, which recognizes a proliferating cell nuclear antigen (PCNA) in formalin-fixed and paraffin-embedded material. Results were correlated with DNA ploidy and S-phase fraction (SPF) analyzed by DNA flow cytometric study. Mitotic count (MC) was analyzed by light microscopic study and histopathologic features. PCNA immunoreactivity was seen in all samples and confined to the nuclei of cancer, but not to the surrounding, tumor-negative cells; its frequency ranged from 0-70% (median, 15%), and tumors expressed either a low (0-25%, n = 25) or intermediate (26-75%, n = 15) proliferative activity. There was no relationship between PCNA immunoreactivity and tumor stage or among size, histologic type, and mitotic count (MC). Tumors with intratumoral blood vessel invasion (BVI) showed a significantly higher (P less than 0.005) PCNA immunoreactivity than BVI-negative tumors. PCNA scores were significantly higher (P less than 0.005) in DNA aneuploid (n = 22) than in DNA diploid (n = 18) tumors and correlated significantly with the SPF of DNA aneuploid tumors (r = 0.825, P less than 0.0001), but not with diploid tumors (r = 0.002, P = 0.9). Intermediate proliferating tumors had a significantly higher (P less than 0.01) MC than their counterparts. In univariate analysis, significant predictors of survival were tumor classification (T1 versus T2), tumor size (less than or equal to 2.6 cm versus more than 2.6 cm), BVI (BVI-negative versus BVI-positive), MC (less than or equal to 8 versus more than 8), and PCNA immunoreactivity (low versus intermediate). DNA ploidy and SPF did not influence survival significantly. Only PCNA immunoreactivity retained its independent level of significance (P = 0.02) by multivariate analysis. It was concluded that PCNA immunostaining is a simple and clinically useful method for estimating cell proliferation in formalin-fixed, paraffin-embedded tissue of resected peripheral, node-negative NSCLC.     

Comparative analysis of p16/CDKN2, p53 and ras gene alterations in human non-small cell lung cancers, with and without associated pulmonary asbestosis

To investigate genetic abnormalities in human non-small cell lung carcinomas (NSCLC) associated with pulmonary asbestosis as compared with nou-asbestos linked lung cancers, twenty-nine primary non-small cell lung carcinomas (NSCLC) were examined for genetic abnormalities of p16/CDKN2, p53 and ras genes by single-strand conformation polymorphism analysis of polymerase chain reaction products (PCR-SSCP) and direct sequencing. Ten specimens were obtained from autopsies in which concurrent pulmonary asbestosis was present, while 19 samples were surgical specimens from asbestosis-free patients. K-ras mutations were detected in 10% each of the cancers from both asbestosis and non-asbestosis cases. p16/CDKN2 deletions or mutations and p53 aberrations were demonstrated in 20% and 10% of tumors from asbestosis cases, whereas, 32% and 21% of the cancers, respectively, from asbestosis-free patients were positive. In conclusion, it is suggested that the enhancement of neoplasia in the lung by asbestos is not dependent on suppression of p16/CDKN2 and p53 or ras activation and therefore, that asbestosis may activate alternate tumorigenic pathways in the development of NSCLC.     

Ras p21 expression in relation to histopathological variables and prognosis in colorectal adenocarcinoma.

Ras gene protein products (p21) reacting with the monoclonal antibodies ras 11, DWP, R256 and E184 were studied with an immunohistochemical method which was applied to 17 normal and 79 colorectal adenocarcinoma specimens. Normal colorectal epithelium showed positive staining for ras 11 in 35% of the cases, but not for DWP, R256 and E184. The antibodies showed positive staining in colorectal adenocarcinomas in 76, 53, 29 and 35% of the cases respectively. The degree of staining for ras 11 was significantly related to the grade of differentiation and increased from Dukes stage A to C. Strong staining for ras 11 predicted a significantly shorter recurrence-free interval (p less than 0.001). In Cox's regression analysis, the degree of staining for ras 11 was a prognostic factor independent of the grade of differentiation and Dukes stage (p less than 0.01). The results indicate that the enhanced expression of pan ras p21 may provide an important biological marker for determining prognosis in colorectal adenocarcinomas.     

Differential expression of p21ras gene products among histological subtypes of fresh primary human lung tumors

Activation of the ras oncogene has been associated with a number of human tumors. In this study, expression of p21ras in different histological types of fresh primary bronchogenic carcinomas was examined. p21ras products were detected in all lung tissues that were analyzed. Only 1 of 23 tumors demonstrated aberrant migration of p21ras. In contrast, 10 tumors had substantially elevated levels of p21ras products with respect to the adjacent normal lung tissues and with respect to the other lung tumors. There was no correlation between increased ras protein expression and tobacco exposure of the patient or extent of disease at the time of diagnosis. However, 9 of 11 tumors with a squamous component as opposed to only 1 of 12 tumors belonging to other histological classifications demonstrated increased p21ras. These data suggest that, in bronchogenic carcinomas, mutations associated with structural abnormalities and aberrant migration of p21ras occur infrequently as compared to quantitative changes in p21ras. Furthermore, differential expression of c-ras products in primary human lung tumors correlates with pathological cell type, and may be a common event in squamous cell carcinomas, but not adenocarcinomas or small cell carcinomas of the lung.