Frequent loss of heterozygosity on chromosome 5 in non-small cell lung carcinoma.

AIMS: Loss of heterozygosity (LOH) at specific chromosomal regions strongly suggests the existence of tumour suppressor genes at the relevant segment. Frequent LOH on chromosome 5q has been reported in a wide variety of human tumours, including those of the lung. The aim of this study was to screen for LOH and to clarify the location of putative tumour suppressor genes on chromosome 5 implicated in the genesis and/or development of non-small cell lung carcinoma. METHODS: Thirty three patients with advanced non-small cell lung carcinoma were screened for LOH with a panel of 21 microsatellite DNA markers spanning the entire chromosome 5, using semi-automated fluorochrome based methodology. RESULTS: Twenty of the non-small cell lung carcinoma samples displayed LOH for one or more informative locus. LOH involving only 5q was found in 10 of 14 of the informative samples. Deletions involving 5p only were not present in the samples under study. There was no evidence of microsatellite instability in any of the analysed loci. These results indicate the presence of five distinct segments displaying high frequencies of deletion on chromosome 5, namely: 5q11.2-q12.2, 5q15 (D5S644 locus), 5q22.3-q23.1, 5q31.1, and 5q35.3. Eight of 14 samples had simultaneous interstitial deletions in at least two different regions. Moreover, concomitant deletion of three and four distinct regions was displayed in three of 14 and two of 14, respectively, of the informative samples. CONCLUSION: Allelic deletion on chromosome 5 is a frequent event in patients with non-small cell lung carcinoma. These results suggest the involvement of these five regions, either independently or simultaneously, in both lung squamous cell carcinoma and lung adenocarcinoma.     

High frequency of coexpression of maspin with p63 and p53 in squamous cell carcinoma but not in adenocarcinoma of the lung

Maspin, a member of the serpin family of protease inhibitors, has been shown to inhibit tumor growth and suppress metastasis in several malignancies, including lung cancer. Previous studies have reported that p63 and p53 control maspin expression by transactivating the promoter. The present study analyzed immunohistochemical studies to determine the expression and coexpression patterns of maspin, p63 and p53 in non-small cell lung carcinoma, specifically squamous cell carcinoma and adenocarcinoma. The results showed that 83/86 cases (96.5%) of squamous cell carcinoma and 82/161 cases (50.9%) of adenocarcinoma included in this study were positive for maspin. There were 79/86 cases (91.9%) of squamous cell carcinoma and 16/161 cases (9.9%) of adenocarcinoma with positive expression for p63. In addition, 77/86 cases (89.5%) of squamous cell carcinoma and 99/161 cases (61.5%) of adenocarcinoma were positive for p53. Maspin, p63 and p53 expression were each significantly higher in squamous cell carcinoma than adenocarcinoma. Squamous cell carcinomas more highly coexpress maspin and p63, as well as maspin and p53, when compared with adenocarcinomas. The high frequency of coexpression of maspin and p63, as well as maspin and p53, in squamous cell carcinoma, suggests that p63 and p53 may be involved in the pathway to control maspin expression. Therapeutic targeting on maspin, p63 and p53 molecules might be beneficial in the management of patients with squamous cell carcinomas of the lung in the future.     

Comparative allelotype of early and advanced stage non-small cell lung carcinomas

To identify chromosomal loci of tumor suppressor genes involved in the genesis and progression of non-small cell lung carcinoma (NSCLC), comparative allelotype analysis was performed in 23 stage I primary lung tumors and in 22 metastatic lung tumors to the brain. In total, 84 loci on all 22 autosomal chromosomes were examined for loss of heterozygosity (LOH) by restriction fragment length polymorphism (RFLP) analysis with 40 polymorphic DNA probes and polymerase chain reaction (PCR)-LOH analysis of 44 polymorphic loci. LOH on chromosome arms 3p, 13q, and 17p was detected frequently (>60%) in both stage I primary lung tumors and brain metastases, whereas the incidence of LOH on chromosome arms 2q, 5q, 9p, 12q, 18q, and 22q was more than 60% only in brain metastases. In particular, the incidence of LOH on chromosome arms 2q, 9p, 18q, and 22q in brain metastases was significantly higher than that in stage I primary lung tumors (P < 0.05). These results indicate that tumor suppressor genes on chromosome arms 3p, 13q, and 17p are involved in the genesis of NSCLC, whereas those on several chromosome arms, especially on 2q, 9p, 18q and 22q, play an important role in the progression of NSCLC. Genes Chromosom Cancer 17:71–77 (1996). © 1996 Wiley-Liss, Inc.     

Alteration of the p53 gene of lung carcinomas with sarcomatous transformation (spindle cell carcinoma): analysis of four cases

Lung carcinoma with sarcomatous transformation (LCST) is highly aggressive and characterized by local invasion and/or distant metastasis, which leads to a shorter survival than ordinary lung carcinomas. Therefore, to elucidate whether the malignant potential of the spindle cell element in LCST is associated with the alteration of the p53 gene, four cases were examined by analyses of overexpression of the p53 oncoprotein, mutation of the p53 gene and loss-of-heterozygosity (LOH) at chromosome 17p. In two cases overexpression of the p53 oncoprotein of the spindle cell component showed a higher degree of staining than that of the carcinoma component; LOH was identified in both carcinoma and sarcomatous components in one case, while in contrast, another case showed LOH in the sarcomatous component only. Mutations were clearly detected in two cases; one showed a CTT to CGT transversion in codon 194 of exon 6 in both components, whereas the other showed a CTG to CAG transversion in codon 265 of exon 8 in the sarcomatous component only. On the basis of these observations, it suggested that the sarcomatous component shows a higher frequency of p53 gene abnormalities in comparison to the carcinoma component. These results also suggested that the acquisition of malignant potential in the sarcomatous component, or the morphological alteration of carcinoma cells, is correlated with abnormalities associated with the p53 gene.     

Transition from squamous cell carcinoma to adenocarcinoma in adenosquamous carcinoma of the lung

The heterogeneity of tumor cells is frequently observed in lung cancer, but the clonality of these cells has not yet been established. The distinct components of 12 lung adenosquamous carcinomas were compared by genetic alterations of p53 and K-ras, chromosomal abnormalities at 9p21 and 9q31-32, and immunohistochemical reactions. The immunoreactivity of p53 was consistent in both adenocarcinomatous and squamous cell carcinomatous components as well as in the transitional areas, retaining the morphological characteristics of the distinct components. The same p53 mutation was found in both components of each tumor with p53 overexpression. No K-ras mutations were detected in any of the tumors examined. Three of the four tumors with chromosomal abnormalities detected, one at 9p21 and two at 9q31-32, had coincident abnormalities between the distinct components, whereas one tumor deleted homozygously at 9p21 (D9S259) in the adenocarcinomatous component with loss of heterozygosity in the other component. The expression of squamous cell carcinoma-related antigen in adenocarcinomatous components was significantly higher than that of lung adenocarcinomas (57 +/- 5.8% vs. 1.0 +/- 0.5%, P < 0.0001), whereas Mucin 1 expression is less in these components (9.0 +/- 4.9% vs. 55 +/- 8.2%, P = 0.003). These results suggest monoclonal transition from squamous cell carcinoma to adenocarcinoma in lung adenosquamous carcinoma.     

p53蛋白堆积和CK-18neo在非小细胞

目的:检测非小细胞肺癌组织的p53蛋白堆积水平和细胞骨架蛋白18新抗原决定簇(cytokeratin18neo-epitope,CK-18neo)的暴露情况,探讨p53蛋白和CK-18neo在肺癌发生发展过程中的作用及其临床病理意义。方法:用免疫组化法检测62例非小细胞肺癌以及10例对照组织中p53蛋白的堆积和CK-18neo的暴露情况。用显微图象分析仪测定p53免疫组化反应的强度,并作定量分析。以凋亡指数(AI%)表示CK-18neo的阳性检出率。结果:①非小细胞肺癌组织中p53的阳性检出率为48.39%(鳞癌为51.72%,腺癌为45.45%),对照组p53的阳性率为0.00%(P＜0.01);②非小细胞肺癌组织的AI%为1.10%(鳞癌0.95%,腺癌1.24%),对照组为1.06%,各组间无显著差异;③非小细胞肺癌组织中p53(-/+)、p53(5级)和p53(PU)呈正直线相关关系(P＜0.01)。结论:本实验结果提示,突变型p53基因可能参与NSCLC的发生机制,NSCLC的发生和发展与癌细胞的过度增生和细胞凋亡减少有关。     

Clonal selection of adenocarcinoma of the lung as determined by loss of heterozygosity

Although the most frequently altered oncogenes and tumor suppressor genes in non-small cell lung carcinoma (NSCLC) have been recognized, the exact mechanisms responsible for the progression and phenotypic expression of carcinoma, particularly adenocarcinoma of the lung are uncertain. Fifty-six cases of adenocarcinoma of the lung (11 bronchioloalveolar carcinoma [BAC], 25 stage 1, 20 stage 2) and paired 19 lymph node metastases (LNM) of stage 2 adenocarcinomas were analyzed for loss of heterozygosity (LOH). Analysis included a panel of 14 polymorphic microsatellite markers located on 1p, 3p, 5q, 9p, 10q, and 17p. LOH on chromosomes 1p (P = 0.0209) and 17p (P = 0.0274) was more frequently present in stage 1 adenocarcinomas than in BAC. There was no significant difference between BAC, stage 1 and stage 2 adenocarcinoma in the frequency of LOH at individual chromosomal arms. The pattern of LOH in LNM of stage 2 adenocarcinoma was similar to the primary tumor. Overall fractional allelic loss (FAL) was significantly different between BAC and stage 1 invasive adenocarcinoma (P = 0.0013), and it was significantly higher in stage 1 adenocarcinoma than in stage 2 adenocarcinoma (P = 0.0062) and their LNM (P = 0.0001). Stage 2 adenocarcinomas showed significantly higher overall FAL than their LNM (P = 0.022). Our study failed to identify a single target gene responsible for progression of lung adenocarcinoma. A trend towards lower overall FAL in advanced stage tumors and in their metastases suggests that clonal selection may play a role in lung adenocarcinoma progression.     

Carcinoma of the lung in Okinawa, Japan: With special reference to squamous cell carcinoma and squamous metaplasia

In Okinawa, a subtroplcal Island In southern Japan, squamous cell Carcinoma (SCC), especially the well-differentiated form, Is prevalent, while this form is relatively rare in both the mainland and other countries (e.g. United States of America). More patlents with SCC from Okinawa, moreover, were positive for human papillomavlrus (HPV) DNA by polymerase chain reaction (PCR) (79%), and harbored HPV types 6, 16 and 18, In combination. On the other hand, less than 30% of the mainland patlents were positive for HPV DNA by PCR. Those patients who were positive all harbored only one HPV type. Furthermore, in Okinawa, there were a signiflcant number of cases with adenosquamous carcinoma, and they too were positive for HPV DNA. The SCC and the adenocarcinoma cells adjacent to the SCC component In these cases were also positive for HPV DNA, and such adenocarcinoma cells were enlarged In size with relatively wide cytoplasm. The authors postulate that HPV infects adenocarcinoma cells and changes them to enlarged cells, followed by squamous metaplasla. In this report, HPV DNA was transfected to adenocarclnoma cells (cultured cell fines) and this showed that HPV causes squamous metaplasla. In addition, aberrant expression of p53 was demonstrated In a large number of the SCC cases In Okinawa. The enlarged adenocarclnoma cells adiacent to the SCC components In adenosquamous carcinomas also showed aberrant expression of p53.The recent advances In the studies of anti-oncogenes, p53, etc. and oncogenes are outlined. It Is to be noted that the molecular mechanisms of carcinogenesis in the lung have been studied In general, classifying lung tumors Into two groups, namely, small cell carcinoma (SCLC) and non-small cell carcinoma (NSCLC). However, because human lung cancer is represented by a wide variety of histological types, molecular genetic studies according to a more detailed histological subclasslflcatlon is needed.     

肺癌p53蛋白表达和基因突变与临床病理的相关研究

目的 检测肺癌中ｐ５３蛋白表达和基因突变状况及其与临床病理和预后的相关性。方法：应用免疫组织化学（ＬＳＡＢ法）和聚合酶链反应－单链构象多态性分析（ＰＣＲ－ＳＳＣＰ）二种方法。结果 检测肺鳞癌４６例，共９５例。免疫组化ｐ５３蛋白总阳性率为５０．５％（４８／９５例），肺鳞癌阳性率为５６．５％（２６／４６例）、肺腺癌为４４．７％（２２／４９例）。ＰＣＲ－ＳＳＣＰ检测ｐ５３基因突变率为４１．１％（３９／９     

A detailed deletion map of chromosome 20 in human oral squamous cell carcinoma

Loss of heterozygosity (LOH) on the long arm of chromosome 20 (20q) has been detected in several human cancers. However, little is known about LOH on chromosome 20 in oral squamous cell carcinoma (OSCC). To determine which loci of chromosome 20 were involved in OSCC tumorigenesis, 41 cases of OSCC were examined for LOH state on chromosome 20 at 17 microsatellite loci by PCR-LOH assay. LOH occurred in 41.5% of tumors in at least one locus. Among the 17 loci, D20S48 on 20p11.2 and RPN2 on 20q12-13.1 exhibited higher frequencies of LOH, 27.6% and 31.4%, respectively. The LOH incidence was significantly higher in tumors in which the primary site was on gingiva compared with other oral sites (p=0.012). Our results indicate that allelic deletions on 20q12-13.1 and 20p11.2 may play roles in OSCC carcinogenesis, and suggest that allelic deletions on 20q might have some relation with the primary site of OSCC.     

Alterations of 9p in squamous cell carcinoma and adenocarcinoma of the lung: association with smoking, TP53, and survival

Tobacco smoke is well recognized as the major etiological contributor to lung cancer, yet the relationship between tobacco smoke exposure and a specific pattern of molecular abnormalities at somatic loci is less well characterized. We analyzed 100 primary tumors from patients undergoing surgical resection of squamous cell carcinoma and adenocarcinoma of the lung for loss of heterozygosity (LOH) and homozygous deletions at two microsatellite markers in a recombinogenic region of 9p13. We describe the relationship of alterations at these markers with tumor characteristics (both clinical and molecular), patient demographics, survival, and measures of tobacco-smoke exposure. Homozygous deletions in this region occurred in 25% (21/85) and LOH in 33% (28/85) of informative tumors examined. These alterations occurred more often in tumors with intense TP53 protein staining by immunohistochemistry, suggesting that inactivation of the TP53 pathway may contribute to these LOH events. Duration of smoking was greatest in patients with the homozygous deletion, intermediate in patients with LOH, and shortest in patients whose tumor did not demonstrate loss in these markers. Unexpectedly, LOH at 9p13 was a significant predictor of improved survival in patients, while the homozygous deletion was associated with the poorest patient survival. Together, these results suggest that TP53 alteration and long-term tobacco smoke exposure may contribute to genetic alterations at 9p13, and that the mechanism and biologic consequences of allele loss reflect individual biologic differences that determine the extent of loss (LOH or homozygous deletion), such that those patients with the deletion of this region face a more aggressive and deadly disease.     

Genetic alterations during the progression of squamous cell carcinomas of the uterine cervix.

Most cervical carcinomas appear to arise from cervical intraepithelial neoplasia (CIN) lesions. In addition to infection with high-risk human papilloma viruses, which is indicative of an increased risk of progression, alterations of oncogenes and tumor suppressor genes play a role. Genetic studies of CIN lesions, primary cervical carcinoma, and metastases may shed light on the relative importance of various genetic alterations involved in the progression of CIN to invasive carcinoma. We examined tumor material from 10 patients with squamous cell carcinoma of the uterine cervix and synchronous CIN lesions and lymph node metastases. The CIN component, invasive carcinoma, and lymph node metastases were analyzed separately for loss of heterozygosity (LOH) on the following loci: VHL (3p21), HLA region (6p22-23), PGL (11q 22-24), E6 associated protein (15q11-13), TP53 (17p13), DCC (18q21.1), and chromosomes 1, 2, 4, 9, 20, and X. Using immunohistochemistry, the expression of the EGF receptor, ERBB2, and TP53 was determined. In CIN lesions, frequent LOH was found at chromosome arms 3p, 6p, and 11q. Primary invasive carcinoma showed additional LOH at chromosome arms 6q, 17p, and 18q. In lymph node metastases, an additional locus on the X chromosome displayed LOH. All carcinomas and synchronous lesions but one showed high expression levels of the EGF receptor. TP53 staining, when present, was found in all synchronous lesions. Focal staining of ERBB2 was found in one CIN lesion, two invasive carcinomas, and four metastases. The molecular alterations accumulated in a fashion that paralleled the progression of the tumors. These results indicate that cervical tumorigenesis occurs in a stepwise fashion, including infection and integration of oncogenic HPV and several specific genetic alterations. Genes Chromosomes Cancer 26:346-354, 1999.     

Primary undifferentiated small cell carcinoma of the esophagus

We histologically examined undifferentiated small cell carcinoma of the esophagus from 21 patients and used immunohistochemical methods for detection of chromogranin A and p53, bcl-2, and Rb oncoproteins. Nine (43%) of the 21 carcinomas consisted solely of undifferentiated cells, but heterogeneous components of in situ or invasive squamous cell carcinoma or mucoepidermoid carcinoma were observed in the other 12 (57%) tumors. Squamous cell carcinoma in situ was observed in the mucosa adjacent to the main tumor in 7 (50%) of the 14 resected esophageal specimens. An admixture of invasive squamous cell carcinoma and undifferentiated carcinoma was observed in 4 (19%) of the 21 tumors, and mucoepidermoid carcinoma was noted in one case. Chromogranin A staining yielded a positive reaction in two (10%) undifferentiated components but was negative in all heterogeneous components. Multiple sites of p53 immunopositivity were seen in the undifferentiated component of 17 (81%) of the 21 tumors, as well as in the in situ or invasive squamous cell carcinoma or mucoepidermoid carcinoma components of 9 (75%) of 12 tumors. Seven (33%) of the 21 tumors showed positive bcl-2 immunoreactivity in the small cell component, but all of the heterogeneous components were negative. Rb protein immunoreactivity was observed in the small cell component of one (5%) case and in 9 (75%) of the 12 heterogeneous components. Six (86%) of the seven in situ squamous cell carcinoma components were positive for Rb protein. Eighteen (86%) of the 21 patients died within 24 months of diagnosis. Two patients (10%) who survived for more than 24 months had received chemotherapy.     

Correlation between morphological heterogeneity and genetic alteration within one tumor in adenocarcinomas of the lung

In some human cancers, multistep carcinogenesis has been advocated on the basis of morphological and genetic analysis. In adenocarcinoma of the lung, a carcinogenetic process from atypical adenomatous hyperplasia (AAH) to bronchiolo-alveolar carcinoma (BAC) and/or more malignant adenocarcinoma has been recently suggested. In the present study, we selected 13 lung tumors which had AAH-like or BAC-like areas at the periphery, and poorly differentiated areas at other sites, and examined their loss of heterozygosity (LOH) on chromosome 3p, 9p and 17p and point mutation of the p53 gene. A heterogeneous pattern of LOH and/or point mutation of the p53 gene was detected in five of 13 cases, and genetic alterations were frequent in the areas of poorer differentiation. These findings suggest that some adenocarcinomas of the lung occur through multistep carcinogenesis.     

A case of double primary adenocarcinoma of the lung with multiple atypical adenomatous hyperplasia

A case of double primary adenocarclnoma of the lung with multiple atypical adenomatous hyperplasla (AAH) In a 77-year-old woman Is reported. Hlstopathologlcally, in the resected left upper lobe of the lung, both cancers were diagnosed as well-differentlated papillary adenocarcinoma, and 161 lesions of AAH were also found. Both the cancer lesions and six AAH (greater than 3 mm In diameter) were examined wlth regard to immunoreactivity of carcinoem-bryonlc antigen (CEA) and p53 gene product, microsatellite lnstabllity (MI) and loss of heterozygosity (LOH) on chromosome 9q and 17q by polymerase chain reaction (PCR). Although both cancers expressed CEA, they did not show clonal lmmunoreactivity for the p53 gene product. Atypical adenomatous hyperplasia expressed CEA weakly and showed no immunoreactlvity for p53 gene protein. Both carcinomas showed LOH on chromosome 17q, and one of them showed LOH on chromosome 9q. In six AAH, LOH on chromosome 17q was detected In two tumors, and one of them also showed LOH on chromosome 9q. One AAH, which was negative for LOH on chromosome 17q and 9q, showed Mi at D17S791. These results indicated that AAH is a clonal neoplastic lesion with genetic abnormalities and should be called intraepithelial pneumocyte neoplasia, and that each of the numerous papillary lesions in this case was considered to be an Independent lesion.     

p53, p16 and RB expression in adenosquamous and squamous cell carcinomas of the stomach

The expression of p53, p16 and RB proteins and their clinicopathologic correlation were investigated in 15 cases of primary gastric adenosquamous carcinoma and 2 cases of squamous cell carcinoma of the stomach. The male to female ratio of the patients was 13:4 and the average age was 55.7 years. None of the cases was early gastric carcinoma, and none of the adenocarcinoma components were of the diffuse or signet ring cell types. Fourteen cases showed metastasis to regional lymph nodes and/or other organs at the time of surgery. The adenocarcinoma component was metastasized to lymph nodes in 12 cases, and both adenocarcinoma and squamous cell carcinoma components were metastasized in three cases. The altered expression of p53 correlated with the advanced stage, but did not correlate with the depth of invasion, lymph node metastasis or recurrence. The altered expression of p16 and RB proteins did not correlate with any of the above clinico-pathologic factors. Both the adenocarcinoma and squamous cell carcinoma components revealed an inverse correlation between the expression pattern of p16 and RB proteins (p < 0.05). This suggests that the two proteins share a role in the carcinogenesis of these tumors. The expression pattern of p53 proteins in the adenocarcinoma and squamous cell carcinoma components was exactly the same in all of the cases. The expression patterns of p16 and RB protein were also identical in most of the cases. The expression patterns of all three proteins in the metastatic lesions were also identical to those in the primary lesions. The fact that the alteration of the three tumor suppressor gene products shares the same pattern suggests that squamous and adenocarcinoma components in the stomach originate from the same or a genetically related clone.     

Abnormalities in chromosome 17 and p53 in lung carcinoma cells detected by fluorescence in situ hybridization

The value of fluorescence in situ hybridization (FISH) as an aid to deciding the prognosis for lung carcinoma patients, comparing quantitatively the signal from the p53 gene (17p13.1) on chromosome 17, was studied. A dual-labeling technique was used, using probes for the centromeric region of chromosome 17 and for the p53 gene locus. FISH was used on frozen sections of 68 surgically resected lung carcinoma (20 adenocarcinoma; 37 squamous cell carcinoma; 11 large, small, and other cell carcinoma). Hybridization signals were counted for 100-200 interphase nuclei per specimen using a Zeiss confocal laser scanning microscope (Carl Zeiss, Oberkochen, Germany) equipped with a bandpass filter for diaminophenolindole and a longpass filter for rhodamine. Clinicopathologic data were evaluated using the Statistical Analysis System. Chromosome 17 polysomy (three or more signals) was greater in poorly differentiated than in well-differentiated lung carcinoma (P < 0.05). p53 deletion correlated with p53 immunostaining (P < 0.05). Thus, analysis by FISH using DNA probes for chromosome 17 and p53 may be of some, albeit limited, value in determination of prognosis.     

Distinct molecular features of colorectal carcinoma with signet ring cell component and colorectal carcinoma with mucinous component.

Signet ring cell carcinoma and mucinous carcinoma are distinct subtypes of colorectal adenocarcinoma. The morphologic and molecular spectra of colorectal carcinomas with various signet ring cell components and colorectal carcinomas with various mucinous components, compared to non-mucinous adenocarcinomas, have not been examined. The study groups consisted of 39 carcinomas with various signet ring cell components ('the signet group'), 167 carcinomas with various mucinous components ('the mucinous group'), and 457 nonmucinous adenocarcinoma. We visually estimated the amounts of signet ring cell and mucinous components in tumors, and subclassified the signet and mucinous groups according to the amount of each component (< or = 19, 20-49, and > or = 50%). We sequenced BRAF and KRAS, analyzed for microsatellite instability (MSI) and 18q loss of heterozygosity (LOH), and performed immunohistochemistry for TP53, cyclooxygenase-2 (COX2), MLH1, O-6-methylguanine DNA methyltransferase (MGMT), p16 (CDKN2A), and fatty acid synthase (FASN). Signet ring cell carcinoma (> or = 50% signet ring cell tumors) and < or = 49% signet ring cell tumors showed similar molecular features. Except for MSI and MGMT, > or = 50% mucinous tumors and < or = 49% mucinous tumors also showed similar molecular features. BRAF mutations, MSI, and MLH1 loss were more frequent in both the signet and mucinous groups than nonmucinous carcinoma. More frequent KRAS mutations and less frequent p16 loss and TP53 positivity were observed in the mucinous group than nonmucinous carcinoma. 18q LOH and COX2 overexpression were less common in the signet group than nonmucinous carcinoma. FASN levels were highest in the mucinous group, followed by nonmucinous carcinoma, and lowest in the signet group. In conclusion, a minor (< or = 49%) signet ring cell or mucinous component in colorectal carcinoma suggests molecular features similar to > or = 50% signet ring cell or mucinous carcinoma, respectively. Signet ring cell carcinoma and mucinous carcinoma are related subtypes of colorectal adenocarcinoma, but have molecular features distinct from each other.     

Prognostic value of P53 protein in cells of non-small cell lung cancer

The aim of the study was to evaluate the prognostic relevance of p53 protein in non-small cell lung cancer. The 95 surgically treated patients were included (53 patients with squamous cell carcinoma, 29--with adenocarcinoma, 5--with large cell carcinoma, and 8--with mixed type). The protein was assessed immunohistochemically with the use of monoclonal antibodies DO7, DAKO. Positive staining was present in 44 patients. There was no survival difference between groups with and without protein (median survival--36 and 33 months, respectively; p = 0.86). In the multivariate analysis the only characteristics with prognostic impact in the entire group was stage of the disease. There was no correlation between the expression of p53 protein and disease-free survival. These results indicate that there is no prognostic relevance of p53 protein in non-small cell lung cancer.     

Apoptosis occurs independently of bcl-2 and p53 over-expression in non-small cell lung carcinoma

Certain oncogenes and tumour suppressor genes are known to modulate apoptosis. To investigate whether over-expressed bcl-2 and abnormally stabilized p53 are associated with reduced apoptosis in paraffin sections of non-small cell lung carcinoma, apoptotic, mitotic, and Ki-67 labelling indices were determined and correlated with bcl-2 and p53 immunoreactivity in 54 squamous cell carcinomas and 22 adenocarcinomas. Nineteen squamous cell carcinomas (35.2%) showed over-expression of bcl-2, but all 22 adenocarcinomas were bcl-2 negative. Thirty-seven squamous cell carcinomas (68.5%) and 13 adenocarcinomas (59.1%) showed p53 over-expression. Apoptotic tumour cells were identified among p53 positive and bcl-2 positive tumour cells. There was a significant linear correlation between apoptotic indices and mitotic indices. bcl-2 over-expression and p53 over-expression were not associated with attenuated apoptosis, or altered mitotic or Ki-67 labelling indices in either tumour type. Neither bcl-2 nor p53 was of prognostic significance. These results suggest that apoptosis in non-small cell lung carcinoma occurs independently, and is not modulated primarily by, bcl-2 or p53. It is likely that the effects on apoptosis of bcl-2 and p53 are countered by those of other oncogene products and/or additional factors that regulate apoptosis in vivo