Expression of oncofetal RNA-binding protein CRD-BP/IMP1 predicts clinical outcome in colon cancer.

The oncofetal CRD-BP/IMP1 RNA binding protein regulates posttranscriptionally a handful of RNA transcripts, implicated in cell adhesion and invadopodia formation and was recently identified as a target of the beta-catenin/Tcf transcription factor that is constitutively activated in colorectal carcinomas (CRCs). The expression of CRD-BP/IMP1 was studied in normal adult intestines and CRCs. In normal mucosa, CRD-BP/IMP1 immunoreactivity was observed in few scattered cells located predominantly at or near the bottom of the crypts, whereas in CRCs the protein was detectable in tumor cells of 50% of the specimens analyzed. CRD-BP/IMP1 mRNA expression was measured by qRT-PCR in 78 CRCs. Thirty-two (41%) of the specimens were negative or had negligible expression, whereas the remaining forty-six (59%) expressed a wide range of CRD-BP/IMP1 mRNA levels. CRD-BP/IMP1 mRNA expression correlated with that of the putative stem/progenitor cell marker Musashi-1 mRNA (p = 0. 035). CRD-BP/IMP1 positive tumors metastasized and/or recurred more frequently (p = 0.001) and its expression defined a group of patients with shorter survival (p = 0.014). Furthermore, in a multivariate analysis CRD-BP/IMP1 expression was found to be an independent predictor of survival (p = 0.015). For stage I & II patients, the differences in metastasis/recurrence and survival rates remained significant (p = 0.001 and 0.033, respectively). These findings indicate that CRD-BP/IMP1 positive tumors exhibit early disease dissemination and unfavorable prognosis.

Cytogenetic manifestations of multiple myeloma heterogeneity.

To investigate the genetic basis of the great heterogeneity observed in the clinical behavior of multiple myeloma (MM), a combined approach of G-banding, interphase fluorescence in situ hybridization (FISH), and multicolor FISH (M-FISH) was employed to analyze 70 samples from 53 patients with MM. G-banding revealed abnormal karyotypes in 77% of the cases. The origin of 31 chromosome markers was identified or revised by M-FISH. Combined metaphase karyotypic data and interphase FISH findings, using the immunoglobulin heavy-chain (IGH), IGH/cyclin D1 gene (CCND1), and D13S319 probes, revealed chromosome abnormalities in all evaluated patients and marked inter- and intratumor cytogenetic heterogeneity in the investigated MM samples. Cytogenetically unrelated clones were detected in 26% of the cases, mostly MM evaluated at diagnosis, whereas cytogenetic clonal evolution, manifested as related clones in 20% of the cases, was associated with disease progression. Among the 14q32 rearrangements, present in 66% of the cases, at least three cytogenetic subsets could be identified: one with t(11;14), usually without 13q14 deletion; another with other IGH changes, often 13q14 deletion, and hypodiploid modal chromosome number; and a third without changes in 14q32 but with abnormalities of chromosome 17. The correlation found between cytogenetic and clinicopathologic characteristics provided support for the concept that general genomic features in conjunction with specific chromosome rearrangements define the malignant phenotype in the various subsets of MM.

Tumor karyotype predicts clinical outcome in colorectal cancer patients.

PURPOSE: To investigate the prognostic value of the overall karyotypic features and specific chromosome aberrations in colorectal cancer (CRC). PATIENTS AND METHODS: Cytogenetic features of 150 primary CRCs investigated at the time of surgery were correlated with patient survival by univariate and multivariate analyses, using classical clinicopathologic parameters as covariates. RESULTS: In univariate analysis, in addition to tumor grade and clinical stage, structural aberrations as well as rearrangements of chromosomes 8 and 16 were significantly correlated with shorter overall survival. Karyotypic complexity, rearrangements of chromosomes 8 and 16, and loss of chromosome 4 were significantly correlated with shorter disease-free survival. In multivariate analysis, in addition to tumor grade, the type of chromosome aberrations (structural or numerical), ploidy, and loss of chromosome 18 came across as independent prognostic factors in the group of all patients. In the subset of patients with stage I and II carcinomas, none of the clinicopathologic variables could independently predict patient survival, whereas the presence of structural chromosomal aberrations was the only independent predictor of poor prognosis. In the subset of patients with stage III carcinomas, the presence of structural changes of chromosome 8 was a stronger independent predictor of prognosis than was tumor grade. CONCLUSION: Cytogenetic tumor features are valuable predictors of prognosis in CRC patients. The tumor karyotype should therefore be taken into account in the clinical management of patients with this disease, especially for patients having cancers of the early or intermediate stages I, II, and III.

Metaphase and interphase cytogenetics in fibroadenomas of the breast.

Short-term cultures of fifty-two samples of fibroadenomas were cytogenetically analyzed. Thirty-three of the successfully karyotyped fibroadenomas were further investigated for the presence of amplifications in the CCND1, c-MYC and HER/2-neu genes by means of FISH analysis. Compared to carcinomas, fibroadenomas seem to have less complex cytogenetic rearrangements and limited alterations on HER-2/neu, CCND1 and c-MYC loci. A cytogenetic subgroup of fibroadenomas with hyperdiploid karyotypes and only numerical changes was observed. Amplification of CCND1 seems to play a more substantial role in benign tumor progression. These findings confirm that fibroadenomas do have genetic alterations and support the hypothesis that a fibroadenoma subset displays changes also found in carcinomas, thus indicating that patients belonging to this group might have an increased risk for subsequent breast cancer.

Cytogenetic profile of unknown primary tumors: clues for their pathogenesis and clinical management.

Unknown primary tumors (UPTs) represent an entity of great clinical and biological interest, whose origin cannot be determined even after medical workup. To better understand their pathogenesis by outlining their genetic composition, 20 UPTs were investigated by G-banding, supplemented with Fluorescence In Situ Hybridization and Comparative Genomic Hybridization analyses. The data obtained were sufficient to reach a diagnosis in five cases-four lymphomas and one Ewing sarcoma-demonstrating that in a subset of UPTs, cytogenetics can be an adjunct for differential diagnosis. In the remaining 15 UPTs, an aggressive cytogenetic pattern was revealed. The most frequently rearranged chromosome regions were 1q21, 3p13, 6q15-23, 7q22, 11p12-5, and 11q14-24, pinpointing gene loci probably associated with the peculiar pathogenesis of UPTs. The preferential involvement of 4q31, 6q15, 10q25, and 13q22 in adenocarcinomas (whereas 11q22 is involved in the rest of the carcinomas)-in addition to the marked divergence in the mean average of chromosomal changes, 16 and 3, respectively-demonstrates genotypic differences between the two histologic subgroups. Furthermore, the significantly shorter survival in cases displaying massive chromosome changes compared with those having a few changes indicates that the cytogenetic pattern might be used as a tool to assess prognosis in UPTs, even without the detection of their primary site.