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M S Tsao

Publications and source records attributed to M S Tsao.

At least 19 recordsLinked to original sources

Binary tree-structured vector quantization approach to clustering and visualizing microarray data.

MOTIVATION: With the increasing number of gene expression databases, the need for more powerful analysis and visualization tools is growing. Many techniques have successfully been applied to unravel latent similarities among genes and/or experiments. Most of the current systems for microarray data analysis use statistical methods, hierarchical clustering, self-organizing maps, support vector machines, or k-means clustering to organize genes or experiments into 'meaningful' groups. Without prior explicit bias almost all of these clustering methods applied to gene expression data not only produce different results, but may also produce clusters with little or no biological relevance. Of these methods, agglomerative hierarchical clustering has been the most widely applied, although many limitations have been identified. RESULTS: Starting with a systematic comparison of the underlying theories behind clustering approaches, we have devised a technique that combines tree-structured vector quantization and partitive k-means clustering (BTSVQ). This hybrid technique has revealed clinically relevant clusters in three large publicly available data sets. In contrast to existing systems, our approach is less sensitive to data preprocessing and data normalization. In addition, the clustering results produced by the technique have strong similarities to those of self-organizing maps (SOMs). We discuss the advantages and the mathematical reasoning behind our approach.

Algorithms↗

Expression of active protein kinase B in T cells perturbs both T and B cell homeostasis and promotes inflammation.

The molecular mechanisms that contribute to autoimmunity remain poorly defined. While inflammation is considered to be one of the major checkpoints in autoimmune disease progression, very little is known about the initiating events that trigger inflammation. We have studied transgenic mice expressing the prosurvival molecule protein kinase B/Akt under control of a T cell-specific CD2 promoter. In this study, we demonstrate that aged mice develop lymphadenopathy and splenomegaly that result from an accumulation of CD4, CD8, and unexpectedly B cells. An increased proportion of T cells express activation markers, while T cell proliferative responses remain normal. B cells are hyperproliferative in response to anti-IgM F(ab')(2) and anti-CD40, and increased IgA and IgG2a were found in the sera. In addition, a profound multiorgan lymphocytic infiltration is observed, and T cells from these mice display a defect in Fas-mediated apoptosis, which may be the mechanism underlying this phenotype. Therefore, T cell expression of active protein kinase B can alter T cell homeostasis, indirectly influence B cell homeostasis, and promote inflammation in vivo.

Animals↗

Giant bronchial carcinoid tumors: a multidisciplinary approach.

BACKGROUND: Bronchial carcinoid tumors account for approximately 2% of all lung tumors. Although they were considered benign lesions, they are now categorized malignant, occasionally with poor prognosis. The clinical symptoms can be highly variable and are often present for many years before diagnosis. Whereas some carcinoids are entirely asymptomatic, others are accompanied by carcinoid or paraneoplastic syndromes. METHODS: We describe the multidisciplinary management of a 34-year-old female patient with a massive actively secreting bronchial carcinoid tumor of the right lung. Furthermore, we provide a review of the literature regarding the operative treatment and the perioperative management of pulmonary carcinoid tumors with respect to surgical, anesthetic, radiologic, and pathologic considerations. RESULTS: In the reported case, the first symptoms were chronic watery diarrhea, skin flushing, progressive shortness of breath, and increasing right shoulder pain. When the patient initially presented at our institution, the tumor had already reached an enormous size and it involved the right and left atrium as well as the atrial septum. Using an evidence-based, multidisciplinary approach the patient was treated successfully with extended surgical resection. CONCLUSIONS: Carcinoid tumors are potentially curable even if they reach a significant size and thus an aggressive strategy is warranted. The management of such cases requires careful investigation, planning, and treatment with collaborative expertise provided by a multidisciplinary team. We demonstrated that this approach can lead to a favorable outcome in what first appeared to be a formidable and unresectable tumor.

Adult↗

Molecular cytogenetic analysis of non-small cell lung carcinoma by spectral karyotyping and comparative genomic hybridization.

The overall pattern of chromosomal changes detected by spectral karyotype (SKY) analysis of two cell lines of each major histological subtype of NSCLC, namely squamous cell carcinoma (SQCC) and adenocarcinoma (ADC), indicated a greater degree of chromosomal rearrangement, than was present or predicted by either comparative genomic hybridization (CGH) or G-banding analysis alone. To investigate these observations, CGH was used to screen DNA derived from 8 primary tumors and 15 cell lines. The results indicated that the most frequently gained chromosome arms were 5p (70%), 8q (65%), 15q (52%), 20q (48%), 1q (43%), 19q (39%), 3q (35%), and 11q (35%). Chromosomal losses were less frequently observed, and included 18q (39%), 9 (35%), 6q (30%), 13q (21%), 5q12-q32 (17%), and 19p (17%). Amplifications were found on 2p23-p24, 3q24-q27, 5p, 6cen-p21.1, 6q26, 7p21, 7q31, 8q, 11q13-qter, 20q12-q13.2. Comparison between CGH findings of the two major histological subtypes showed that gains at 1q22-q32.2, 15q, 20q, and losses at 6q, 13q, and 18q was common in ADCs, whereas SQCCs exhibited gains/amplifications at 3q. Distal 8q was gained by CGH in 65% of tumors of both subtypes. Low level MYCC amplification was confirmed by direct fluorescence in situ hybridization (FISH) analysis. The pattern of overall chromosomal changes detected using combinations of molecular cytogenetic analytical methods suggests that it will be easier to detect recurrent subtype-dependent aberrations in NSCLC.

Adenocarcinoma↗

Deletion of Pten in mouse brain causes seizures, ataxia and defects in soma size resembling Lhermitte-Duclos disease.

Initially identified in high-grade gliomas, mutations in the PTEN tumor-suppressor are also found in many sporadic cancers and a few related autosomal dominant hamartoma syndromes. PTEN is a 3'-specific phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P3) phosphatase and functions as a negative regulator of PI3K signaling. We generated a tissue-specific deletion of the mouse homolog Pten to address its role in brain function. Mice homozygous for this deletion (PtenloxP/loxP;Gfap-cre), developed seizures and ataxia by 9 wk and died by 29 wk. Histological analysis showed brain enlargement in PtenloxP/loxP;Gfap-cre mice as a consequence of primary granule-cell dysplasia in the cerebellum and dentate gyrus. Pten mutant cells showed a cell-autonomous increase in soma size and elevated phosphorylation of Akt. These data represent the first evidence for the role of Pten and Akt in cell size regulation in mammals and provide an animal model for a human phakomatosis condition, Lhermitte-Duclos disease (LDD).

Animals↗

Hepatocyte growth factor is predominantly expressed by the carcinoma cells in non-small-cell lung cancer.

Hepatocyte growth factor (HGF) exerts multifunctional regulatory roles in the growth, morphogenesis, differentiation, and motility of epithelial cells, and putatively plays important roles in tumor angiogenesis and metastasis. Aside from the full-length protein, 2 naturally occurring truncated HGF isoforms (NK1 and NK2) have been identified. Recent evidence suggests that a high level of HGF in surgically resected non-small-cell lung carcinoma (NSCLC) is a negative prognostic marker for NSCLC patients' survival. The origin of HGF in these tumors remains uncertain. We show here by in situ hybridization and immunohistochemistry that HGF messenger RNA (mRNA) and protein were predominantly expressed by the tumor cells in a high percentage of primary NSCLC. Stromal cell expression of HGF was limited to some lymphocytes and endothelial cells. Normal bronchial and bronchiolar epithelial cells also expressed HGF mRNA and immunoreactive protein. The mRNA transcripts and putative proteins of all 3 known HGF isoforms were detected in both normal lung and lung cancer tissues, but the full-length HGF was predominantly expressed. Our findings indicate that both autocrine and paracrine functions of HGF are likely to contribute to the pathobiology of lung cancer in vivo.

Adenocarcinoma↗

Wortmannin inhibits pkb/akt phosphorylation and promotes gemcitabine antitumor activity in orthotopic human pancreatic cancer xenografts in immunodeficient mice.

Pancreatic cancer is resistant to almost all classes of cytotoxic agents. Gemcitabine seems to be the current drug of choice. We have recently reported that inhibition of the phosphatidylinositide 3-kinase-protein kinase B (PKB/Akt) cell survival pathway by wortmannin enhances gemcitabine-induced apoptosis in cultured human pancreatic cancer cells (1). The present study investigated the effects of wortmannin on orthotopic human pancreatic cancer xenografts implanted in severe combined immunodeficient mice. Animals were given single i.v. bolus injections of 0.175, 0.35, or 0.7 mg/kg of wortmannin and killed at 0.5, 1, 2, or 4 h after treatment. Phosphorylated PKB/Akt levels in tumor tissues were measured by fluorescence image analysis. Wortmannin was found to inhibit PKB/Akt phosphorylation in a time- and dose-dependent manner, reaching a plateau at 4 h and at 0.7 mg/kg. The levels of phosphorylated PKB/Akt were maximally decreased by approximately 50% relative to the vehicle control. Subsequently, the extent of apoptosis in tumors treated with gemcitabine or wortmannin alone or in combination was determined using terminal deoxynucleotidyl transferase-mediated nick end labeling assay and computerized image analysis. Orthotopic tumors exposed to 80 mg/kg gemcitabine for 48 h and then 0.7 mg/kg wortmannin for 4 h showed a 5-fold increase (P = 0.002) in apoptosis compared with those treated with each agent alone and with the vehicle control. The combination treatment also significantly (P < 0.001) inhibited tumor growth. Taken together, our findings support the potential of phosphatidylinositide 3-kinase inhibitors as adjuncts to conventional chemotherapy in the treatment of pancreatic cancer.

Androstadienes↗

Inhibition of phosphatidylinositide 3-kinase enhances gemcitabine-induced apoptosis in human pancreatic cancer cells.

Human pancreatic adenocarcinoma cell lines PK1 and PK8 are resistant to the clinically relevant chemotherapy agent gemcitabine. Cell cycle analysis demonstrated an accumulation of cells in the early S phase during treatment with 20 microM gemcitabine, consistent with its mode of action as a DNA chain terminator. However, apoptosis was evident in only a small percentage of cells. Similar to pancreatic cancers in the clinic, PK1 and PK8 cells carry constitutively active Ki-Ras and overexpress multiple receptor tyrosine kinases. Both genetic abnormalities may potentially up-regulate the activity of the phosphatidylinositide 3-kinase (P13K)-protein kinase B (PKB)/Akt cell survival pathway. The current study examined the relevance of this pathway in the modulation of drug resistance in PK1 and PK8 cells. After exposure to 20 microM gemcitabine for 48 h and in the continuous presence of the drug, treatment with the P13K inhibitors wortmannin (50-200 nM) and LY294002 (15-120 microM) for 4 h substantially enhanced apoptosis in a concentration-dependent manner as compared with treatment with gemcitabine alone, as determined by the loss of mitochondrial membrane potential and the increase in propidium iodide uptake using flow cytometry. Furthermore, Western blotting showed that the reduction of phosphorylated PKB/Akt levels correlated with the enhancement of gemcitabine-induced apoptosis, suggesting that the PI3K-PKB/Akt pathway plays a significant role in mediating drug resistance in human pancreatic cancer cells. PI3K inhibitors may have therapeutic potential when combined with gemcitabine in the treatment of pancreatic cancers.

Adenocarcinoma↗

Requirement for glycogen synthase kinase-3beta in cell survival and NF-kappaB activation.

Glycogen synthase kinase-3 (GSK-3)-alpha and -beta are closely related protein-serine kinases, which act as inhibitory components of Wnt signalling during embryonic development and cell proliferation in adult tissues. Insight into the physiological function of GSK-3 has emerged from genetic analysis in Drosophila, Dictyostelium and yeast. Here we show that disruption of the murine GSK-3beta gene results in embryonic lethality caused by severe liver degeneration during mid-gestation, a phenotype consistent with excessive tumour necrosis factor (TNF) toxicity, as observed in mice lacking genes involved in the activation of the transcription factor activation NF-kappaB. GSK-3beta-deficient embryos were rescued by inhibition of TNF using an anti-TNF-alpha antibody. Fibroblasts from GSK-3beta-deficient embryos were hypersensitive to TNF-alpha and showed reduced NF-kappaB function. Lithium treatment (which inhibits GSK-3; refs 8, 9) sensitized wild-type fibroblasts to TNF and inhibited transactivation of NF-kappaB. The early steps leading to NF-kappaB activation (degradation of I-kappaB and translocation of NF-kappaB to the nucleus) were unaffected by the loss of GSK-3beta, indicating that NF-kappaB is regulated by GSK-3beta at the level of the transcriptional complex. Thus, GSK-3beta facilitates NF-kappaB function.

Animals↗

High incidence of breast and endometrial neoplasia resembling human Cowden syndrome in pten+/- mice.

PTEN is one of the most commonly mutated tumor suppressor genes in human cancer. PTEN mutations have been implicated in the development of a variety of human neoplasia, including high-grade glioblastoma, prostate, breast, endometrial, and thyroid carcinoma. Germ-line mutations of PTEN cause Cowden's syndrome (CS), a multiple hamartoma condition resulting in increased susceptibility for the development of cancer. When more than 6 months old, pten+/- mice develop a range of tumors, partially resembling the spectrum of neoplasia observed in CS patients. One-half (32 of 65) of pten+/- females developed breast tumors, whereas all (65 of 65) of the females had endometrial hyperplasia, and there was a high incidence (14 of 65) of endometrial cancer. Hamartoamous tumors of the gastrointestinal tract, as well as prostate and adrenal neoplasia, were also frequently observed. Significantly, the spectrum of neoplasia observed in pten+/- mice partially overlaps with the types of tumors frequently detected in CS patients. The majority of tumors in pten+/- mice exhibit loss of heterozygosity at the pten locus, which indicates the importance for loss of PTEN function in tumor formation. Consistent with the role of PTEN in negative regulation of PKB/Akt phosphorylation and activity, pten loss of heterozygosity is accompanied by hyperphosphorylation of PKB/Akt in tumors. Taken together, our results establish pten+/- mice as an excellent animal model system for the investigation of PTEN-related hamartoma syndromes, as well as the role of PTEN in breast and endometrial carcinogenesis.

Aging↗

Differential expression of matrix metalloproteinases and their inhibitors in non-small cell lung cancer.

In a comprehensive immunohistochemical study of the expression of ten metalloproteinases (MMPs) and their four inhibitors (TIMPs) in 115 non-small cell lung carcinomas (NSCLCs), the findings have been correlated with the histological and clinical features of the tumours. All MMPs and TIMPs were expressed in tumours, with frequencies ranging from 41% for MMP-2 to 68% for MMP-13. Stromal immunoreactivity ranged from 6% for TIMP-4 to 87% for MMP-13. In some tumours, an overexpression of these proteins, as revealed by stronger staining in cancer cells than in adjacent normal bronchial epithelium, was also observed. The frequency ranged from 1% for MMP-3 to 28% for MMP-13. Compared with squamous cell carcinoma (SqCC), adenocarcinoma (AdC) more frequently overexpressed MMP-1, -11, -13, -14, and TIMP-2, and TIMP-1 and/or TIMP-2 overexpression positively correlated with more advanced stage disease. None of the MMP or TIMP expression correlated with the ras genotype of the tumours. The higher frequency of MMP overexpression in AdC than in SqCC may relate to the greater tendency of the former for systemic metastasis. The association of TIMP-1 overexpression with more advanced disease may suggest a role in prognosis.

Adult↗

Immortal human pancreatic duct epithelial cell lines with near normal genotype and phenotype.

Immortal epithelial cell lines were previously established after transduction of the HPV16-E6E7 genes into primary cultures of normal pancreatic duct epithelial cells. Single clones were isolated that demonstrated near normal genotype and phenotype. The proliferation of HPDE6-E6E7c7 and c11 cells is anchorage-dependent, and they were nontumorigenic in SCID mice. The cell lines demonstrated many phenotypes of normal pancreatic duct epithelium, including mRNA expression of carbonic anhydrase II, MUC-1, and cytokeratins 7, 8, 18, and 19. These cells have normal Ki-ras, p53, c-myc, and p16(INK4A) genotypes. Cytogenetic studies demonstrated losses of 3p, 10p12, and 13q14, the latter included the Rb1 gene. The wild-type p53 protein was detectable at very low levels consistent with the presence of E6 gene product, and the lack of functional p53 pathway was confirmed by the inability for gamma-irradiation to up-regulate p53 and p21waf1/cip1 protein. The p110/Rb protein level was also not detectable consistent with the expression of E7 protein and haploid loss of Rb1 gene. Despite this, the proliferation of both c7 and c11 cells were markedly inhibited by transforming growth factor-beta1. This was associated with up-regulation of p21cip1/waf1 but not p27kip1. Further studies showed that p130/Rb2 and cyclin D3 were expressed, suggesting that p130/Rb2 may have partially assumed the maintenance of G(1) cell cycle checkpoint regulation. These results indicate that except for the loss of p53 functional pathway, the two clones of HPDE6-E6E7 cells demonstrated a near normal genotype and phenotype of pancreatic duct epithelial cells. These cell lines will be useful for future studies on the molecular basis of pancreatic duct cell carcinogenesis and islet cell differentiation.

Animals↗

Co-expression of epidermal growth factor receptor and transforming growth factor-alpha is independent of ras mutations in lung adenocarcinoma.

The interaction of epidermal growth factor receptor (EGFR) and its ligand transforming growth factor-alpha (TGF-alpha) leads to an autocrine activation of the ras signaling pathway and putatively its oncogenic activity. It is thus hypothesized that the co-overexpression of EGFR-TGFalpha will be redundant hence rare in tumors with oncogenic ras mutations. To test this hypothesis, we studied by immunohistochemistry the expression of EGFR and TGF-alpha in primary non small cell lung cancers. Such putative EGFR autocrine loop activation was found in 73% of squamous cell carcinomas that rarely develop ras mutations. In contrast, EGFR-TGFalpha co-expression occurred with equal frequency in adenocarcinomas irrespective of their ras genotype. The results indicate that EGFR autocrine loop activity in adenocarcinoma may have alternative signaling activities aside from the activation of ras-MAP kinase pathway.

Adenocarcinoma↗

A study of smoking, p53 tumor suppressor gene alterations and non-small cell lung cancer.

PURPOSE: The purpose of this study was to investigate the relationship between smoking and p53 tumor suppressor gene alterations, and their association with clinicopathologic features and prognosis in non-small cell lung cancer (NSCLC). METHODS: For 111 of 119 stage I-III NSCLC patients that had been followed prospectively, tumor p53 protein accumulation was measured immunohistochemically (IHC). Staining was evaluated as a score (p53IHCS) combining intensity and percent distribution. RESULTS: Forty-eight of 111 (43%) tumors had p53IHCS > 1. p53 IHC was associated with increasing tumor size (T) (p = 0.035), nodal status (N) (p = 0.091), stage (p = 0.054), and histology: squamous cell carcinoma (70%) and adenocarcinoma (27%) (p = 0.0002). In logistic regression analysis, p53 IHC was associated with squamous cell histology versus other histotypes [adjusted odds ratio (OR)5.90, 95% confidence interval (CI) 2.34-14.90]. p53 IHC was not associated with smoking variables. In multivariate proportional hazards analysis, p53IHCS and pack-years smoked (PY), both as continuous variables, were negative prognostic factors. The adjusted hazard ratios (HR) for the survival outcome recurrence for p53IHCS and PY were 1.20 (95% CI 1.02-1.40) and 1.03 (95% CI 1.01-1.04), and for death due to recurrent disease (DRD) were 1.35 (95% CI 1.11-1.64) and 1.03 (95% CI 1.01-1.04), respectively. Comparing the 75th percentile to the baseline 0, the adjusted HR for p53IHCS (5 vs. 0) was 4.5 and for PY (55 vs. 0) was 5.1 for the outcome DRD. Both variables demonstrated a dose-response relationship with survival. CONCLUSIONS: PY and p53IHCS are significant, independent and important predictors of recurrence and DRD in stage I-III NSCLC.

Adenocarcinoma↗

zo-2 gene alternative promoters in normal and neoplastic human pancreatic duct cells.

We have observed that 2 forms of zonula occludens 2 (ZO-2) protein, ZO-2A and ZO-2C, are expressed in normal human pancreatic duct cells, but only ZO-2C in pancreatic duct adenocarcinoma. We report here partial organization of the zo-2 gene. Transcription of 2 forms of ZO-2 mRNA is driven by alternative promoters P(A) and P(C). Lack of expression of ZO-2A in neoplastic cells is caused by inactivation of the downstream promoter P(A). Analysis of the promoter P(A) sequence and function in normal and neoplastic cells demonstrated that neither structural changes (mutations) nor a change in the pool of transcription factors is responsible for its inactivation. Although hypermethylation was found in a large number of cancer clones, treatment with 5-aza-2'-deoxycytidine did not fully cause the promoter function to recover. We conclude that the initial down-regulation of zo-2 promoter P(A) activity in pancreatic duct carcinomas is due to the structural or functional alteration(s) in the regulatory elements, localized outside the analyzed promoter region. Methylation of P(A) is responsible for the inactivation of the suppressed promoter at the late stages of tumor development.

Base Sequence↗

Prognostic role of p53 protein expression in epidermoid carcinoma of the anal canal.

PURPOSE: To assess the prognostic significance of p53 protein expression in patients with primary epidermoid carcinoma of the anal canal managed by radiation therapy (XRT), 5-fluorouracil (5-FU), and mitomycin C (MMC). METHODS AND MATERIALS: From January 1991 to December 1993, 58 consecutive patients with primary epidermoid carcinoma of the anal canal were treated in a prospectively designed protocol of XRT (24 Gy/12--3(1/2) wk split--28 Gy/14) and concurrent 5-FU (1000 mg/m2/day 1-4) and MMC (10 mg/m2 day 1) of each cycle of XRT. Paraffin-embedded tumor samples were unavailable in 9 patients, leaving 49 patients in the study. Expression of p53 protein was studied using immunohistochemistry and quantified as percent tumor nuclei showing positive staining. Actuarial survival and disease-free survival (DFS) rates were estimated by the Kaplan-Meier method, and compared using the log-rank test. A Cox proportional hazard model was used for the multivariable analysis. RESULTS: There were 6 T1, 26 T2, 7 T3, and 10 T4 lesions. Primary tumor sizes ranged from 1-15 cm with a median of 4 cm. There were 6 patients with nodal metastases. Median follow-up was 4.5 years. Positive nuclear immunostaining for p53 was observed in 40 of 49 patients. The median percent positive staining was 5%, with 13, 9, and 18 patients showing staining in <5%, 5 to <10%, and 10-50% of tumor nuclei respectively. There was no correlation of percent p53 staining with gender, age, tumor stage, size, or histology. Local, regional, and distant failures were observed in 12, 2, and 2 patients respectively. The 5-yr survival and DFS were 84% and 64% respectively. In univariate analysis, the only prognostic variable for survival was gender. For DFS, advanced T category and large tumor size were predictive of poor DFS. In multivariate analysis, poor DFS was associated with high T category (p = 0.0008), basaloid histology (p = 0.001), male gender (p = 0.002), and increasing percent of p53 protein expression (p = 0.01). CONCLUSIONS: It is concluded that expression for p53 protein is present in a high percentage of patients with epidermoid carcinoma of the anal canal. For patients managed with combined XRT, 5-FU, and MMC, percent p53 protein expression is of prognostic value for DFS independent of other clinical factors such as T category, gender, and histology.

Adult↗

Tight junction protein ZO-2 is differentially expressed in normal pancreatic ducts compared to human pancreatic adenocarcinoma.

Differential display of hamster mRNA identified a fragment present in normal pancreatic duct cells that is not expressed in pancreatic duct carcinoma cells. Sequence analysis showed an 88% and 82% identity, respectively, to the cDNA of the canine and human tight junction zo-2 gene. Semi-quantitative RT-PCR analysis of human ZO-2 revealed a striking difference in the expression of various regions of the ZO-2 transcript in normal and neoplastic cells and the presence of an abnormality at the 5'-end of mRNA. RACE analysis identified 2 human ZO-2 mRNAs that encode proteins of different lengths, designated as ZO-2A and ZO-2C. The difference between the 2 forms of ZO-2 is the absence of 23 amino acid residues at the N terminus of ZO-2C compared with ZO-2A. Although ZO-2C was expressed in normal pancreatic cells and a majority of neoplastic tissues analyzed, ZO-2A was undetectable except in one case in all of the pancreatic adenocarcinomas analyzed. This suggests the presence of a yet to be identified motif important for cell-growth regulation within the 23-amino acid residue N-terminal peptide of ZO-2A, MPVRGDRGFPPRRELSGWLRAPG.

Adenocarcinoma↗

Reduced expression of the cell cycle inhibitor p27Kip1 in non-small cell lung carcinoma: a prognostic factor independent of Ras.

Levels of p27 have been found to have independent prognostic significance in a variety of tumors including breast, colon, prostate, ovary, and gastric carcinomas. We investigated p27 levels and determined ras mutational status in 136 non-small cell lung cancers. We found reduced levels of p27 in 86% of cases and showed a statistically significant inverse correlation between p27 levels and tumor grade. ras mutations were found exclusively in adenocarcinomas and showed no relationship to p27 levels. Clinical data on a subset of the patients studied indicated that all 16 patients who died of disease and 21 of 22 patients who relapsed had low p27 levels, whereas all patients with high p27 levels were alive at last follow up. These findings suggest that alteration in p27 levels plays an important role in lung tumor progression and that p27 levels may have independent prognostic significance in non-small cell lung cancer.

Carcinoma, Non-Small-Cell Lung↗