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PubMed1983

Isozyme alterations, gene regulation and the neoplastic transformation.

Studies of isozyme composition in the rat liver-hepatocellular carcinoma model system have revealed wide-ranging abnormalities of gene expression. Isozymes geared for adult liver function are lost in tumors to varying degrees, depending on growth rate and degree of tumor dedifferentiation; whereas isozymes low or absent in normal adult liver become predominant or sole forms in fast growing, poorly differentiated hepatic tumors. The prevailing pattern is a switch from the adult to fetal forms, thereby indicating that genes coding for adult isozymes are suppressed in liver neoplasms, while genes active in fetal stages but inactivated during normal embryonic development become re-activated in cancer. These isozyme alterations not only are a key to neoplastic behavior, but are a striking example, among many, of pervasive abnormalities of gene expression involving virtually every means of identification of gene products; for example, the expression in tumors of fetal antigens, growth factors, angiogenesis factors, membrane components, and ectopic polypeptide hormones. Most important is the recently discovered activation of normally silent host oncogenes associated with and probably causally related to viral or chemical carcinogenesis. Despite compelling evidence for somatic mutation, these findings argue for abnormal gene regulation in cancer rather than gene mutation. Uriel has proposed that retrodifferentiation to an embryonal stage is a normal response to cell injury, and is an essential step preceding normal re-ordering of gene regulation. Under the influence of a carcinogen, however, normal differentiation may be aborted before differentiation is complete and the resultant transformed cell would then not be subject to normal regulatory restraints. A similar hypothesis has been expressed by Potter in the aphorism "Oncogeny is blocked ontogeny." Evidence exists for a role of 5-methylcytosine as a regulatory site in gene transcription. Jonathan Nyce, in a Ph.D. thesis presented to the Biology Department of Temple University, has proposed a mechanism of chemical carcinogenesis, based on the loss of cytosine residues, and therefore of methylation sites, in DNA as a result either of mispairing of bases resulting from O6-alkylation of guanines in DNA: or by inhibition of cytosine methylation. This plausible proposal provides a molecular basis for the many aberrations of gene regulation in cancer.

Animals↗
PubMed2002

Detailed genomic mapping and expression analyses of 12p amplifications in pancreatic carcinomas reveal a 3.5-Mb target region for amplification.

Previous cytogenetic and comparative genomic hybridization (CGH) analyses have shown that the gain of chromosome arm 12p is frequent in pancreatic carcinomas. We investigated 15 pancreatic carcinoma cell lines using CGH, fluorescence in situ hybridization (FISH), and semiquantitative polymerase chain reaction (PCR) to characterize 12p amplifications in detail. The CGH analysis revealed gains of 12p in four of the cell lines and local amplification within 12p11-12 in six cell lines. By FISH analysis, using precisely mapped YAC clones, the commonly amplified region was found to be approximately 5 Mb. The amplified segment extended from YAC 753f12, covering the KRAS2 locus, to YAC 891f1, close to the centromere. A semiquantitative PCR methodology was used to estimate genomic copy numbers of 14 precisely mapped expressed sequence tags (ESTs) and sequence-tagged sites, located within this interval. The level of amplification ranged from two- to 12-fold. The produced gene copy profiles revealed a 3.5-Mb segment with various local amplifications. This region includes KRAS2 and ranges from D12S1617 to sts-N38796. Two of the cell lines (primary and metastatic tumor from the same patient) showed amplification peaks within the distal region of this segment, two had peaks within the proximal region, one showed subpeaks in both regions, and one displayed amplification of the entire region. Chromosome segment-specific cDNA array analysis of 29 expressed sequences within the whole interval between D12S1617 and sts-N38796 indicated overexpression of four ESTs, two corresponding to DEC2 and PPFIBP1, and two to ESTs with unknown function. Expression analysis of these and of KRAS2 showed specific overexpression in the six cell lines with local 12p amplifications. These findings indicate two target regions within the 3.5-Mb segment in 12p11-12, one proximal including PPFIBP1, and one distal including KRAS2.

Carcinoma↗
PubMed2000

Identification of a gene coding for a new squamous cell carcinoma antigen recognized by the CTL.

Peptide-based specific immunotherapy has resulted in tumor regression in some melanoma patients. However, tumor Ags and peptides for specific immunotherapy, except for treatment of melanomas, have not yet been well identified. In this study, we report a gene encoding a new squamous cell carcinoma (SCC) Ag recognized by cells of the HLA-A24-restricted and tumor-specific CTL line. This gene with 3958-bp length was transcribed from the chromosome 6q22 with six exons, and its mRNA was ubiquitously expressed in both SCCs and normal tissues, and partly expressed in adenocarcinomas. The deduced 958-aa sequence encoded by this gene showed no similarity to any known amino acid sequences. This gene product had a characteristic of an endoplasmic reticulum-resident protein. A 100-kDa protein was detected in the vast majority of SCCs from various tissues, in majority of renal cell carcinomas and brain tumors, and in about one-third of melanomas and adenocarcinomas from various organs other than the breast. In contrast, it was not expressed at all in any of the normal cells or tissues tested, including the testis and fetal liver. Three different peptides at positions 93-101, 161-169, and 899-907 of this Ag were recognized by this CTL line, and all of them induced HLA-A24-restricted and tumor-specific CTLs from PBMCs of SCC patients. Therefore, these peptides may be useful for peptide-based specific immunotherapy of HLA-A24+ patients with SCC in various organs, as well as for treatment of other cancer.

Amino Acid Sequence↗
PubMed1999

Recurrent DNA copy number losses associated with metastasis of larynx carcinoma.

Squamous cell carcinomas of the head and neck show frequent and complex chromosome aberrations, but little is known about the changes that occur during the metastatic process. To compare the accumulation of changes in primary and metastatic tumors we analyzed 19 pairs of primary larynx cancer tumors and their metastases. The most frequent changes were found at 3p, 3q, 5p, 9, and 13. Losses at 13, 8p, and 9q were more frequent in metastases than in primary tumors.

Adult↗
PubMed2000

p53 mutations and loss of p53 function confer multidrug resistance in neuroblastoma.

BACKGROUND: Neuroblastomas often acquire sustained drug resistance during therapy. Sensitivities to carboplatin, etoposide, or melphalan were determined for 18 neuroblastoma cell lines; eight were sensitive and ten were resistant. As p53 mutations are rare in neuroblastomas studied at diagnosis, we determined if acquired p53 mutations and loss of function conferred multidrug resistance. RESULTS: Loss of p53 function (p53-LOF), defined as a failure to induce p21 and/or MDM2 in response to melphalan, was seen in 1/8 drug-sensitive and 6/10 drug-resistant cell lines. In four cell lines p53-LOF was associated with mutations in the DNA binding region of p53, while three cell lines with LOF and four cell lines with functional p53 had no evidence of p53 muta-tions. Nonfunctional and mutated p53 was detected in one resistant cell line, while a sensitive cell line derived from the same patient prior to treatment had functional and wild type (wt) p53. We transfected HPV 16 E6 (which mediates degradation of p53, causing LOF) into two drug-sensitive neuroblastoma cell lines with functional p53. LC(90) values of HPV 16 E6 transfected cell lines were 3-7-fold (melphalan), 8-109-fold (carboplatin), and 2-158-fold (etoposide) greater than that of LXSN-transfected controls. CONCLUSIONS: These data suggest that some neuroblastomas acquire p53 mutations during therapy, which is associated with a loss of p53 function, and can confer high-level multidrug resistance.

Chromosome Deletion↗
PubMed1990

DNA alterations at proto-oncogene loci and their clinical significance in operable non-small cell lung cancer.

DNA from tumor samples of 54 patients with operable non-small cell lung cancer (NSCLC) was analyzed to determine whether proto-oncogene alterations could be correlated with the clinical behavior of lung cancer. Among seven proto-oncogenes tested, changes in the copy number of Ha-ras, c-myc and c-raf-1 were found in only seven tumors. Most of them were epidermoid carcinomas without lymph node involvement (N0). In spite of a localized disease with complete surgical resection, six of these patients relapsed within a mean disease-free interval (DFI) of only 6.5 months. There is a significant correlation between DNA alterations at proto-oncogene loci and clinical relapse within 12 months of surgical resection (P less than 0.025).

Blotting, Southern↗
PubMed2002

p53 mutation analysis for definite diagnosis of multiple primary lung carcinoma.

BACKGROUND: The detection of a second tumor in patients with lung carcinoma raises the question whether this lesion is a metastasis or a second primary lung carcinoma. Patients cannot always be categorized satisfactorily according the criteria of multiple lung carcinoma proposed by Martini and Melamed. This may result in an inadequate treatment schedule in individual patients. Because p53 mutations can be used as clonal marker, the authors investigated whether p53 mutation analysis can differentiate between primary lung carcinomas and metastatic disease. METHODS: Sixty-four tumors in 31 patients with synchronous and metachronous lung tumors were investigated by p53 mutation analysis. RESULTS: In 21 patients, the tumors showed different p53 mutations, and therefore a definite diagnosis of multiple primary lung carcinoma was made. One of these patients did not meet the criteria of Martini and Melamed. In two other patients not matching these criteria, identical mutations were demonstrated in both tumors, indicating the presence of metastatic disease. In eight patients, analysis was not conclusive or possible. CONCLUSIONS: p53 mutation analysis can be a useful tool to confirm or rule out multiple primary lung carcinoma, and the results confirm the criteria of Martini and Melamed. However, in patients not meeting these criteria, the diagnosis of multiple lung carcinoma still has to be considered, and metastatic disease has to be ruled out. P53 mutation analysis can be helpful for this purpose.

Adenocarcinoma↗
PubMed2006

Similar chromosomal changes in cisplatin and oxaliplatin-resistant sublines of the H69 SCLC cell line are not associated with platinum resistance.

Small cell lung cancer (SCLC) initially responds well to DNA damaging drugs such as cisplatin, however this is transitory as resistance normally develops. To investigate whether changes in chromosomal copy number caused by platinum drug treatment contributes to platinum resistance, we have analyzed H69 SCLC cells and two low-level platinum-resistant sublines, H69CIS200 and H69OX400, derived by cisplatin and oxaliplatin treatment, respectively. Affymetrix 10K SNP array showed that cisplatin and oxaliplatin have independently caused similar changes including loss of segments 6q21-qter and 13pter-13q.14.11 and duplication of chromosome 21. Interestingly, despite using equally cytotoxic doses of drug in the development of the cell lines, oxaliplatin caused three times more chromosomal changes than cisplatin. The resistant cell lines lose their resistant phenotype after 3 months of drug-free culture. The revertant cell lines, denoted H69CIS200-S and H69OX400-S, were also analyzed by Affymetrix array to determine if chromosomal changes associated with resistance remain after the resistant phenotype is lost. In the H69OX400-S many of the changes observed in the resistant cells were absent suggesting that they contributed to the resistant phenotype including: loss of 1q23.3-qter, 10q11.23, and 19q13.12-q13.2 and duplication of segments 6p21.2-p12.3, 16q12.1-16q13, 16q21-q23.1, and 19q12. However, out of the similar changes induced by cisplatin and oxaliplatin, both the loss of 6q21-qter and gain of 21 were still present in the H69CIS200-S and H69OX400-S cells. This suggests that cisplatin and oxaliplatin induced similar changes due to inherent vulnerabilities in the H69 cells rather than changes associated with platinum resistance.

Antineoplastic Agents↗
PubMed1994

Allelic loss at 1p is associated with tumor progression of meningiomas.

Next to chromosome 22 anomalies, deletions of the short arm of chromosome 1 have previously been described as the most frequent alteration detected by cytogenetic analysis of meningiomas. To determine the incidence of these deletions, we have analyzed a series of 50 meningiomas for the loss of alleles at four chromosome 1 loci. Thirteen samples displayed LOH for the markers studied; in one instance, the results were compatible with loss of the entire chromosome 1, whereas in the other 12 samples deletions of the short arm were observed. Eleven of the meningiomas had previously been shown to have loss of alleles on chromosome 22, and 12 of them were characterized by increased tumor aggressiveness. These findings suggest that deletion of Ip (or the alteration of a locus located there) might represent a secondary, but nonrandom alteration in meningiomas, perhaps contributing to meningioma tumor progression.

Alleles↗
PubMed2004

Harmonized microarray/mutation scanning analysis of TP53 mutations in undissected colorectal tumors.

Both the mutational status and the specific mutation of TP53 (p53) have been shown to impact both tumor prognosis and response to therapies. Molecular profiling of solid tumors is confounded by infiltrating wild-type cells, since normal DNA can interfere with detection of mutant sequences. Our objective was to identify TP53 mutations in 138 stage I-IV colorectal adenocarcinomas and liver metastases without first enriching for tumor cells by microdissection. To achieve this, we developed a harmonized protocol involving multiplex polymerase chain reaction/ligase detection reaction (PCR/LDR) with Universal DNA microarray analysis and endonuclease V/ligase mutation scanning. Sequences were verified using dideoxy sequencing. The harmonized protocol detected all 66 mutations. Dideoxy sequencing detected 41 out of 66 mutations (62%) using automated reading, and 59 out of 66 mutations (89%) with manual reading. Data analysis comparing colon cancer entries in the TP53 database (http://p53.curie.fr) with the results reported in this study showed that distribution of mutations and the mutational events were comparable.

Adenocarcinoma↗
PubMed2002

Toward a more complete recognition of immunoreactive antigens in squamous cell lung carcinoma.

There is very limited knowledge about the antibody response against tumor-expressed antigens in lung cancer. To arrive at a more complete picture of lung cancer antigens, we generated 2 cDNA libraries from squamous cell lung carcinoma and isolated 15 immunogenic antigens using autologous sera. Among the antigens most frequently identified were the lymphoid blast crisis oncogene (LBC), an unknown hypothetical protein and the p53-binding protein (TP53 BP), which have already been associated with tumor development. Of the immunogenic antigens, 6 map to chromosomes that are frequently altered in squamous cell lung carcinoma. SEREX database analysis showed that 7 of the identified immunogenic antigens have been associated with the humoral immune response in other human tumors. Screening with heterologous sera of patients with lung carcinoma identified 4 antigens, including human protein kinase C and TP53 BP, which have also been found by autologous screening. Only 1 of the 15 identified antigens reacted with any of the 36 control sera, which were taken from individuals without known disease. Sera from adenocarcinoma and large cell carcinoma of the lung were not reactive for the antigens. In summary, using 2 newly established cDNA libraries, we isolated 15 novel antigens, which were subsequently evaluated for the frequency of their corresponding antibodies in autologous, normal and heterologous sera; their chromosomal localization; and their correlation with survival after surgery.

Antibodies, Neoplasm↗
PubMed1993

Characterization of four new cell lines derived from small-cell gastrointestinal carcinoma.

Four human small-cell gastrointestinal carcinoma cell lines were established from tumor tissues of patients with esophageal, gastric or rectal cancer, and were studied morphologically and biochemically in comparison with small-cell lung carcinoma (SCLC) cell lines and common gastric cancer cell lines. Cells from all the small-cell gastrointestinal carcinoma lines were as small as classic SCLC cells and had characteristic neurosecretory granules. Cells from only one line grew as tightly packed spherical aggregates of floating cells, and those of the other 3 grew attached to substrate. Although high levels of creatine kinase brain isoenzyme (CK-BB) were detected in all 4 cell lines, 2 of them showed low levels of aromatic L-amino-acid decarboxylase and 3 had low levels of neuron-specific enolase (NSE). None of the lines showed simultaneous elevation of enzymes. C-myc, N-myc, and L-myc were not amplified in any of the cell lines, but c-myc mRNA was expressed in 2 lines. Our findings indicate that all small-cell gastrointestinal carcinoma cells examined belong to the variant type which is used in the classification of SCLC. Furthermore, the ECC18 line, derived from esophageal cancer, seemed to be of true endocrine cell origin, while the 3 other small-cell gastrointestinal carcinoma lines seemed to arise via neoplastic neometaplasia from adenocarcinoma cells to endocrine cells.

Aged↗
PubMed1990

Frequent expression of receptors for granulocyte-macrophage colony-stimulating factor on human nonhematopoietic tumor cell lines.

Receptors for granulocyte-macrophage colony-stimulating factor (GM-CSF) were identified on 9 of 35 (26%) human nonhematopoietic tumor cell lines including non-small cell lung cancer, stomach cancer, colon cancer, and osteosarcoma cells. GM-CSF receptors distributed on these human tumor cells were low affinity types with an equilibrium dissociation constant of 1.5-10.0 nM. Cross-linking studies revealed that the molecular weights of the low affinity GM-CSF receptors were 65-85 kilodaltons. The high affinity receptors identified on hematopoietic cells were not detected on human nonhematopoietic tumor cells which we studied, and we could detect no effects of GM-CSF on cell growth of these tumor cells.

Carcinoma, Non-Small-Cell Lung↗