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T Liloglou

Publications and source records attributed to T Liloglou.

At least 19 recordsLinked to original sources
PubMed2006

Family history and risk of lung cancer: age-at-diagnosis in cases and first-degree relatives.

To investigate the little known risk of lung cancer at an early age when a first-degree relative has had such a diagnosis, 579 incident cases and 1157 population controls were studied in Liverpool between 1998 and 2004 using standardised questionnaires covering demography and lifestyle. A history of lung cancer in first-degree relatives was associated with a significantly increased risk in the proband where in both individuals the cancers were diagnosed before the age of 60 years (odds ratio (OR)=4.89; 95% confidence interval (CI): 1.47-16.25). A significantly elevated risk of lung cancer was also observed in association with a relative affected before the age of 60 years, regardless of age-at-onset of the disease (OR=2.08; 95% CI: 1.20-3.59). This finding is strongly consistent with a genetic component in early-onset lung cancer risk.

Age of Onset↗
PubMed2006

Promoter methylation of P16, RARbeta, E-cadherin, cyclin A1 and cytoglobin in oral cancer: quantitative evaluation using pyrosequencing.

Methylation profiling of cancer tissues has identified this mechanism as an important component of carcinogenesis. Epigenetic silencing of tumour suppressor genes through promoter methylation has been investigated by a variety of means, the most recent of which is pyrosequencing. We have investigated quantitative methylation status in oral squamous cell carcinoma patients. Fresh tumour tissue and normal control tissue from resection margin was obtained from 79 consecutive patients undergoing resection of oral squamous cell carcinoma. DNA was extracted and bisulphite treated. PCR primers were designed to amplify 75-200 bp regions of the CpG rich gene promoters of p16, RARbeta, E-cadherin, cytoglobin and cyclinA1. Methylation status of 4-5 CpG sites per gene was determined by pyrosequencing. Significant CpG methylation of gene promoters within tumour specimens was found in 28% for p16, 73% for RARbeta, 42% for E-cadherin, 65% for cytoglobin and 53% for cyclinA1. Promoter methylation was significantly elevated in tumours compared to normal tissue for p16 (P = 0.048), cytoglobin (P = 0.002) and cyclin A1 (P = 0.001) but not in RARbeta (P = 0.088) or E-cadherin (P = 0.347). Concordant methylation was demonstrated in this tumour series (P = 0.03). Significant differences in degree of methylation of individual CpG sites were noted for all genes except RARbeta and these differences were in a characteristic pattern that was reproduced between tumour samples. Cyclin A1 promoter methylation showed an inverse trend with histological grade. Promoter methylation analysis using pyrosequencing reveals valuable quantitative data from several CpG sites. In contrast to qualitative data generated from methylation specific PCR, our data demonstrated p16 promoter methylation in a highly tumour specific pattern. Significant tumour specific methylation of cyclin A1 promoter was also seen. Cytoglobin is a novel candidate tumour suppressor gene highly methylated in upper aero-digestive tract squamous cancer.

Adult↗
PubMed2005

Colorectal adenomas with a low frequency of ki-ras mutations: a sample from a population with a low mortality rate from colorectal cancer.

OBJECTIVE: To detect and analyse ki-ras point mutations in colorectal adenomas and carcinomas in patients from Greece, where mortality rate from colorectal cancer is lower than that in other European countries and the USA. PATIENTS AND METHODS: As a method we used PCR-RFLP technique, to examine ki-ras codons 12 and 13 mutations in 450 paraffin embedded tissues, consisting of 141 normal mucosas, 165 adenomas and 144 sporadic colorectal cancers taken from 141 patients. RESULTS: Frequency of ki-ras mutations was 3.2% (3/93) in small adenomas, 5.2% (3/57) in greater than 1 cm adenomas, 20% (3/15) in tissues where adenoma and cancer coexisted and 39.5% (57/144) in colorectal cancer. CONCLUSION: These data showed that the frequency of ki-ras mutations was low in all sizes of polyps and high in carcinomas in a sample of a population, characterized by a low mortality rate from colorectal cancer. Ki-ras mutations were not an early event of colon carcinogenesis in these patients and the low frequency of ki-ras mutations in adenomas may probably have some relevance to the low mortality rate. Our findings could be explained, not by the dietary habits of this population, but by the presence of other hitherto unknown environmental factors.

Adenoma↗
PubMed2005

Methylation discriminators in NSCLC identified by a microarray based approach.

Aberrant DNA methylation is a frequent phenomenon in non-small cell lung cancers. We have used a microarray approach to assess the methylation status of 245 CpG positions in 59 candidate genes in 26 squamous cell carcinomas, and 22 adenocarcinomas as well as 26 normal adjacent lung tissue samples from smokers to identify genes that show a distinct methylation status difference between the two different tumour type tissues and normal adjacent tissue. Tumour tissue samples were grouped together and compared to the normal tissue sample group. A multivariate test was performed, taking into account all CpG positions that were analyzed for a particular gene, to calculate p-values for each gene based on the observed methylation difference between the two groups, p-values obtained were corrected for multiple testing. The highest degree of differential DNA methylation in squamous cell carcinoma compared to normal was observed in ARHI, MGMT, GP1bbeta, RARbeta and TMEFF2 genes, while TMEFF2, MGMT and CDKNIC genes differentiated between adenocarcinomas and normal tissue. It is of note that some of the genes for which differential methylation status was observed, have not been previously described in lung cancer. Our results provide compelling evidence that different histological types of lung cancer may be distinguished from normal tissue based on methylation profiles of specific genes.

Adenocarcinoma↗
PubMed2004

Absence of association with cancer risk and low frequency of alterations at a p53 responsive PIG3 gene polymorphism in breast and lung carcinomas.

The mechanisms of p53-dependent apoptosis involve a set of genes that possess the ability to modulate oxidative stress. One of them PIG3, is induced by p53 through a microsatellite in its promoter region. This microsatellite was found to acquire its full structure and p53-functional dependence only in Hominoidea (apes and humans) and has been proposed to represent an evolutionary adaptation of tumor suppressor mechanisms. Microsatellite instability and genetic constitution, comprising the presence of the low repetition allele (10 TGYCC repeats), at this locus have been hypothesized to provide an increased risk for cancer development. Therefore, in the present analysis we examined this polymorphism in two common human cancers, lung and breast and compared it with corresponding control cases. Furthermore, for lung cancer we employed two different ethnic groups, Greek and British. Analysis of this locus in this types of tumors showed: (1) a very low frequency of microsatellite instability and loss of heterozygosity (1.4% and 4%, respectively) in the examined carcinomas, (2) the homozygous presence of the 10 repeats allele only in the control cases, and (3) a non-significant increase of the most frequent allele (15 repeats) in the cancer groups as compared to control ones. The last two observations were found in both Greek and British populations. Taken together, these data do not support the notion that this PIG3 polymorphism is associated with an increased risk for cancer susceptibility. Larger studies including other types of cancer should also be performed.

Base Sequence↗
PubMed2004

METH-2 silencing and promoter hypermethylation in NSCLC.

The antiangiogenic factor METH-2 (ADAMTS-8) was identified in a previous dual-channel cDNA microarray analysis to be at least two-fold under-represented in 85% (28 out of 33) of primary non-small-cell lung carcinomas (NSCLCs). This observation has been validated in an independent series of NSCLCs and adjacent normal tissues by comparative multiplex RT-PCR, and METH-2 mRNA expression was dramatically reduced in all 23 tumour samples analysed. Immunohistochemical analysis of the same sample set demonstrated that METH-2 was strongly expressed in 14 out of 19 normal epithelial sites examined but only one out of 20 NSCLCs. DNA methylation analysis of the proximal promoter region of this gene revealed abnormal hypermethylation in 67% of the adenocarcinomas and 50% of squamous cell carcinomas, indicating that epigenetic mechanisms are involved in silencing this gene in NSCLC. No homozygous deletions of METH-2 were found in lung cancer cell lines. Allelic imbalance in METH-2 was assessed by an intronic single nucleotide polymorphism (SNP) assay and observed in 44% of informative primary samples. In conclusion, the downregulation of METH-2 expression in primary NSCLC, often associated with promoter hypermethylation, is a frequent event, which may be related to the development of the disease.

ADAM Proteins↗
PubMed2003

Absence of mutations in the VHL gene but frequent loss of heterozygosity at 3p25-26 in non-small cell lung carcinomas.

In this study we have examined 79 primary non-small cell lung tumours for the presence of mutations of the VHL gene as well as for allelic imbalance at the gene surrounding loci. While allelic imbalance was found in 83% of specimens, frequently affecting the whole 3p25-p26 region, no mutations were detected in the VHL coding region. The fractional regional loss (FRL) was significantly higher in squamous cell carcinomas (0.746) than adenocarcinomas (0.493) (Wilcoxon P=0.002). This is the first investigation of the VHL gene mutational status in primary lung tumours. Our results indicate that mutation is not a common means of VHL inactivation in NSCLC.

Adenocarcinoma↗
PubMed2003

Allelic imbalance at the DNA mismatch repair loci, hMSH2, hMLH1, hPMS1, hPMS2 and hMSH3, in squamous cell carcinoma of the head and neck.

BACKGROUND: Squamous cell carcinoma of the head and neck (SCCHN) is one of the 10 most frequently occurring cancers in the world. Defective mismatch repair, as exhibited by the phenomenon of microsatellite instability, has been observed in SCCHN although no reports of mismatch repair gene mutations or altered protein expression have been published. In a variety of microsatellite instability (MSI) positive cancers where mutations in the mismatch repair (MMR) genes were not observed, allelic imbalance at the loci of the MMR genes was prevalent. OBJECTIVE: To investigate whether allelic imbalance at the MMR genetic loci contributes to the development of SCCHN. MATERIALS AND METHODS: 35 matched normal/tumour SCCHN pairs were studied using 29 microsatellite markers located within and adjacent to six known DNA mismatch repair genes. In addition, mutational analysis and protein expression of hMSH2 and hMLH1 were investigated. RESULTS AND CONCLUSIONS: We demonstrated that 36 and 17% of the analysed SCCHN specimens exhibited allele imbalance at the hMLH1 and hMSH3 genetic loci, respectively. Allelic instability at these two loci was found to be correlated with the MSI status of the SCCHN tumours. Allelic instability was found to be uncommon at the other MMR gene loci analysed. One mutation was found in hMSH2 and none in hMLH1 in this series of tumours. 23 of 24 (96%) of the examined SCCHN tumours showed reduced expression of either hMSH2 or hMCH1 genes. Allelic instability in the MMR genes, hMLH1 and hMSH3, is proposed to be involved in the aetiology of SCCHN tumours.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Mutational analysis of CDKN2A genes in patients with squamous cell carcinoma of the skin.

BACKGROUND: Nonmelanoma skin cancers [squamous cell carcinomas (SCC) and basal cell carcinomas (BCC)] are the most common neoplasias of the Caucasian population. OBJECTIVES: The purpose of our study was to determine the involvement of CDKN2A genes in the development of sporadic nonmelanoma skin cancer in Greek patients. PATIENTS AND METHODS: Allelic imbalance analysis was performed in 22 SCC and five Bowen's disease specimens. Mutational analysis was performed on exons 1alpha, 1beta and 2 of the CDKN2A locus in 22 SCC, five Bowen's disease and 39 BCC specimens. Exon 1alpha was additionally screened in 28 BCC specimens to complete the mutational analysis of a previous study. RESULTS: Overall, 52% (14 of 27) of the SCC and Bowen's disease specimens exhibited loss of heterozygosity (LOH) in at least one microsatellite marker, whereas, only two of 27 (7%) exhibited microsatellite instability. LOH in 9p appears to be equally involved in both BCC and SCC tumours. Exons 1alpha, 1beta and 2 of the CDKN2A locus were screened for mutations. A Val28Gly substitution in exon 1alpha and a CCC-->TTT (Ala57Val and Arg58Ter) substitution in exon 2, resulting in a change in the amino acid sequence, are reported for the first time in two SCCs, the latter being indicative of a combination of an ultraviolet (UV) radiation-induced mutation and a point mutation. A previously described polymorphism of CDKN2A, the gene for p16INK4a, Ala148Thr, was also detected in an allelic frequency of 3.72%. No mutation was found in any of the five Bowen's disease specimens, or in exon 1beta of CDKN2A, also the gene for p14ARF. CONCLUSIONS: Mutations and the high incidence of 9p LOH detected in our SCC samples imply that inactivation of CDKN2A genes, via allelic loss and/or mutation (probably UV-induced) may play a significant role in nonmelanoma skin cancer development, particularly in the more aggressive SCC type.

Adult↗
PubMed2001

Additional characterization of a hexanucleotide polymorphic site in the first intron of human H-ras gene: comparative study of its alterations in non-small cell lung carcinomas and sporadic invasive breast carcinomas.

Intron 1 of the human H-ras gene possesses a polymorphism consisting of repetitions of the GGGCCT consensus. Three alleles have been reported at this locus. We confirmed that two, P1 and P2, display four and two repeats, respectively, with their internal sequence structure similar to that previously described. The third, P3, previously assigned as a three-unit repetition allele according to its electrophoretic mobility and with no other information regarding its internal structure, was also found. Sequence analysis of the P3 allele revealed that it consists of three perfect repeats of the GGGCCT consensus. This polymorphism is present only in human c-H-ras gene, although single hexanucleotide repeats are found scattered within intron 1 of this gene in rodents. Analysis of this locus in matched tumor/distant normal samples from: (i) 38 patients with non-small-cell lung carcinoma (NSCLC), and (ii) 35 patients with sporadic invasive breast carcinoma, revealed: (1) 6.6% and 19% loss of heterozygosity (LOH) respectively, and (2) 10.5% and 2.9% hexanucleotide instability (HI) respectively, detected by the presence of shifted in length alleles. Shifted alleles exhibited altered internal sequence structure in comparison to normal ones, suggesting complex mutational events. The same pattern of alterations was also detected in tissues adjacent to lung adenocarcinomas and dysplasias adjacent to squamous cell carcinomas (7.7% LOH, 5.9% HI), implying that abnormalities at this locus may be early events in lung carcinogenesis. The frequency of alterations (LOH vs. HI) was significantly different among NSCLC and breast cancer (P=.005), probably due to the different tumor biology of each system. Finally, altered mRNA expression of H-ras gene was detected in all cases with HI, but this finding was also observed in samples without HI. In view of reports showing that elements in intron 1 of H-ras gene potentially influence its transcriptional regulation, from our results we cannot exclude that the hexanucleotide locus could be an element with possible involvement in expressional regulation of this gene.

Base Sequence↗
PubMed2001

Cancer-specific genomic instability in bronchial lavage: a molecular tool for lung cancer detection.

We examined genomic instability in DNA from 80 bronchial lavage samples from patients with lung cancer and individuals with no malignant lung disease. We used a multiplex assay of eight fluorescent-tagged microsatellite markers that have a very high incidence of allelic imbalance in lung tumors. When genomic instability at individual loci was analyzed statistically against diagnosis, markers D3S1289 (P = 0.033), D3S1300 (P = 0.001), D13S171 (P = 0.009), and D17S2179E (P = 0.017) demonstrated significantly higher frequency of instability in bronchial lavage specimens from lung cancer cases than those with nonmalignant conditions. In contrast, markers D9S157, D9S161, D13S153, and D5S644 demonstrated lower specificity (P > 0.05) for lung tumors. These results suggest that genomic instability in some loci may be related to high proliferation rates but not necessarily to cell commitment to malignancy. When genomic instability was scored with only the four cancer-specific markers, the assay produced a sensitivity of 73.9% and a specificity of 76.5%. On combining the results from the cytological examination and the molecular assay, the sensitivity reached 82.6%. These results indicate that in our efforts to investigate genomic instability as a potential marker for the early detection of lung cancer, we need to identify cancer-specific genomic instability markers. This paper has shown that these first four markers may be considered to form an individual set of cancer-specific genomic instability markers.

Adult↗
PubMed2001

Deregulated expression of c-mos in non-small cell lung carcinomas: relationship with p53 status, genomic instability, and tumor kinetics.

Little is known about the status of the mitogen-activating protein kinase pathways in lung cancer. One of the key molecules taking part in these pathways is the product of the c-mos proto-oncogene, which plays an important role in oocyte maturation. In vitro investigations in somatic cells have shown that c-mos expression has opposing effects on the cell cycle, which suggests that this proto-oncogene may represent an important determinant of aberrant cell function (genomic instability and altered kinetics). A recent study suggests that these effects may be p53 dependent. In view of the apparent link between c-mos and p53, we investigated in a series of 56 non-small cell lung carcinomas: a) the status of c-mos; b) its relationship to genomic instability (aneuploidy) and two kinetic parameters of the tumors, proliferation and apoptotic indexes (AI); and c) its association with p53 alterations and their concomitant relationship with the above parameters. We found c-mos overexpression in 27% of the tumors. Expression was higher in stages II/III (34%) than in stage I (17%; P = 0.018). Complete concordance was observed between c-mos overexpression and elevated c-mos mRNA levels. Because c-mos gene amplification was not detected, its deregulated expression may be attributable to increased transcription. Of the c-mos positive [c-mos(P)] cases, 77% were associated with aneuploidy. Sequencing showed two silent mutations and one missense (R-->L) at codon 22, located in a region critical for c-mos stability. In contrast to the findings of some in vitro studies, c-mos(P) tumors had a lower mean AI score than the c-mos negative [c-mos(N)] tumors had, implying that induction of apoptosis may have been defective. Indeed, 86% of the tumors overexpressing c-mos showed p53 alterations. The carcinomas with concomitant alterations of c-mos and p53 [c-mos(P)/p53 positive] had significantly lower AI values (P < 0.001) and were more frequently associated with aneuploidy (P = 0.015) than the c-mos(N)/p53 negative tumors but not the c-mos(N)/p53 positive tumors, which suggests that p53 status is the main determinant of ploidy status and apoptosis in our series. This finding also strengthens the concept that wild-type p53 plays a "safeguard" role in preventing oncogene-mediated activation.

Aged↗
PubMed2001

Association of allelic loss at the FHIT locus and p53 alterations with tumour kinetics and chromosomal instability in non-small cell lung carcinomas (NSCLCs).

The FHIT gene, located at the FRA3B fragile site of chromosome 3p14.2, encodes a 16.8 kD homologue of the yeast enzyme diadenosine tetraphosphate (Ap(4)A) hydrolase. Frequent allelic losses at this region in various malignancies, including non-small cell lung carcinomas (NSCLCs), imply that FHIT may represent a tumour suppressor gene (TSG). Increasing evidence suggests that multiple TSG impairment has a synergistic effect on tumour growth. The present study of 67 NSCLCs investigated the allelic imbalance (AIm) within the FHIT locus and its relationship with p53 abnormalities, kinetic parameters [proliferative activity or proliferation index (PI) and apoptotic index (AI)], and ploidy status of the carcinomas. Allelic imbalance at FHIT was observed in 35 out of 55 informative (heterozygous: H) cases (64%). Similar frequencies of loss of heterozygosity (LOH) were noticed among squamous cell lung carcinomas and adenocarcinomas. The high percentage of AIm in stage I tumours (71%) is indicative of its relatively early involvement in NSCL carcinogenesis. No association was found between LOH at FHIT, kinetic parameters, and ploidy status of the tumours. Concurrent loss at FHIT and p53 overexpression [FHIT(LOH)/p53(P)] was the most frequent pattern and was observed in 39% of the informative cases. The latter pattern was not associated with smoking, supporting the hypothesis that in patients with a history of tobacco exposure, FHIT allelic loss may not be a consequence of p53 checkpoint defects, but the outcome of tobacco-induced mutagenesis. Statistically significant differences in the presence of FHIT(LOH)/p53(P) and FHIT(LOH)/p53(N) patterns were noted at the proliferative and apoptotic level, whereas ploidy was similar amongst all groups, implying that wild-type (wt) p53 may play a safeguard role against altered FHIT function. However, the possibility of a masking effect from wt p53 cannot be excluded, since the FHIT(LOH)/p53(P) profile demonstrated a higher growth index (GI=PI/AI mean value ratio) than FHIT(H)/p53(P) (32 vs. 8), although this was not significant. Further studies are needed in order to elucidate the role of FHIT and its relationships with other cell-cycle regulatory molecules involved in NSCL carcinogenesis.

Acid Anhydride Hydrolases↗
PubMed2001

Loss of heterozygosity on chromosomes 3, 9, 13, and 17, including the retinoblastoma locus, in uveal melanoma.

PURPOSE: To identify tumor-suppressor loci that may contribute to the pathogenesis of uveal melanoma. METHODS: Multiplex fluorescence microsatellite assays were performed on 27 uveal melanomas using markers at 3p25-p26, 3p14.2, 9p21-p23, 13q14, 13q12.3-q13, and 17p13, close to or within the von Hippel Lindau (VHL), fragile histidine triad (FHIT), p16/cyclin-dependent kinase inhibitor 2 (CDKN2A), retinoblastoma (RB1), breast cancer 2 (BRCA2), and p53 tumor suppressor loci, respectively. Further markers on chromosomes 3 and 9 were analyzed individually. RESULTS: Loss of heterozygosity (LOH) was identified in 63% of tumors, most frequently on chromosome 3 (52%), in association with epithelioid cells (P = 0.0002) and microvascular loops (P = 0.0008). In the majority of cases, LOH on chromosome 3 was detected at all informative markers. The second most common alteration was LOH at an RB1 intragenic marker (21% tumors), with retention of a more centromeric 13q marker (near BRCA2). The pattern of LOH on chromosome 9p was consistent with the involvement of a region telomeric to CDKN2A. LOH at TP53 was infrequent. CONCLUSIONS: In the majority of cases, chromosome 3 LOH involves an entire chromosome homologue, which hampers identification of the relevant suppressor loci. This LOH correlates with the presence of microvascular loops and epithelioid cells, two of the recognized histologic indicators of poor prognosis. Data for chromosomes 13 and 9 support a role for RB1 in the pathogenesis of uveal melanoma but also raise the possibility of the involvement of additional loci close to RB1 and CDKN2A.

Acid Anhydride Hydrolases↗
PubMed2000

Association of allelic imbalance at locus D13S171 (BRCA2) and p53 alterations with tumor kinetics and chromosomal instability (aneuploidy) in nonsmall cell lung carcinoma.

BACKGROUND: BRCA2 gene, located at chromosome 13q12.3, frequently is altered in familial types of cancer in which a "double-hit" inactivation model seems to occur. In contrast, in sporadic forms of cancer there is frequent absence of a second event (point mutations) suggesting that allelic imbalance at the BRCA2 locus may be associated with a "gene dosage effect" of BRCA2 function. Little is known about BRCA2 allelic alterations in nonsmall cell lung carcinomas (NSCLCs). Furthermore, recent studies suggest that BRCA2 and p53 participate in a common pathway involved in DNA damage repair. In view of this putative link, the authors investigated in a series of 63 NSCLCs: 1) the allelic imbalance (AIm) at the D13S171 (BRCA2) locus, 2) the possible relation with tumor kinetics (proliferation [PI] and apoptotic indices [AI]) and chromosomal instability (aneuploidy) of the carcinomas, and 3) the mutual impact of D13S171 AIm and p53 altered status on the above-mentioned parameters. METHODS: Allelic status of the BRCA2 region was examined in a series of 63 NSCLCs, by using the polymorphic marker D13S171, which is located in the center of it. Most information regarding the status of p53 at the immunohistochemical and genetic levels was obtained from a previous analysis. Tumor kinetic parameters (proliferation and apoptotic indices) were determined using Ki-67 immunohistochemical analysis and Tdt-mediated dUTP nick end labeling assay, respectively. Chromosomal instability (aneuploidy) was assessed by measuring nuclear DNA ploidy with an image analysis system. RESULTS: Allelic imbalance at D13S171(BRCA2) was observed in 70% of the informative cases (H: heterozygous) with a rather high frequency of occurrence (50%) in Stage I disease, suggesting a possible early involvement in the development of NSCLCs. Although no association was found among loss of heterozygosity (LOH) at D13S171, kinetic parameters and ploidy status of the tumors and concurrent alterations in BRCA2 and p53 (BRCA2[LOH]/p53[P]), which was the most frequent profile (37.2%), had the highest growth index (PI/AI mean value ratio) that differed significantly only from the BRCA2(LOH)/p53(N) pattern (P = 0.027). This difference was attributed to the high AI of the BRCA2(LOH)/p53(N) pattern (P < 0.001), whereas PI was similar among all BRCA2/p53 profiles. Also the "full abnormal pattern" was associated with aneuploidy, whereas the BRCA2(LOH)/p53(N) profile was mainly diploid. When these indicators and conventional prognostic ones were examined for effect on patient survival, only stage and lymph node status showed a significant correlation, whereas LOH at D13S171 (BRCA2), p53 abnormalities, proliferative and apoptotic indices, ploidy status, smoking history, and histology and combinations of LOH and p53 abnormalities failed to show significant correlation with survival. CONCLUSIONS: These findings suggest that in BRCA2(LOH) NSCLCs the status of p53 (wild type or mutant) represents a decisive determinant of tumor growth and chromosomal instability. Nevertheless, a possible synergistic effect from loss of D13S171 region with p53 abnormalities cannot be excluded because the BRCA2(LOH)/p53(P) profile compared with the BRCA2(H)/p53(P) one had a higher PI/AI mean value ratio (31.05 vs. 22.97), although it was not statistically significant. However, we cannot exclude the possibility that LOH at D13S171 reflects deletion of other putative tumor suppressor gene(s) in the proximity of BRCA2. In this respect, more studies are needed to understand the involvement of BRCA2 region alterations in nonsmall cell lung carcinogenesis. (c) 2000 American Cancer Society.

Aneuploidy↗
PubMed2000

hMLH1 and hMSH2 expression correlates with allelic imbalance on chromosome 3p in non-small cell lung carcinomas.

DNA mismatch repair genes have been implicated in the pathogenesis and predisposition of certain malignancies through a mutator phenotype. In this study, we investigated, in 150 non-small cell lung carcinomas, the expression levels of hMLH1 and hMSH2 proteins in relation to loss of heterozygosity on chromosomes 3p and 2p, the mutational status of these genes' promoters and the hot spot exons. We have demonstrated that 88 of 150 (58.6%) tumor specimens had reduced expression levels of the hMLH1 protein, whereas 85 of 147 (57.8%) specimens had reduced expression levels of the hMSH2 protein. Reduced expression levels of both proteins were observed in 51 of 150 (34%) specimens. In adenocarcinomas, the reduction of hMSH2 expression was more frequently observed than that of hMLH1 (P<0.003), whereas in squamous cell carcinoma of the lung hMLH1 expression was more frequently reduced than hMSH2 (P<0.006). Reduced expression of hMLH1correlated with allelic imbalance on loci D3S1289 (P<0.0002) and D2S391 (P<0.05). It is of note that an inverse correlation was found between hMSH2 reduced expression and loss of heterozygosity at locus D3S1300 (P = 0.016). In addition, hMLH1 reduced expression was more frequently associated with heavy smokers, assessed by daily tobacco uptake (P = 0.018) and total smoking exposure (pack-years; P<0.05). In addition, a correlation between hMLH1 reduced expression and nodal metastasis in squamous cell carcinoma of the lung was observed (P = 0.015). No mutations were identified in the promoters or exons examined in these two genes. These findings indicate that hMLH1 and hMSH2 gene inactivation is a common event in the development of non-small cell lung carcinoma and allelic loss seems to be a major genetic event involved in hMLH1 silencing. In addition, we propose that a putative negative regulator of hMSH2 gene may be located at the locus 3p14.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Expression of p16(INK4A) and alterations of the 9p21-23 chromosome region in non-small-cell lung carcinomas: relationship with tumor growth parameters and ploidy status.

The 9p21-23 chromosome region harbors a number of known and putative tumor-suppressor genes (TSGs). The best characterized gene in this area is p16(INK4A) (CDKN2A). Alterations of its product have been observed in various malignancies, including non-small-cell lung carcinomas (NSCLCs). We earlier investigated the mechanisms underlying p16(INK4A) inactivation. In the present study, we examined, in a series of 87 NSCLCs, its relationship with the kinetic parameters [proliferation index (PI) and apoptotic index (Al)] and the ploidy status of the tumors. In addition, we extended our previous LOH analysis of the 9p21-23 region by examining flanking areas of p16(INK4A). Aberrant p16 expression was observed in 41.4% of the carcinomas. A significant association was found with increased PI (p = 0.037), but not with apoptosis. Aneuploid tumors were more frequently correlated with abnormal p16 staining (p = 0. 05). A high frequency of allelic imbalance (Alm) was noticed at the D9S161 (51.3%) and D9S157 (64.5%) loci, which lie approximately 4cM centromeric and 7cM telomeric, respectively, to CDKN2A. Abnormal p16(INK4A) expression was strongly correlated with Alm at D9S161 (p = 0.004). Allelic losses at D9S157 occurred more frequently in early stages (p = 0.018) and were significantly associated with deletions at D9S161 (p = 0.035). We conclude that, in a sub-set of NSCLCs, (i) abnormal p16 expression contributes to tumor growth mainly by increasing the proliferative activity in the initial stages of carcinogenesis; (ii) the association with aneuploidy merely reflects the impact of aberrant p16 on proliferative activity; and (iii) other putative TSGs possibly reside within the 9p21-23 region that possibly co-operate in certain cases with CDKN2A in the development of NSCLCs.

Aged↗