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Joe W Gray

Publications and source records attributed to Joe W Gray.

46 records · Page 3Linked to original sources
PubMed2003

End-sequence profiling: sequence-based analysis of aberrant genomes.

Genome rearrangements are important in evolution, cancer, and other diseases. Precise mapping of the rearrangements is essential for identification of the involved genes, and many techniques have been developed for this purpose. We show here that end-sequence profiling (ESP) is particularly well suited to this purpose. ESP is accomplished by constructing a bacterial artificial chromosome (BAC) library from a test genome, measuring BAC end sequences, and mapping end-sequence pairs onto the normal genome sequence. Plots of BAC end-sequences density identify copy number abnormalities at high resolution. BACs spanning structural aberrations have end pairs that map abnormally far apart on the normal genome sequence. These pairs can then be sequenced to determine the involved genes and breakpoint sequences. ESP analysis of the breast cancer cell line MCF-7 demonstrated its utility for analysis of complex genomes. End sequencing of approximately 8,000 clones (0.37-fold haploid genome clonal coverage) produced a comprehensive genome copy number map of the MCF-7 genome at better than 300-kb resolution and identified 381 genome breakpoints, a subset of which was verified by fluorescence in situ hybridization mapping and sequencing.

Animals↗
PubMed2003

Induction of tumors in mice by genomic hypomethylation.

Genome-wide DNA hypomethylation occurs in many human cancers, but whether this epigenetic change is a cause or consequence of tumorigenesis has been unclear. To explore this phenomenon, we generated mice carrying a hypomorphic DNA methyltransferase 1 (Dnmt1) allele, which reduces Dnmt1 expression to 10% of wild-type levels and results in substantial genome-wide hypomethylation in all tissues. The mutant mice were runted at birth, and at 4 to 8 months of age they developed aggressive T cell lymphomas that displayed a high frequency of chromosome 15 trisomy. These results indicate that DNA hypomethylation plays a causal role in tumor formation, possibly by promoting chromosomal instability.

Alleles↗
PubMed2003

Evidence emerges for early metastasis and parallel evolution of primary and metastatic tumors.

Tumor progression to metastasis usually is assumed to occur through clonal genomic and epigenetic evolution. However, present evidence that challenges this paradigm. They show that genomic aberrations in tumor cells disseminated in the bone marrows of patients with no clinical evidence of metastasis generally do not resemble the aberrations in the primary tumors from which they arose. They interpret this to mean that tumor cells disseminate very early and evolve to metastatic disease independent from the primary tumor. Their model suggests that adjuvant therapies should be targeted to lesions in the disseminated cells rather than lesions found in primary tumors.

Animals↗
PubMed2003

Genome amplification of chromosome 20 in breast cancer.

Recurrent gain and amplification of the long arm of chromosome 20 (20q) has been observed in a wide variety of cancers. This suggests that a gene or genes encoded on 20q play important roles in contributing to the cancer phenotype when overexpressed. In the quest to discover cancer genes, this region of the genome has been exhaustively studied, and the results demonstrate remarkable complexity. Multiple regions of low and high-level 20q copy number gain correlate with poor clinical prognosis and appear to contribute to the cancer phenotype, especially aspects of immortalization, genome instability, apoptosis, and increased proliferation. Gene discovery efforts have revealed a number of interesting candidate genes on chromosome 20 that may contribute to oncogenic progression. The study of 20q serves as a model for positional cloning enthusiasts, demonstrating the path typically taken when moving from initial discovery of an important genomic abnormality to identification of genes likely to be significant players in disease progression. This review will summarize approximately a decade of study on 20q and is structured as moving from an introduction to the techniques used in 20q analyses, to the details of 20q genomic complexity and its involvement with cancer, and finally to a detailed gene-specific look at this region.

Breast Neoplasms↗
PubMed2003

Chromosome aberrations in solid tumors.

Chromosome aberrations in human solid tumors are hallmarks of gene deregulation and genome instability. This review summarizes current knowledge regarding aberrations, discusses their functional importance, suggests mechanisms by which aberrations may form during cancer progression and provides examples of clinical advances that have come from studies of chromosome aberrations.

Biological Evolution↗
PubMed2002

Genomic copy number analysis of non-small cell lung cancer using array comparative genomic hybridization: implications of the phosphatidylinositol 3-kinase pathway.

Genomic abnormalities at 348 loci encoding genes that may contribute to lung cancer transformation and progression were assessed using array comparative genomic hybridization in 21 squamous carcinomas (SqCas) and 16 adenocarcinomas (AdCas). Hierarchical clustering showed a clear pattern of gains and losses for the SqCas, whereas the pattern for AdCas was less distinct. Cross-validated classification using a K-nearest-neighbor assigned, on average, 32 of 37 samples to their proper histological subtype. The most noticeable differences between SqCas and AdCas were gain of chromosome 3q22-q26 and loss of chromosome 3p. These occurred almost exclusively in SqCas. The region of recurrent increase is approximately 30 Mb in extent, ranging from EVI1 to TFRC. PIK3CA, the alpha catalytic subunit of phosphatidylinositol 3-kinase (PI3K), is in this region. The PIK3CA copy number increase was validated using fluorescence in situ hybridization to lung cancer tissue microarrays. Activity of the downstream PI3K effector protein kinase B (PKB) was higher in SqCas than in AdCas and was correlated with PIK3CA copy number (r = 0.75), suggesting that these copy number increases contribute to activation of PI3K signaling in SqCas of the lung.

Adenocarcinoma↗
PubMed2002

Protein elongation factor EEF1A2 is a putative oncogene in ovarian cancer.

We have found that EEF1A2, the gene encoding protein elongation factor EEF1A2 (also known as eEF-1 alpha 2), is amplified in 25% of primary ovarian tumors and is highly expressed in approximately 30% of ovarian tumors and established cell lines. We have also demonstrated that EEF1A2 has oncogenic properties: it enhances focus formation, allows anchorage-independent growth and decreases the doubling time of rodent fibroblasts. In addition, EEF1A2 expression made NIH3T3 fibroblasts tumorigenic and increased the growth rate of ES-2 ovarian carcinoma cells xenografted in nude mice. Thus, EEF1A2 and the process of protein elongation are likely to be critical in the development of ovarian cancer.

3T3 Cells↗
PubMed2002

Biallelic inactivation of the thyroid hormone receptor beta1 gene in early stage breast cancer.

Loss of heterozygosity within the short arm of chromosome 3 is a common molecular event in several types of solid tumors. In breast cancer, 3p loss of heterozygosity occurs in invasive tumor cells as well as in morphologically normal terminal ductal lobular units adjacent to carcinoma in some cases [G. Deng et al., Science (Wash. DC), 274: 2057-2059, 1996.]. The most frequent region of allelic loss at 3p24.3 in morphologically normal terminal ductal lobular units encompasses the thyroid hormone receptor beta1 (TRbeta1) gene. Here we have observed a variable degree of TRbeta1 promoter hypermethylation in all 11 cases of primary breast cancer examined. Moreover, hypermethylation occurred at the same CpG sites in nonmalignant tissue peripheral to carcinoma in 4 of 11 cases. The lack of TRbeta1 nuclear staining, a likely result of biallelic gene inactivation, was observed in 25% (22 of 85) of primary tumors. This is a first demonstration of promoter hypermethylation and a concurrent reduction of TRbeta1 transcripts in breast cancer cell lines, although specific CpG sites targeted for gene silencing remain to be determined. Gene expression was restored by treatment with 5-aza-deoxycytidine in such cases. The observation of early, frequent, and multiple mechanisms of TRbeta1 inactivation suggests a potential role for this gene in the suppression of breast tumorigenesis.

Alleles↗
PubMed2002

Increased risk of local recurrence is associated with allelic loss in normal lobules of breast cancer patients.

Allelic losses characteristic of tumor cells, when displayed by morphologically normal terminal ductal lobular units (TDLUs) adjacent to carcinoma [G. Deng et al., Science (Wash. DC), 274: 2057-2059, 1996], may indicate an extended field of increased cancer susceptibility within the affected breast tissue. We investigated this possibility by asking whether the presence of loss of heterozygosity (LOH) at chromosome 3p11-26 in histologically normal TDLUs (3pLOHn) could lead to an increased risk of local tumor recurrence. We assessed LOHs in normal TDLUs adjacent to 48 informative cases of early-stage invasive breast cancer samples and found 3pLOHn in approximately 25% (13 of 48) of patients whose tumors had 3pLOH in this region. Our analyses suggest that the most frequent region of LOH is localized at 3p24.3. We also demonstrate, using a Cox proportional hazards regression model, that the presence of 3pLOHn was the only variable significantly related to local tumor recurrence, leading to a 3.9-5.2-fold increase in the hazard ratio (P < 0.05). The time to recurrence was longer in such cases than in those without 3pLOHn, suggesting de novo tumor development. These data provide a strong rationale to assess histologically normal breast tissue at the margins of surgically excised cancers for molecular predictors of local recurrence after breast-conserving treatment.

Adult↗