[Show abstract][Hide abstract] ABSTRACT: Lung cancer usually is disseminated (advanced) and has a poor prognosis at diagnosis. Current and former smokers are at a high risk for lung cancer and are candidates for prevention and early detection strategies. Sputum is a potential source of biomarkers that might determine either lung cancer risk or the presence of early lung cancer, but no current sputum test is sufficiently sensitive and specific for effective screening. We used fluorescence in situ hybridization (FISH) to measure chromosomal aneusomy (CA) in sputum samples collected prospectively from 100 incident lung cancer cases and 96 controls (matched on age, gender, and date of collection) nested within an ongoing high-risk cohort. The CA-FISH assay was aimed at four DNA targets: epidermal growth factor receptor, MYC, 5p15, and CEP 6. The sensitivity of a positive CA-FISH assay (abnormal for two or more of the four markers) for lung cancer was substantially higher for samples collected within 18 months (76% sensitivity) than for samples collected more than 18 months (31%) before lung cancer diagnosis. Sensitivity was higher for squamous cell cancers (94%) than for other histologic types (69%). CA-FISH specificity based on samples collected within 18 months before diagnosis was 88%. The adjusted odds ratio (OR) of lung cancer for specimens collected within 18 months before a cancer diagnosis was higher for the CA-FISH assay [OR, 29.9; 95% confidence interval (95% CI), 9.5-94.1] than for previously studied ORs of cytologic atypia (OR, 1.8; 95% CI, 1.3-2.6) and gene promoter methylation (OR, 6.5; 95% CI, 1.2-35.5). Whether CA-FISH is an indicator of extreme risk for incident lung cancer or detects exfoliated cancer cells is unknown. The apparent promise of CA-FISH in sputum for assessing lung cancer risk and/or for lung cancer early detection now needs to be validated in a clinical screening trial.
Cancer Prevention Research 03/2010; 3(4):447-53. DOI:10.1158/1940-6207.CAPR-09-0165 · 4.44 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The Six1 homeoprotein plays a critical role in expanding progenitor populations during normal development via its stimulation of proliferation and inhibition of apoptosis. Overexpression of Six1 is observed in several tumor types, suggesting that when expressed out of context, Six1 may contribute to tumorigenesis by reinstating properties normally conveyed on developing cells. Indeed, Six1 contributes to tumor cell proliferation both in breast cancer and in rhabdomyosarcomas, in which it is also implicated in metastasis. Whereas Six1 overexpression has been reported in several tumor types, the mechanism responsible for its overexpression has not previously been examined. Here we show that a change in gene dosage may contribute to Six1 mRNA overexpression. Significant Six1 gene amplification and overrepresentation occurs in numerous breast cancer cell lines as compared with normal mammary epithelial cells, and the changes in gene dosage correlate with increased Six1 mRNA levels. Of 214 human infiltrating ductal breast carcinomas examined for Six1 gene dosage, 4.7% show Six1 amplification/overrepresentation, and tumors that exhibit an increase in Six1 gene dosage overexpress Six1 mRNA. These data implicate Six1 gene amplification/overrepresentation as a mechanism of Six1 mRNA overexpression in human breast cancer.
Cancer Research 05/2005; 65(7):2668-75. DOI:10.1158/0008-5472.CAN-04-4286 · 9.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Survival rates for lung cancer are low because patients have disseminated disease at diagnosis; therefore tests for early diagnosis are highly desirable. This pilot study investigated occurrence of chromosomal aneusomy in sputum from a 33 case-control cohort matched on age, gender, and date of sample collection. Subjects had chronic obstructive pulmonary disease and > or = 30 pack-years of tobacco use, and aneusomy was tested using a multi-target DNA FISH assay (LAVysion, Abbott/Vysis). In specimens collected within 12 months of lung cancer diagnosis, abnormality was more frequent among the 18 cases (41%) than the 17 controls (6%; P = 0.04). Aneusomy had no significant association with cytologic atypia, which might indicate that molecular and morphological changes could be independent markers of tumorigenesis. Combining both tests, abnormality was found in 83% of the cases and 20% of the controls (P = 0.0004) suggesting that FISH may improve the sensitivity of cytologic atypia as a predictor of lung cancer.
Cancer Detection and Prevention 01/2004; 28(4):244-51. DOI:10.1016/j.cdp.2004.04.007 · 2.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Well-characterized in vitro model systems provide an invaluable tool for studying prostate cancer in the laboratory. Detailed karyotypes have been reported using modern techniques such as multiplex fluorescence in situ hybridization (M-FISH) and spectral karyotyping (SKY) for LNCaP, DU 145, NCI-H660, and PC-3 cell lines. However, karyotypic data for more recently established prostate carcinoma cell lines are still limited.
Classical (G-banding) and SKY analyses were performed on ten prostate carcinoma cell lines: 22Rv1, CWR-R1, DuCaP, LAPC-4, MDA PCa 1, MDA PCa 2a, MDA PCa 2b, PC-346C, PSK-1, and VCaP.
Chromosomal abnormalities were identified in all cell lines, although the number and complexity varied greatly among them. PC-346C, established from a primary tumor, exhibited the lowest number (3) of clonal structural abnormalities, while DuCaP, established from a metastasis from a hormone-refractory patient, exhibited both the highest number (31) and largest complexity of structural abnormalities. In various subsets of these models, breakpoints were identified in chromosomal regions previously described as being involved in prostate cancer (e.g., 8p, 10q, 13q, and 16q).
The present study provides a comprehensive karyotypic analysis of a large number of prostate carcinoma cell lines, and offers a valuable resource for future investigations.
The Prostate 11/2003; 57(3):226-44. DOI:10.1002/pros.10291 · 3.57 Impact Factor