Citations

Abstract Purpose: Only a limited number of genetic studies have been conducted in primary central nervous system lymphomas (PCNSL), partly due to the rarity of the tumors and the very limited amount of available tissue. In this report, we present the first molecular characterization of copy number abnormalities (CNA) of newly diagnosed PCNSL by array-based comparative genomic hybridization (aCGH) in formalin-fixed paraffin-embedded (FFPE) specimens and compare the results with matched, frozen tumor specimens. Experimental Design: We conducted aCGH in FFPE tissues from PCNSL. Results were compared with matched, paired, frozen tumors. Results: Our analysis confirmed the good to fair quality and reliability of the data generated from limited amounts of tumoral FFPE tissue. Overall, all PCNSL cases were characterized by highly complex karyotypes, with a median of 23 CNAs per patient (range, 17–47). Overall, 20 chromosomal regions were recurrently found in more than 40% of cases. Deletions of 6p21, 6q, and 9p21.3 and gain of 12q12-q24.33 were the commonest CNAs. Other minimal affected regions were defined, and novel recurrent CNAs affecting single genes were identified in 3q26.32 (TBL1XR1) and 8q12.1 (TOX). Conclusions: The results obtained are encouraging. Larger archival tissue collections can now be analyzed to complement the still fragmented knowledge we have of the genetic basis of the PCNSL. Clin Cancer Res; 17(13); 4245–53. ©2011 AACR.

Abstract Multiple genome-wide association studies have identified several susceptibility variants for colon cancer at 8q24. However, the functional roles of these variants have yet to be elucidated. Here, we evaluated the potential role of these markers in tumor progression and examined association with commonly observed structural abnormalities in this region, c-MYC amplification and chromosome fragility at FRA8C and FRA8D. We first replicated the previously reported association by testing 1,178 cases and 1,009 clinic-based controls with eight markers localized to three specific regions at 8q24. We observed significant associations with colon cancer risk with markers rs13254738 (ordinal odds ratio, 0.82; 95% confidence interval, 0.072-0.94; Ptrend = 0.0037) and rs6983267 (ordinal odds ratio, 1.17; 95% confidence interval, 1.03-1.32, Ptrend = 0.013). Survival analysis was done using a separate set of 460 cases to evaluate the clinical significance of these markers. Overall, univariate analysis did not detect survival differences for any of the markers. We also tested a subset of the 460 cases (n = 380) for structural abnormalities at or near the c-MYC locus using fluorescence in situ hybridization analysis. Furthermore, we evaluated a small number of cases homozygous for the rs6983267 alleles to test for differences in fragile site induction. None of the 8q markers correlated with amplification at the c-MYC locus as detected by fluorescence in situ hybridization, and no clear pattern of breakage was observed at the FRA8C and FRA8D sites. In this study, we confirm the association for several single nucleotide polymorphisms at 8q24 in colon cancer but have not detected any structural role relating to c-MYC amplification or chromosomal fragility. Finally, these risk alleles do not seem to be associated with survival. (Cancer Epidemiol Biomarkers Prev 2009;18(9):2492–500)

Purpose Retrospective studies suggest cytogenetic abnormalities detected by interphase fluorescent in situ hybridization (FISH) can identify patients with chronic lymphocytic leukemia (CLL) who will experience a more aggressive disease course. Other studies suggest that patients may acquire chromosome abnormalities during the course of their disease. There are minimal prospective data on the clinical utility of the widely used hierarchical FISH prognostic categories in patients with newly diagnosed early-stage CLL or the frequency of clonal evolution as determined by interphase FISH. Patients and Methods Between 1994 and 2002, we enrolled 159 patients with previously untreated CLL (83% Rai stage 0/I) on a prospective trial evaluating clonal evolution by FISH. Patients provided baseline and follow-up specimens for FISH testing during 2 to 12 years. Results Chromosomal abnormalities detected by FISH at study entry predicted overall survival. Eighteen patients experienced clonal evolution during follow-up. The rate of clonal evolution increased with duration of follow-up with only one occurrence in the first 2 years (n = 71; 1.4%) but 17 occurrences (n = 63; 27%) among patients tested after 5+ years. Clonal evolution occurred among 10% of ZAP-70–negative and 42% of ZAP-70–positive patients at 5+ years (P = .008). Conclusion This clinical trial confirms prospectively that cytogenetic abnormalities detected by FISH can predict overall survival for CLL patients at the time of diagnosis, but also suggests that many patients acquire new abnormalities during the course of their disease. Patients with higher ZAP-70 expression may be more likely to experience such clonal evolution. These findings have important implications for both clinical management and trials of early treatment for patients with high-risk, early-stage CLL.

AbstractThe clinical efficacy of evaluating genetic anomalies in metaphase cells versus interphase nuclei for multiple myeloma (MM) is poorly understood. Therefore, survival for 154 patients with newly diagnosed untreated MM was compared with results from analysis of metaphase and interphase cells. Metaphases were studied by conventional cytogenetics and fluorescent-labeled DNA probes (fluorescence in situ hybridization [FISH]), whereas inter-phase nuclei were evaluated only by FISH. All FISH studies were done using DNA probes to detect t(4;14)(p16;q32), t(11;14)(q13;q32), t(14;16)(q32;q23), del(17) (p13.1), and chromosome 13 anomalies. Metaphases were abnormal by cytogenetics and/or metaphase FISH in 61 (40%) patients. Abnormal interphase nuclei were observed in 133 (86%) patients, including each patient with abnormal metaphases. FISH was a necessary adjunct to cytogenetics to detect t(4;14) and t(14;16) in metaphase cells. Patient survival was especially poor for patients with greater than 50% abnormal interphase nuclei, although this result was more likely due to level of plasma cells than specific chromosome anomalies. For metaphase data, patients with t(4;14), t(14;16), del(17) (p13.1), and/or chromosome 13 anomalies (primarily monosomy 13) had poor survival. A different outcome was observed for interphase data as patients with t(4;14) or t(14;16) had poor survival, whereas patients with chromosome 13 anomalies had intermediate survival: interphase FISH did not substitute for metaphase analysis.