Browsing by Author "Virmani, AK"

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    Allelic losses at chromosome 8p21-23 are early and frequent events in the pathogenesis of lung cancer
    (AMER ASSOC CANCER RESEARCH, 1999) Wistuba, II; Behrens, C; Virmani, AK; Milchgrub, S; Syed, S; Lam, S; Mackay, B; Minna, JD; Gazdar, AF
    Allelic Losses on the short arm of chromosome 8 (8p) have been reported as frequent events in several cancers, including Lung. However, no comprehensive mapping analysis of chromosome 8p in Lung cancer tumors has been performed, and no data are available about the stage at which these abnormalities occur during the multistage development of lung cancer. Using 26 microsatellite markers, we mapped the chromosome 8 regions frequently deleted in lung cancer in 13 small cell carcinoma and 17 non-small cell lung carcinoma cell Lines and in 68 microdissected archival primary lung tumors (22 small cell lung carcinomas, 25 squamous cell carcinomas, and 21 adenocarcinomas), We also studied the role of 8p deletions in lung cancer pathogenesis by examining 95 microdissected normal epithelium and preneoplastic samples from 11 surgically resected squamous cell Lung carcinomas and from 58 bronchoscopy biopsy samples obtained from 31 current and former smokers. High frequencies of deletions at 8p21-23 regions were detected in lung cancer cell lines and in primary lung tumors. Deletions commenced early during the multistage development of lung cancer at the hyperplasia/metaplasia stage in cancer patients and in smokers without cancer. Allelic deletions persisted for up to 48 years after smoking cessation. There was a progressive increase of the overall 8p21-23 loss of heterozygosity frequency and in the size of the deleted region with increasing severity of histopathological preneoplastic changes. In epithelial samples from resected squamous cell Lung carcinomas, we compared the presence of loss of heterozygosity at 8p21-23 with deletions at chromosomes 3p and 9p, Of interest, the pattern of deletions was not random, and 8p21-23 allelic Losses always followed 3p deletions and usually followed 9p deletions. We conclude that 8p21-23 deletions are frequent and early events in the pathogenesis of Lung carcinomas.
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    Comparison of features of human breast cancer cell lines and their corresponding tumors
    (AMER ASSOC CANCER RESEARCH, 1998) Wistuba, II; Behrens, C; Milchgrub, S; Syed, S; Ahmadian, M; Virmani, AK; Kurvari, V; Cunningham, TH; Ashfaq, R; Minna, JD; Gazdar, AF
    Although human tumor-derived cell lines play an important role in the investigation of cancer biology and genetics, there is no comprehensive study comparing tumor cell line properties with those of the individual tumors from which they were derived. We compared the properties of a series of 18 human breast cancer cell lines that were cultured for a median period of 25 months (range, 9-60 months) and their corresponding archival tumor tissues. We compared morphological characteristics, ploidy, and immunohistochemical expression of estrogen receptors, progesterone receptors, and HER2/neu and p53 proteins. For 17 of these cases, we also tested for allelic losses at 18 chromosomal regions frequently deleted in breast tumors using 51 polymorphic microsatellite markers, and we determined the TP53 gene mutation status in exons 5 to 10, There was an excellent correlation between the breast tumor cell lines and their corresponding tumor tissues for morphological features (100%); presence of aneuploidy (87%); immunohistochemical expression of estrogen receptors (87%), progesterone receptors (73%), and HER2/neu (93%) and p53 proteins (100%); allelic loss at all of the chromosomal regions analyzed (82-100% concordance); and TP53 gene mutations (75%), The same parental allele was lost in 279 (99%) of 281 of the comparisons of allele losses. The fractional allelic loss indices (a reflection of the total allelic loss) of the cell lines and their corresponding tumor tissues were identical or similar in 15 (88%) of 17 paired comparisons, Although our previous studies (A, Gazdar et at, Int. J, Cancer, in press) indicated that only a subset of primary breast carcinomas that have several features indicative of advanced tumors with poor prognosis can be successfully cultured, the cell lines retain the properties of their parental tumors for lengthy culture periods and, thus, provide suitable model systems for biomedical studies.
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    Comparison of features of human lung cancer cell lines and their corresponding tumors
    (AMER ASSOC CANCER RESEARCH, 1999) Wistuba, II; Bryant, D; Behrens, C; Milchgrub, S; Virmani, AK; Ashfaq, R; Minna, JD; Gazdar, AF
    Although human lung tumor-derived cell lines play an important role in the investigation of lung cancer biology and genetics, there is no comprehensive study comparing the genotypic and phenotypic properties of lung cancer cell lines with those of the individual tumors from which they were derived, We compared a variety of properties of 12 human non-small cell lung carcinoma (NSCLC) cell lines (cultured for a median period of 39 months; range, 12-69) and their corresponding archival tumor tissues. There was, in general, an excellent concordance between the lung tumor cell lines and their corresponding tumor tissues for morphology (100%), the presence of aneuploidy (100%), immunohistochemical expression of HER2/neu (100%) and p53 proteins (100%), loss of heterozygosity at 13 chromosomal regions analyzed (97%) using 37 microsatellite markers, microsatellite alterations (MAs, 75%), TP53 (67%), and K-ras (100%) gene mutations, In addition, there was 100% concordance for the parental allele lost in all 115 comparisons of allelic losses. Some discrepancies were found; more aneuploid subpopulations of cells were detected in the cell lines as well as higher incidences of TP53 mutations (4 of 10 mutations not found in the tumors) and microsatellite alterations (two cell lines with MAs not detected in the tumors). Similar loss of heterozygosity frequencies by chromosomal regions and mean fractional allelic loss index were detected between successfully cultured and 40 uncultured lung tumors (0.45 and 0.49, respectively), indicating that both groups were similar. Our findings indicate that the NSCLC cell lines in the large majority of instances retain the properties of their parental tumors for lengthy culture periods. NSCLC cell lines appear very representative of the lung cancer tumor from which they were derived and thus provide suitable model systems for biomedical studies of this important neoplasm.
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    Comparison of molecular changes in lung cancers in HIV-positive and HIV-indeterminate subjects
    (AMER MEDICAL ASSOC, 1998) Wistuba, II; Behrens, C; Milchgrub, S; Virmani, AK; Jagirdar, J; Thomas, B; Ioachim, HL; Litzky, LA; Brambilla, EM; Minna, JD; Gazdar, AF
    Context.-Human immunodeficiency virus (HIV) infection has been associated with an increasing incidence of malignancy, and HIV-infected persons have an increased incidence of primary lung carcinoma compared with the general population,
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    Deletions of chromosome 3p are frequent and early events in the pathogenesis of uterine cervical carcinoma
    (AMER ASSOC CANCER RESEARCH, 1997) Wistuba, II; Montellano, FD; Milchgrub, S; Virmani, AK; Behrens, C; Chen, HL; Ahmadian, M; Nowak, JA; Muller, C; Minna, JD; Gazdar, AF
    To study the molecular abnormalities involved in the multistage development of cervical carcinoma (CC), we investigated the presence of oncogenic human papillomavirus (HPV) sequences, loss of heterozygosity (LOH), and microsatellite alterations at several genes/loci at 3p (3p14.2 at the FHIT gene, 3p14.3-21.1, 3p21, and 3p22-24.2), 9p21, RB and P53, and P53 gene point mutations in precisely microdissected archival tissues from 20 CCs and their accompanying precursor lesions (cervical intraepithelial neoplasia, CIN; n = 40) and normal epithelia (n = 20). In all HPV-positive cases (90% of CCs), HPV sequences were detected as the earliest appearing molecular change or simultaneously with other changes. LOH at any 3p region was found in 70% of CCs, and 3p14.2 (FHIT gene/FRA3B fragile site) (56%) and 3p21 (57%) were the most frequent 3p sites of loss. LOH at some 3p region was in the CIN I stage, and the 3p deletions in precursor CIN lesions were smaller than the 3p losses found in the associated invasive CC. LOH at the other regions studied and P53 gene mutations were less frequent and later events. Microsatellite alterations were detected in 35% of CCs, and identical abnormalities were detected in the associated precursor lesions. Although infection with oncogenic HPV strains is the earliest and most frequent molecular event, progressive deletions at one or more 3p regions (particularly at 3p14.2, and 3p21) are also frequent events occurring early in the pathogenesis of CC.