Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To determine the role of the FHIT gene, which encompasses the fragile site at 3p14.2, we analyzed 59 tumors of the small cell and non-small cell type by reverse transcription of FHIT mRNA, followed by PCR amplification and sequencing of products. Allelic losses affecting the gene were evaluated by microsatellite polymorphism analysis and genomic alterations by hybridization using cDNA and genomic probes. Small cell lung tumors (80%) and non-small cell lung cancers (40%) showed abnormalities in RNA transcripts of FHIT, and 76% of the tumors exhibited loss of FHIT alleles. Abnormal lung tumor transcripts lack two or more exons of the FHIT gene. Small cell lung cancer tumors and cell lines were analyzed by Southern blotting and showed rearranged BamHI fragments. These data suggest a critical role of the FHIT gene in lung carcinogenesis.
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PMID:The FHIT gene 3p14.2 is abnormal in lung cancer. 862 May 33

Allelic deletion of multiple regions on the short arm of chromosome 3 (3p) implies the presence of multiple important tumor suppressor genes in human carcinogenesis. The FHIT gene, identified recently in chromosome 3p14.2, shows frequent allelic deletion and aberrant transcripts in gastrointestinal tumors. After determining the intron sequences flanking each of the coding exons of the FHIT gene and designing intron primers to facilitate mutation analysis of genomic DNA samples, we analyzed the complete coding sequences in matched cancer and normal tissues from 40 cases with primary gastric cancer using intron primers, PCR-single-strand conformation polymorphism analysis, and direct sequencing. A somatic missense mutation in exon 6, codon 61, ACG (threonine) --> ATG (methionine) was found in a signet ring cell adenocarcinoma. We also evaluated allelic deletion in these tumors by PCR-based microsatellite analysis; allelic deletion occurred in 42.1% (16 of 38) of evaluable cases. This is the first report of a somatic missense mutation of the FHIT gene in a primary tumor. Presence of a point mutation and frequent allelic deletions are consistent with the hypothesis that FHIT gene alterations are involved in the development of primary gastric cancers.
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PMID:FHIT mutations in human primary gastric cancer. 910 41

To elucidate the role of the recently identified FHIT gene, located at 3p14.2 in human brain tumor carcinogenesis, a total of 259 tumors were analyzed for loss of heterozygosity (LOH) at microsatellite loci D3S1313, D3S1234, D3S1300, and D3S1481. In primary brain tumors, LOH was detected at a frequency of 8.4% (n = 214). Low-grade gliomas exhibited insignificantly lower LOH rates in comparison to high-grade gliomas (5.3%, n = 19, versus 11.1%, n = 90). Notably, no allelic loss was observed in 12 recurrent glioblastomas analyzed in comparison to their corresponding primary tumor lesions and in two astrocytomas with progression to higher grades of malignancy. Our data indicate that allelic loss of the FHIT gene is neither a critical event in carcinogenesis of primary brain tumors nor tumor grade-associated in astrocytic tumors. In contrast, observed LOH rate for brain metastases was as high as 54.5% (n = 45), in accordance with data thus far accumulated from analyses of corresponding primary tumors.
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PMID:The putative tumor suppressor gene FHIT at 3p14.2 is rarely affected by loss of heterozygosity in primary human brain tumors. 920 70

Chromosomal or allelic losses at 3p14 are common in a variety of human tumors, including those of the lung, breast, kidney, and head and neck. This suggests the existence of a tumor suppressor gene in this band. A promising candidate is the recently cloned FHIT gene, which spans the common fragile site, FRA3B, at 3p14.2. We previously identified a region of fragility at 3p14.2 (FRA3B) of > 85 kb by cloning DNA flanking pSV2neo integrations and constructed a partial genomic contig of the region. Using probes from the contig, we tested for deletions within this region in DNA from 105 human tumor cell lines, predominantly derived from lung cancers. We identified one gastric and four lung cancer cell lines with homozygous interstitial deletions involving the FRA3B region. The deletion in one lung cancer cell line lies entirely within our contig and is < 65 kb. We have identified, cloned, and sequenced this breakpoint junction. We have also shown that our probes lie within intron S of the FHIT gene and, furthermore, that exon 5 is located approximately 1 kb from one of our probes and, thus, lies within the region of fragility. Two lines with entirely intronic deletions yield FHIT transcripts of normal size. In one of these, this was the sole transcript identified. In the other line, an FHIT transcript completely normal in sequence was accompanied by two larger abnormal transcripts. These results leave open the possibility that some homozygous deletions within the FHIT gene are without phenotypic effect and result from genetic instability of this region. However, taken together, our results provide evidence that breakage and rearrangement within the FRA3B fragile site sequences result in alterations of FHIT and are likely to be involved in carcinogenesis.
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PMID:Precise localization of the FHIT gene to the common fragile site at 3p14.2 (FRA3B) and characterization of homozygous deletions within FRA3B that affect FHIT transcription in tumor cell lines. 929 Sep 49

The FHIT (fragile histidine triad) gene has been isolated from the chromosome region 3p14.2, which includes the fragile site locus FRA3B and the breakpoint of the t(3;8) of familial renal carcinoma. FHIT has been suggested to be a candidate tumor suppressor gene for digestive tract carcinomas. To evaluate the significance of FHIT gene abnormalities in gastric carcinogenesis, we examined the allelic status and transcripts of the gene in 23 primary gastric carcinomas as well as 7 gastric carcinoma cell lines. Four of the seven (57%) cell lines exhibited homozygous deletions of variable sizes at 3p14.2 all of which included D3S1300, which is located close to, or within, FRA3B. However, only 2 of 16 (13%) informative cases showed loss of heterozygosity at D3S1300 in the primary tumors. Direct analysis by reverse transcriptase polymerase chain reaction failed to reveal abnormal transcripts, including exon skipping and sequence changes, in the primary tumors or in the cell lines without homozygous deletions. These results suggest that FHIT gene abnormalities are infrequent in primary gastric carcinomas and that the frequent homozygous deletions seen in cell lines might simply reflect the plasticity of the genome at FRA3B under culture conditions.
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PMID:Analysis of the fragile histidine triad gene in primary gastric carcinomas and gastric carcinoma cell lines. 929 Sep 61

Loss of heterozygosity (LOH) on 3p is frequent in human renal cell carcinomas, lung cancers, and breast cancers. To define the region(s) on 3p that harbor presumptive tumor suppressor gene(s) for breast cancer, we examined 196 primary breast tumors for their patterns of LOH at 22 microsatellite marker loci distributed along this chromosome arm. Allelic loss at one or more loci was observed in 101 (52%) of these tumors. Detailed deletion mapping identified two distinct commonly deleted regions; one was localized to a 2-cM interval flanked by D3S1547 and D3S1295 at 3p14.3-21.1, and the other to a 5-cM interval flanked by D3S1286 and D3S1585 at 3p24.3-25.1. The FHIT gene lies in the vicinity of the proximal commonly deleted region. Attempts to correlate LOH on 3p to clinicopathological parameters detected an association with the absence of the progesterone receptor (P = 0.0096). The results suggest that inactivation of unidentified tumor suppressor genes on 3p plays a role in the mechanism whereby hormone dependency is lost in the course of breast carcinogenesis.
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PMID:Detailed deletion mapping of chromosome arm 3p in breast cancers: a 2-cM region on 3p14.3-21.1 and a 5-cM region on 3p24.3-25.1 commonly deleted in tumors. 936 34

Genomic alterations and abnormal expression of the FHIT gene at 3p14.2 have been observed in cell lines and primary tumors of the lung. To correlate FHIT locus DNA and RNA lesions with effects on Fhit protein expression, we have analyzed 11 lung cancer cell lines, 15 small cell lung carcinomas, and 38 pairs of non-small cell primary tumors and bronchial mucosa specimens by molecular genetic and immunocytochemical methods. Using specific antibodies against the Fhit protein, we observed concordance between RNA abnormalities and lack of Fhit protein expression in lung tumors and cell lines. In addition, absence of Fhit protein in some precancerous dysplastic lesions suggested that FHIT inactivation may occur at an early phase of lung carcinogenesis.
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PMID:Absence of Fhit protein in primary lung tumors and cell lines with FHIT gene abnormalities. 939 35

Recently the FHIT gene (fragile histidine triad gene) has been identified at chromosome 3p14.2 and a high frequency of abnormalities in this gene has been demonstrated in various cancers. To determine the role of the FHIT gene in leukaemia, bone marrow or peripheral blood from 62 acute myeloid leukaemia patients and five haemopoietic cell lines (HL60, U937, Raji, KC-1, K562) were analysed by reverse transcription of the FHIT mRNA followed by PCR amplification and sequencing of the products. To detect the deletion of the FHIT gene, 17 cases were evaluated using microsatellite polymorphism analysis. In this study, 17/62 (27%) AML patients expressed aberrant transcripts which lack two or more exons of the FHIT gene, and all the cell lines exhibited the aberrant FHIT transcripts. No cases exhibited a loss of the FHIT alleles. Our data indicated that the FHIT gene may play a role in myeloid carcinogenesis and may be indicated in the late progression of the disease.
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PMID:Aberrant FHIT transcripts in acute myeloid leukaemia. 940 Oct 74

The FHIT gene is localized on chromosome 3p14, a region including a tumor cell-specific, commonly deleted region. To determine the role of the FHIT gene in pancreatic carcinogenesis, 14 pancreatic carcinoma cell lines were analyzed by reverse transcription-PCR and exon-specific PCR amplification of genomic DNA. The full-length FHIT transcript was lost in 70% of the pancreatic carcinoma cell lines analyzed, while 66% also revealed intragenic homozygous deletions of exons 3, 4, and 5. Truncated FHIT transcripts lacking a variable number of exons most likely represented alternative splicing products. Fhit protein expression was dependent on a full-length FHIT transcript. The results suggest that the FHIT gene may be a target tumor suppressor gene involved in pancreatic carcinogenesis.
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PMID:Frequent abnormalities of the putative tumor suppressor gene FHIT at 3p14.2 in pancreatic carcinoma cell lines. 956 64

The FHIT gene has been implicated as a tumor suppressor gene in human malignancies. To determine if FHIT alterations play a role in human squamous cell carcinogenesis of the head and neck (HNSCC), we examined the gene and its product by RT-PCR, SSCP, Northern, Southern, and Western blot analysis in primary HNSCC and/or HNSCC cell lines. Three of 32 tumor samples lacked detectable expression of FHIT by RT-PCR but showed amplification of a control gene of similar size. One of 29 primary tumors and 2/9 HNSCC cell lines exhibited aberrant transcripts generated by RT-PCR methods using one set of 40 cycles of amplification. FHIT mRNA expression was absent in seven HNSCC cell lines but detectable in primary keratinocytes by Northern analysis. Using specific polyclonal antiserum to the full-length FHIT protein in immunoblot analyses, 4/9 cell lines analysed showed no expression of pFhit, two exhibited low levels of expression, and three expressed a putative truncated pFhit. One of 15 tumors analysed also exhibited an overexpressed truncated protein. PCR/SSCP and Southern analysis of one cell line DNA that expressed a truncated protein indicated that it sustained homozygous loss of FHIT exon 5. Our results suggest that alterations in FHIT at the DNA, RNA, and protein levels exist at a low but significant frequency in HNSCCs. Further studies regarding the potential biological activity of FHIT are needed to clarify the role of this gene in HNSCC tumorigenesis.
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PMID:Analysis of the FHIT gene and its product in squamous cell carcinomas of the head and neck. 967 17


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