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A F Gazdar

Publications and source records attributed to A F Gazdar.

At least 55 records · Page 3Linked to original sources
PubMed2001

Molecular genetics of small cell lung carcinoma.

The etiology of small cell lung cancer (SCLC) is strongly tied to cigarette smoking, and now there is considerable information concerning molecular abnormalities involved in the pathogenesis of SCLC. Autocrine growth factors such as neuroendocrine regulatory peptides (eg, bombesin/gastrin-releasing peptide) are prominent in SCLC. Dominant oncogenes of the Myc family are frequently overexpressed in both SCLC and non-small cell lung cancer (NSCLC), while the K-RAS oncogene is never mutated in SCLC but it is in 30% of NSCLCs. The most frequent genetic abnormalities involve tumor suppressor genes (TSGs). The TSG p53 is mutated in more than 90% of SCLCs and more than 50% of NSCLCs; the retinoblastoma TSG is inactivated in over 90% of SCLC but only 15% of NSCLCs, and p16, the other component of the retinoblastoma/p16 pathway, is almost never abnormal in SCLC but is inactivated in more than 50% of NSCLCs. The FHIT TSG is inactivated in 50% to 70% of all lung cancers. Recently, we completed a genome-wide allelotyping study using approximately 400 polymorphic markers distributed at around 10 cM resolution across the human genome comparing SCLCs and NSCLCs, looking for all possible TSG sites by loss of heterozygosity. We found that, on average, 17 loci showed loss of heterozygosity in individual SCLCs and 22 for NSCLC, with an average size of loss of 50 to 60 cM, and an average frequency of microsatellite abnormalities of five per tumor. There were 22 different "hot spots" for loss of heterozygosity, 13 with a preference for SCLC, seven for NSCLC, and two affecting both. This provides clear evidence on a genome-wide scale that SCLC and NSCLC differ significantly in the TSGs that are inactivated during their pathogenesis. Acquired hypermethylation of the promoter region of key genes has become one of the most common mechanisms that tumors use to inactivate the function of tumor suppressor and other genes. We recently completed a study of tumor-acquired promoter hypermethylation for nine genes (p16, DAPK, MGMT, GSTP1, RAR beta, FHIT, ECAD, p14ARF, and TIMP1). We found differences in the frequency of RAR beta methylation (70% for SCLC and 40% for NSCLCs). Finally, we looked at the bronchial epithelium accompanying SCLC and NSCLC for the occurrence of clonal alterations using precise laser capture microdissection with subsequent allelotyping for polymorphic markers. In NSCLC, we frequently find clones of cells with molecular abnormalities in histologically affected epithelium (eg, carcinoma in situ, dysplasia, hyperplasia) and occasionally in normal-appearing epithelium in the cases of current or former smokers. In SCLC these histologic preneoplastic changes were minimal. However, in studies of histologically normal respiratory epithelium, we found a several-fold increased rate of allele loss in SCLC compared with NSCLC patients. Thus, the smoking-damaged histologically normal epithelium associated with SCLC appeared genetically scrambled and has incurred significantly more damage than the epithelium accompanying NSCLCs. We conclude that SCLC and NSCLCs do not differ significantly in the number of genetic alterations that occur. However, SCLCs do differ significantly from NSCLCs in the specific genetic alterations that occur. In addition, smoking-damaged bronchial epithelium accompanying SCLCs appears to have undergone significantly more acquired genetic damage than that accompanying NSCLCs. Future studies need to identify the specific genes involved at these multiple sites and determine if these provide new tools for early molecular detection and monitoring of chemoprevention efforts, and serve as specific targets for developing new therapies. Semin Oncol 28 (suppl 4):3-13.

Carcinoma, Non-Small-Cell Lung↗
PubMed2001

DNA methylation profiles of lung tumors.

Aberrant methylation of CpG islands in promoter regions of tumor cells is one of the major mechanisms for silencing of tumor suppressor genes. We determined the frequency of aberrant promoter methylation of the p16, adenomatous polyposis coli (APC), H-cadherin (CDH13), glutathione S-transferase P1 (GSTP1), O6-methylguanine-DNA-methyltransferase (MGMT), retinoic acid receptor beta-2 (RAR beta), E-cadherin (CDH1), and RAS association domain family 1A (RASSF1A) genes in 198 tumors consisting of small cell lung cancers [SCLCs (n = 43)], non-small cell lung cancers [NSCLCs (n = 115)], and bronchial carcinoids (n = 40). The profile of methylated genes in the two neuroendocrine tumors (SCLC and carcinoids) were very different from that of NSCLC. However, whereas the overall pattern of aberrant methylation of carcinoids was similar to that of SCLC, carcinoids had lower frequencies of methylation for some of the genes tested. There were also significant differences in the methylation profiles between the two major types of NSCLC, adenocarcinoma and squamous cell carcinoma. We performed cluster analysis and found that SCLCs clustered with other SCLCs and carcinoids but not with NSCLCs, whereas the NSCLCs tended to cluster together. Within NSCLCs, adenocarcinomas and squamous cell carcinomas clustered with their respective histological types. Finally, we compared the methylation profiles of SCLC and NSCLC tumors and their respective cell lines (n = 44). In general, methylation frequencies were higher in tumor cell lines, but these differences were seldom significant. Thus, tumor cell lines appear to be suitable models to study aberrant DNA methylation. We conclude that SCLC, carcinoids, squamous cell carcinomas, and adenocarcinomas of the lung have unique profiles of aberrant methylation. Our findings should help us understand differences in the pathogenetic mechanisms of lung cancers.

Adenomatous Polyposis Coli Protein↗
PubMed2000

Abnormal expression of BRCA1 and BRCA1-interactive DNA-repair proteins in breast carcinomas.

Breast cancer is one of the most common malignancies among women. The molecular mechanisms involved in breast carcinogenesis, however, remain to be elucidated. Although somatic mutation of BRCA1 is rare, BRCA1 protein expression is reduced in about 30% of sporadic breast carcinomas (Yoshikawa et al., Clin. Cancer Res., 5:1249-1261, 1999), indicating its possible involvement even in sporadic breast carcinogenesis. Among the BRCA1-interactive proteins are hRAD51 (a human homologue of Escherichia coli rec A protein), BARD1 (BRCA1-associated RING domain 1) and p53, all of which are involved in DNA repair. We have analyzed the expression patterns of the hRAD51, BARD1 and p53 proteins in five breast cancer cell lines, including a BRCA1-deficient cell line, and in 179 breast cancer tissue samples from Japanese women, including 113 sporadic, 47 hereditary (i.e., BRCA1 status unknown), and 19 BRCA1-associated cases. Of the 179 breast carcinomas, fifty-four (30%) exhibited reduced hRAD51 expression, and sixty-two (35%) exhibited p53 overexpression. On the other hand, reduced expression level of BARD1, and of hMSH2 and hMLH1, which are components of DNA mismatch-repair pathway and are involved in colorectal carcinogenesis, was observed respectively in only 10 (6%), 8 (5%) and 3 (2%) cases. The overall frequency of sporadic breast carcinomas with abnormal expression of either BRCA1 or the BRCA1-interactive proteins was 67% (76/113). These results indicate that there may be an important role for the BRCA1-associated DNA-repair pathway, not only in BRCA1-associated breast carcinomas, but also in sporadic breast carcinomas.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Genome-wide allelotyping of lung cancer identifies new regions of allelic loss, differences between small cell lung cancer and non-small cell lung cancer, and loci clustering.

To identify the major tumor suppressor gene (TSG) loci involved in the pathogenesis of lung cancer, we have conducted a high-resolution (10 cM), genome-wide search of loss of heterozygosity (LOH). Thirty-six lung cancer cell lines [14 small cell lung cancers (SCLCs) and 22 non-SCLCs (NSCLCs)] and their matched control DNAs were analyzed using 399 fluorescent microsatellite markers from the ABI Prism linkage mapping set v.2 on an ABI 377 sequencer/genotyper. Overall, 22 different regions with more than 60% LOH were identified: (a) 13 regions with a preference for SCLC; (b) 7 regions with a preference for NSCLC; and (c) 2 regions affecting both SCLC and NSCLC. The chromosomal arms with the most frequent LOH were 1p, 3p, 4p, 4q, 5q, 8p, 9p (p16), 9q, 10p, 10q, 13q (Rb), 15q, 17p (p53), 18q, 19p, Xp, Xq. In addition, new homozygous deletions were found at 2p23, 8q24, 18q11, and Xq22. On average, 34% (SCLC) to 36% (NSCLC) of markers showed allele loss in individual tumors, with an average size of subchromosomal region of loss of five to six markers (50-60 cM). Whereas SCLC and NSCLC had different regions of frequent LOH (hot spots), and NSCLC had more of these regions (n = 22) than SCLC (n = 17), in all other parameters (fractional allelic loss, number of breakpoints, and number of microsatellite alterations), SCLC and NSCLC were not significantly different. Clustering analysis revealed correlations between LOH on different chromosomes that suggest previously unknown genetic interactions for lung cancer development. We conclude that (a) in lung cancer cell lines, at least 17-22 chromosomal regions with frequent allele loss are involved, suggesting that the same number of putative TSGs are inactivated; (b) SCLC and NSCLC frequently undergo different specific genetic alterations; and (c) clusters of TSGs are likely to be inactivated together. Overall, these data provide global estimates of the extent of genetic changes leading to lung cancer and will be useful for the positional cloning of new TSGs and for the identification of multiple new biomarkers for translational research.

Alleles↗
PubMed2000

Promoter methylation and silencing of the retinoic acid receptor-beta gene in lung carcinomas.

BACKGROUND: Retinoic acid plays an important role in lung development and differentiation, acting primarily via nuclear receptors encoded by the retinoic acid receptor-beta (RARbeta) gene. Because receptor isoforms RARbeta2 and RARbeta4 are repressed in human lung cancers, we investigated whether methylation of their promoter, P2, might lead to silencing of the RARbeta gene in human lung tumors and cell lines. METHODS: Methylation of the P2 promoter from small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) cell lines and tumor samples was analyzed by the methylation-specific polymerase chain reaction (PCR). Expression of RARbeta2 and RARbeta4 was analyzed by reverse transcription-PCR. Loss of heterozygosity (LOH) was analyzed by PCR amplification followed by electrophoretic separation of PCR products. Statistical differences were analyzed by Fisher's exact test with continuity correction. RESULTS: The P2 promoter was methylated in 72% (63 of 87) of SCLC and in 41% (52 of 127) of NSCLC tumors and cell lines, and the difference was statistically significant (two-sided P:<.001). By contrast, in 57 of 58 control samples, we observed only the unmethylated form of the gene. Four tumor cell lines with unmethylated promoter regions expressed both RARbeta2 and RARbeta4. Four tumor lines with methylated promoter regions lacked expression of these isoforms, but demethylation by exposure to 5-aza-2'-deoxycytidine restored their expression. LOH at chromosome 3p24 was observed in 100% (13 of 13) of SCLC lines and 67% (12 of 18) of NSCLC cell lines, and the difference was statistically significant (two-sided P: =.028). CONCLUSIONS: Methylation of the RARbeta P2 promoter is one mechanism that silences RARbeta2 and RARbeta4 expression in many lung cancers, particularly SCLC. Chemical demethylation is a potential approach to lung cancer therapy.

Carcinoma, Non-Small-Cell Lung↗
PubMed2000

High resolution chromosome 3p allelotyping of human lung cancer and preneoplastic/preinvasive bronchial epithelium reveals multiple, discontinuous sites of 3p allele loss and three regions of frequent breakpoints.

Allele loss involving chromosome arm 3p is one of the most frequent and earliest known genetic events in lung cancer pathogenesis and may affect several potential tumor suppressor gene regions. To further study the role of chromosome 3p allele loss in the pathogenesis of lung cancer, we performed high resolution loss of heterozygosity (LOH) studies on 97 lung cancer and 54 preneoplastic/preinvasive microdissected respiratory epithelial samples using a panel of 28 3p markers. Allelic losses of 3p were detected in 96% of the lung cancers and in 78% of the preneoplastic/preinvasive lesions. The allele losses were often multiple and discontinuous, with areas of LOH interspersed with areas of retention of heterozygosity. Most small cell lung carcinomas (91%) and squamous cell carcinomas (95%) demonstrated larger 3p segments of allele loss, whereas most (71%) of the adenocarcinomas and preneoplastic/preinvasive lesions had smaller chromosome areas of 3p allele loss. There was a progressive increase in the frequency and size of 3p allele loss regions with increasing severity of histopathological preneoplastic/preinvasive changes. In analyses of the specific parental allele lost comparing 42 preneoplastic/preinvasive foci with those lost in the lung cancer in the same patient (n = 10), the same parental allele was lost in 88% of 244 comparisons for 28 3p markers (P = 1.2 x 10(-36) for this occurring by chance). This indicates the occurrence of allele-specific loss in these foci similar to that seen in the tumor by a currently unknown mechanism. Analysis of all of the data indicated multiple regions of localized 3p allele loss including telomere-D3S1597, D3S1111-D3S2432, D3S2432-D3S1537, D3S1537, D3S1537-D3S1612, D3S4604/Luca19.1-D3S4622/Luca4.1, D3S4624/Luca2.1, D3S4624/Luca2.1-D3S1582, D3S1766, D3S1234-D3S1300 (FHIT/FRA3B region centered on D3S1300), D3S1284-D3S1577 (U2020/DUTT1 region centered on D3S1274), and D3S1511-centromere. A panel of six markers in the 600-kb 3p21.3 deletion region showed loss in 77% of the lung cancers, 70% of normal or preneoplastic/preinvasive lesions associated with lung cancer, and 49% of 47 normal, mildly abnormal, or preneoplastic/preinvasive lesions found in smokers without lung cancer; however, loss was seen in 0% of 18 epithelial samples from seven never smokers. The 600-kb 3p21.3 region and the 3p14.2 (FHIT/FRA3B) and 3p12 (U2020/DUTT1) regions were common, independent sites of breakpoints (retention of heterozygosity by some markers and LOH by other markers in the immediate region). We conclude that 3p allele loss is nearly universal in lung cancer pathogenesis; involves multiple, discrete, 3p LOH sites that often show a "discontinuous LOH" pattern in individual tumors; occurs in preneoplastic/preinvasive lesions in smokers with and without lung cancer (multiple lesions often lose the same parental allele); frequently involves breakpoints in at least three very small defined genomic regions; and appears to have allele loss and breakpoints first occurring in the 600-kb 3p21.3 region. These findings are consistent with previously reported LOH studies in a variety of tumors showing allele loss occurring by mitotic recombination and induced by oxidative damage.

Adult↗
PubMed2000

Molecular identification of metastatic cancer to the skin using laser capture microdissection: a case report.

BACKGROUND: In the current study the authors report a 57-year-old woman with a scalp tumor and cervical lymphadenopathy who had a previously resected duodenal carcinoid. Histologic and immunophenotypic characteristics of the duodenal carcinoid differed from those of the scalp and cervical lymph node tumors, prompting the use of molecular methodologies to make the diagnosis. METHODS: Paraffin embedded tissues from the duodenal carcinoid, scalp, and lymph node tumors were dissected using microscopic visualization and laser capture microdissection. DNA was extracted and polymerase chain reaction (PCR) was performed to evaluate loss of heterozygosity and microsatellite alterations using primers flanking 22 polymorphic microsatellite markers from 9 chromosomal regions, including genes associated with MEN-1 (11q), CDKN2 (9p), p53 (17p), and bronchial carcinoid (3p). Microdissected lymphocytes from the three tissues were used as source of constitutional DNA (controls). RESULTS: Fourteen of the 22 markers were informative (heterozygous in control lymphocytes). A marker on 3p12 showed loss of the same parental allele in the three tumors. A different marker on 3p14.2 showed an identical shifted band in the three tumors indicative of a common microsatellite alteration. CONCLUSIONS: The shared molecular abnormalities among the three tumors indicated a common clonal origin, leading to a diagnosis of primary duodenal carcinoid with clear cell metastases to the scalp and cervical lymph nodes. These findings led to radiation therapy and immunotherapy rather than chemotherapy. This case illustrates the novel application of laser capture microdissection combined with PCR-based analyses of genomic markers for the identification of the origin of metastatic disease.

Alleles↗
PubMed2000

Two identical triplet sisters carrying a germline BRCA1 gene mutation acquire very similar breast cancer somatic mutations at multiple other sites throughout the genome.

Monozygotic twins, each of whom has breast cancer, offer a natural study population for gene-environmental interactions as causation of cancer, because they are genetically identical. If heritable factors play a large role in the origin of a neoplasm, disease concordance should be significant in monozygotic twins. Two monozygotic triplet sisters carrying a germline BRCA1 gene mutation (5382insC) who both developed breast cancer at early ages were studied for loss of heterozygosity (LOH) in their microdissected, paraffin-embedded tumors along with control blood and stromal breast tissue at 19 chromosomal arms using 161 microsatellite markers. Microdissected areas of normal lobular and ductal epithelium and ductal in situ carcinoma were also studied for LOH using a subset of microsatellite markers. The mother's DNA (extracted from peripheral blood lymphocytes) was analyzed to determine the parental allele under LOH in each case. Both tumors demonstrated similar histologic features suggestive of a secretory variant of ductal carcinoma. The tumors from both sisters had similar overall LOH frequency expressed by the fractional allelic loss (FAL) indices (0.56 vs. 0.60) and demonstrated concordance for loss or retention at 82 of 97 informative markers (85% correlation). In addition, detailed mapping analysis of several chromosomal arms revealed that identical breakpoints were detected in both tumors at several chromosome regions. Finally, in both sisters' tumors, when a chromosome exhibited allelic loss, all of the markers exhibited LOH of the same parental allele even when there were intervening regions of retention of heterozygosity. In contrast, 17 archival sporadic breast carcinomas demonstrated a wide range of FAL indexes and highly individual patterns of LOH. Our findings support the hypothesis that inherited factors play a role in the development of the multiple somatic deletions occurring in breast carcinomas. Whether one of these factors is the mutant BRCA1 allele or some other gene(s) remains to be determined. Genes Chromosomes Cancer 28:359-369, 2000.

Adult↗
PubMed2000

Chromosome 4 deletions are frequent in invasive cervical cancer and differ between histologic variants.

OBJECTIVE: Patterns of discontinuous deletion of chromosome 4 have been described in histologic variants of lung carcinomas and may represent different "hotspot" targets for gene-environment interactions. Since similar environmental risks exist for cervical cancer, we investigated patterns of discontinuous deletion in two major histologic variants. METHODS: Thirteen archival cases of squamous cell cancer (SCCA) and 11 cases of adenocarcinoma (AC) were precisely microdissected. Matched normal and tumor DNA were used for polymerase chain reaction (PCR) based loss of heterozygosity (LOH) analyses using 19 polymorphic markers spanning chromosome 4. Human papillomavirus (HPV) detection was determined by PCR using general and type-specific primers (HPV 16, 18). Differences in LOH between histologic tumor types and chromosomal regions were determined using Fisher's exact test. RESULTS: Loss at any chromosome 4 locus occurred in 92% of all tumors studied, with the majority of deletions occurring on the long arm of the chromosome. Four discrete minimal regions of discontinuous deletion (R) were identified. For these regions, LOH frequencies were 76% (R1, 4q34-q35), 48% (R2, 4q25-q26), 36% (R3, 4p15.1-p15.3), and 26% (R4, 4p16). Loss in SCCA predominated at 4q (4q34-q35; 83%) and in AC at 4p (4p15.3; 50%). Overall LOH on the p arm was significant in AC (82%) compared to SCCA (31%) (P = 0.02). HPV detection was similar in SCCA (85%) and AC (73%), and HPV 16/18 subtypes were similarly represented in both histologies. CONCLUSIONS: Chromosome 4 deletions are frequent in cervical carcinomas. Different patterns of deletion between SCCA and AC may represent gene regions targeted by different gene-environment interactions in these tumor subtypes.

Adenocarcinoma↗
PubMed2000

Comparative genomic hybridization reveals complex genetic changes in primary breast cancer tumors and their cell lines.

DNA copy number changes were characterized by comparative genomic hybridization (CGH) in 18 breast cancer cell lines. In 5 of these, the results were comparable with those from the primary tumors of which the cell lines were established. All of the cell lines showed extensive DNA copy number changes, with a mean of 16.3 +/- 1.1 aberrations per sample (range 7-26). All of the cell lines had a gain at 8q22-qter. Other common gains of DNA sequences occurred at 1q31-32 (89%), 20q12-q13.2 (83%), 8q13 (72%), 3q26.1-qter (67%), 17q21-qter (67%) 5p14 (61%), 6p22 (56%), and 22pter-qter (50%). High-level amplifications were observed in all cell lines; the most frequent minimal common regions were 8q24.1 (89%), 20q12 (61%), 1q41 (39%), and 20p11.2 (28%). Losses were observed less frequently than gains and the minimal common regions of the most frequent losses were Xq11-q12 (56%), Xp11.2-pter (50%), 13q21 (50%), 8p12-pter (44%), 4p13-p14 (39%), 6q15-q22 (39%), and 18q11.2-qter (33%). Although the cell lines showed more DNA copy number changes than the primary tumors, all aberrations, except one found in a primary tumor, were always present in the corresponding cell line. High-level amplifications found both in primary tumors and cell lines were at 1q, 8q, 17q, and 20q. The DNA copy number changes detected in these cell lines can be valuable in investigation of tumor progression in vitro and for a more detailed mapping and isolation of genes implicated in breast cancer.

Breast Neoplasms↗
PubMed2000

Molecular Papanicolaou tests in the twenty-first century: molecular analyses with fluid-based Papanicolaou technology.

OBJECTIVE: This study was undertaken to demonstrate the feasibility of performing molecular analyses at the deoxyribonucleic acid, ribonucleic acid and protein levels of cervical cytologic examination with a methanol fluid-based Papanicolaou specimen collection system. STUDY DESIGN: Genomic deoxyribonucleic acid and total ribonucleic acid were extracted from cell pellets obtained from the residual fluid-based Papanicolaou specimen collection buffer after clinical processing. Genomic and human papillomavirus deoxyribonucleic acid polymerase chain reaction and reverse transcriptase-polymerase chain reaction were performed. Messenger ribonucleic acid transcript analysis and human papillomavirus 16 E6 mutational analysis were also performed. Methylation-specific polymerase chain reaction was used to evaluate hypermethylation status of the p16 gene and the gene for E-cadherin. Immunohistochemical staining for protein expression was performed on the processed monolayer slides. RESULTS: Cell pellets from the residual fluid-based cytologic specimen yielded good quality deoxyribonucleic acid and ribonucleic acid. Molecular analyses of genomic deoxyribonucleic acid were successful for the identification of human papillomavirus E6 and p53 polymorphism status by means of restriction enzyme digestion and direct sequencing. Methylation status of the promotor regions of the p16 tumor suppressor gene and the gene for E-cadherin were also successfully identified. Ribonucleic acid was used as the template for transcript analysis and mutational analysis of the corresponding complementary deoxyribonucleic acid of the p53 gene. Protein expression analysis was demonstrated by immunohistochemical staining for carcinoembryonic antigen. CONCLUSION: It is feasible to conduct multiple molecular analyses at the deoxyribonucleic acid, ribonucleic acid, and protein levels of the cervicovaginal cell pellets from the residual fluid-based Papanicolaou cytologic specimen. This relatively simple and widely used collection system will allow significant advances in molecular epidemiology and eventual development of a molecular Papanicolaou test.

Carcinoembryonic Antigen↗
PubMed2000

Overexpression of human telomerase RNA in Helicobacter pylori-infected human gastric mucosa.

Telomerase, an enzyme associated with cellular immortality and malignancy, plays an important role in cellular immortalization and tumorigenesis. Furthermore, overexpression of the RNA component of the telomerase, called human telomerase RNA (hTR), has been demonstrated in various human cancers as an early event. The pattern of hTR expression following Helicobacter pylori (H. pylori) infection in human gastric mucosa was investigated by a radioactive in situ hybridization (ISH) assay. Paraffin-embedded sections of 50 biopsy specimens taken from the gastric antrum of individual patients infected to different extents with H. pylori, as well as normal gastric mucosa, were studied. In normal gastric mucosa, only weak hTR expression was noted and the expression was limited to basal cells of the gastric glands. However, the degree of hTR expression gradually increased in parallel with the degree of H. pylori infection. The mean scores of gastric mucosa with mild, moderate and severe degrees of H. pylori infection were 2.3, 2.8, and 3.7 times higher than that of normal gastric mucosa, respectively. The results of this study suggested that up-regulation of hTR expression is a frequent and early event associated with H. pylori infection in the gastric mucosa and may play some role in gastric carcinogenesis. Sufficient synthesis of hTR during this early stage may be a prerequisite for telomerase reactivation to occur in gastric cancer.

Adult↗
PubMed2000

Fragile histidine triad (FHIT) gene abnormalities in lung cancer.

Lung cancer is the most common cause of cancer death in the world. In recent years, enormous progress has been made in understanding the molecular and cellular biology of lung cancer. The fragile histidine triad (FHIT) gene, a candidate tumor-suppressor gene, was recently identified at chromosome 3p14.2, spanning the FRA3B common fragile site. Frequent allelic losses as well as homozygous deletions have been described at the FHIT locus, making FHIT a strong candidate as a tumor-suppressor gene. However, the occurrence of mutations is very rare. Aberrant FHIT transcripts, including deletions of exons, insertions between exons, and insertions replacing exons, are detected in a high percentage of lung tumors. Reduction or complete loss of FHIT expression by immunohistochemical testing is seen in about 30%-70% of non small-cell lung cancer and in about 20% of bronchial biopsies from chronic smokers without evidence of lung cancer. This finding supports the theory that FHIT is a molecular target of tobacco smoke carcinogens. However, the location of the gene in one of the most fragile sites of the human genome and the paucity of mutations have led to an alternative hypothesis that abnormalities of the gene are bystander effects resulting from disruption of the FRA3B locus. Thus, the function of FHIT as a candidate tumor-suppressor gene is still controversial, and additional studies are necessary to clarify the role of FHIT in lung cancer pathogenesis.

Journal Article↗
PubMed2000

Molecular changes in the bronchial epithelium of patients with small cell lung cancer.

To better understand the pathways involved in the pathogenesis of small cell lung carcinoma (SCLC), we compared the patterns of molecular changes present in these tumors and their accompanying bronchial epithelium with those present in the other two major types of lung cancer [squamous cell carcinoma (SQC) and adenocarcinoma (ADC)]. We obtained DNA from 68 microdissected invasive lung tumors (22 SCLCs, 21 ADCs, and, 25 SQCs) and 119 noncontiguous foci of histologically normal or hyperplastic epithelia from 10 tumors of each histological type. We determined loss of heterozygosity and microsatellite alterations at 12 chromosomal regions frequently deleted in lung cancers using 19 polymorphic microsatellite markers. Our major findings are as follows: (a) the mean index of allelic loss in SCLC (0.85) and SQC (0.71) tumors was higher than that in ADC (0.39) tumors; (b) although there was considerable overlap, each tumor type had a characteristic pattern of allelic loss; (c) most samples of bronchial epithelium accompanying SCLC (90%) had allelic loss at one or more loci compared with samples accompanying SQC (54%) or ADC (10%); (d) the mean index of allelic loss was much higher in bronchial epithelial samples from SCLC (0.27) than in those from SQC (0.08) or ADC (0.01); and (e) although the mean indices of microsatellite alterations in the tumor types were similar, the bronchial epithelial samples accompanying SCLC had a 10-fold higher mean index (0.063) than those accompanying SQC (0.006) or ADC (0.006). Our findings indicate that extensive genetic damage in the accompanying normal and hyperplastic bronchial epithelium is characteristic of SCLC tumors and suggest major differences in the pathogenesis of the three major lung cancer types.

Adenocarcinoma↗
PubMed2000

Molecular changes in second primary lung and breast cancers after therapy for Hodgkin's disease.

The risk of lung and breast cancer is significantly increased after therapy for Hodgkin's disease (HD), but there are few data that describe the molecular profiles of these tumors. We investigated the genetic abnormalities in second primary lung (n = 19) and breast cancers (n = 19) that follow therapy for HD ("post-HD cancers") and compared these with changes observed in corresponding tumor types (57 lung and 20 breast cancers) arising in the general population ("sporadic cancers"). DNA obtained from archival tissues was examined using PCR-based analyses for loss of heterozygosity and microsatellite alterations (MAs) at several chromosomal regions, TP53 and K-ras gene mutations, and frameshift mutations at minisatellite sequences at the coding regions of several genes (TGF-betaRII, IGFIIR, BAX, hMSH6, and hMSH3). The occurrence of loss of heterozygosity at all chromosomal regions taken together and frequencies at most individual areas were similar for the post-HD and sporadic cancers for both lung and breast sites. The overall frequency of MAs in the post-HD tumors was substantially greater (lung, 2.4-fold, P = 0.004; breast, 4.2-fold, P = 0.16) than that in the respective sporadic cancers. No differences in the pattern of TP53 and K-ras mutations were detected between post-HD and sporadic cancers. No mutations were detected at the minisatellite sequences examined. MAs, which reflect widespread genomic instability, occur at greatly increased frequency in post-HD lung and breast cancers. Although the mechanisms underlying the development of increased MAs are unknown, they have been associated with immunosuppression and radiation exposure. Future research should address the role that MAs, as well as other influences, may play in the development of neoplasias that occur after therapy for HD.

Adenocarcinoma↗