613 Homozygous deletions of human chromosome 3p in lung tumors

Todd, S.; Franklin, Wilbur A.; Varella‐Garcia, Marileila; Kennedy, Timothy C.; Hilliker, Carl; Hahner, Lisa; Anderson, Megan; Wiest, Jonathan S.; Drabkin, Harry A.; Gemmill, Robert M.

doi:10.1016/s0169-5002(97)89990-4

Cited by 37 publications

(46 citation statements)

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“…Further deletion mapping of the 3p region has revealed chromosomal regions 3p21 and 3p14 to be most frequently deleted in many cancer types including NSCLC (Mitsudomi et al, 1996;Todd et al, 1997;Benachenhou et al, 1998;Nelson et al, 1998). The relationship between allelic losses at the various loci, may indicate an interaction between various gene(s) in these loci during the process of clonal selection.…”

Section: Discussionmentioning

confidence: 99%

Loss of heterozygosity is related to p53 mutations and smoking in lung cancer

et al. 2001

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Summary Carcinogenesis results from an accumulation of several genetic alterations. Mutations in the p53 gene are frequent and occur at an early stage of lung carcinogenesis. Loss of multiple chromosomal regions is another genetic alteration frequently found in lung tumours. We have examined the association between p53 mutations, loss of heterozygosity (LOH) at frequently deleted loci in lung cancer, and tobacco exposure in 165 tumours from non-small cell lung cancer (NSCLC) patients. A highly significant association between p53 mutations and deletions on 3p, 5q, 9p, 11p and 17p was found. There was also a significant correlation between deletions at these loci. 86% of the tumours with concordant deletion in the 4 most involved loci (3p21, 5q11-13, 9p21 and 17p13) had p53 mutations as compared to only 8% of the tumours without deletions at the corresponding loci (P < 0.0001). Data were also examined in relation to smoking status of the patients and histology of the tumours. The frequency of deletions was significantly higher among smokers as compared to non-smokers. This difference was significant for the 3p21.3 (hMLH1 locus), 3p14.2 (FHIT locus), 5q11-13 (hMSH3 locus) and 9p21 (D9S157 locus). Tumours with deletions at the hMLH1 locus had higher levels of hydrophobic DNA adducts. Deletions were more common in squamous cell carcinomas than in adenocarcinomas. Covariate analysis revealed that histological type and p53 mutations were significant and independent parameters for predicting LOH status at several loci. In the pathogenesis of NSCLC exposure to tobacco carcinogens in addition to clonal selection may be the driving force in these alterations.

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Section: Discussionmentioning

confidence: 99%

Loss of heterozygosity is related to p53 mutations and smoking in lung cancer

et al. 2001

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“…The presence of a functional tumor suppressor activity encompassing this region (Cheng et al, 1998) supports such a hypothesis. Homozygous deletions have been described in this region both in vitro and in vivo (Todd et al, 1997), but no mutations of any of the genes in this deleted region have been reported with high frequency in carcinomas in (Haber and Harlow, 1997;Sager, 1997). Although the HYAL1 gene product is not produced in the majority of HNSCC lines examined, the mechanism appears to be independent of the loss of heterozygosity.…”

Section: Discussionmentioning

confidence: 99%

HYAL1LUCA-1, a candidate tumor suppressor gene on chromosome 3p21.3, is inactivated in head and neck squamous cell carcinomas by aberrant splicing of pre-mRNA

et al. 2000

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The hyaluronidase ®rst isolated from human plasma, Hyal-1, is expressed in many somatic tissues. The Hyal-1 gene, HYAL1, also known as LUCA-1, maps to chromosome 3p21.3 within a candidate tumor suppressor gene locus de®ned by homozygous deletions and by functional tumor suppressor activity. Hemizygosity in this region occurs in many malignancies, including squamous cell carcinomas of the head and neck. We have investigated whether cell lines derived from such malignancies expressed Hyal-1 activity, using normal human keratinocytes as controls. Hyal-1 enzyme activity and protein were absent or markedly reduced in six of seven carcinoma cell lines examined. Comparative genomic and¯uorescence in situ hybridization identi®ed chromosomal deletions of one allele of HYAL1 in six of seven cell lines. Initial RT ± PCR analyses demonstrated marked discrepancies between levels of HYAL1 mRNA and protein. Despite repeated sequence analyses, no mutations were found. However, two species of transcripts were identi®ed when primers were used that included the 5' untranslated region. The predominant mRNA species did not correlate with protein translation and contained a retained intron. A second spliced form lacking this intron was found only in cell lines that produced Hyal-1 protein. Inactivation of HYAL1 in these tumor lines is a result of incomplete splicing of its pre-mRNA that appears to be epigenetic in nature.

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“…Homozygous deletions at 3p21.3 have been described in several cancer cell lines and in primary lung tumors (Killary et al, 1992;Yamakawa et al, 1993;Wei et al, 1996;Kok et al, 1997;Todd et al, 1997). Recently, a region of minimum homozygous deletion was narrowed to 120 kb using several lung cancer and a breast cancer cell line (Sekido et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

The CpG island of the novel tumor suppressor gene RASSF1A is intensely methylated in primary small cell lung carcinomas

2001

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Loss of heterozygosity at 3p21.3 occurs in more than 90% of small cell lung carcinomas (SCLCs). The Ras association domain family 1 (RASSF1) gene cloned from the lung tumor suppressor locus 3p21.3 consists of two major alternative transcripts, RASSF1A and RASSF1C. Epigenetic inactivation of isoform A (RASSF1A) was observed in 40% of primary non-small cell lung carcinomas and in several tumor cell lines. Transfection of RASSF1A suppressed the growth of lung cancer cells in vitro and in nude mice. Here we have analysed the methylation status of the CpG island promoters of RASSF1A and RASSF1C in primary SCLCs. In 22 of 28 SCLCs (=79%) the promoter of RASSF1A was highly methylated at all CpG sites analysed. None of the SCLCs showed evidence for methylation of the CpG island of RASSF1C. The results suggest that hypermethylation of the CpG island promoter of the RASSF1A gene is associated with SCLC pathogenesis.

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613 Homozygous deletions of human chromosome 3p in lung tumors

Cited by 37 publications

References 0 publications

Loss of heterozygosity is related to p53 mutations and smoking in lung cancer

Loss of heterozygosity is related to p53 mutations and smoking in lung cancer

HYAL1LUCA-1, a candidate tumor suppressor gene on chromosome 3p21.3, is inactivated in head and neck squamous cell carcinomas by aberrant splicing of pre-mRNA

The CpG island of the novel tumor suppressor gene RASSF1A is intensely methylated in primary small cell lung carcinomas

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