Abstract 320: Fine structure genomic mapping of chromosome 10q23 interstitial deletions in prostate cancer reveals the <i>PTEN</i> gene locus as the minimum region deleted
Bibliographic record
Abstract
Abstract Interstitial genomic deletions of the PTEN tumor suppressor gene and neighboring loci at 10q23 are detected in approximately 40% prostate cancer (CaP). Previously we have shown that the presence of PTEN genomic losses at surgery can be predictive of a shorter time to biochemical recurrence and that homozygous PTEN deletions portend early recurrence and metastatic disease. Although PTEN inactivation is strongly associated with CaP onset and progression, the genetic and molecular events leading to PTEN deletion are poorly understood. The reported breakpoints of PTEN genomic deletions in CaP vary significantly but at the present time there has been no systematic mapping of genomic losses at 10q23 and neighboring regions in tumors with interstitial deletions. This study examined the breakpoint regions associated with PTEN deletions and analyzed involvement of flanking genomic regions using fluorescence in situ hybridization (FISH) analysis of CaP tissue microarrays (n = 132 patients) and available online SNP databases (n = 27 metastases; from 9 patients) to determine the genomic locations of the most frequent tumor-specific 10q23 alterations. Four-color FISH was performed on the tissue microarrays using 6 bacterial artificial chromosome (BAC) clones spanning both flanking PTEN genomic regions (88.2 - 90.8 Mb) and the gene locus (89.61 - 89.72 Mb), with a centromeric DNA probe (CEP10) for region 10p11.1-q11.1. The configuration of the FISH probes allowed us to determine the genomic size of deletion events at cytoband 10q23 in CaP. FISH analyses showed that the most frequent genomic losses (including both hemi- and homozygous deletions) at 10q23 are interstitial and restricted to the PTEN gene locus. The second most frequent class of deletion is larger, and includes the PTEN gene and both up- and downstream flanking genomic regions. Similarly, in silico copy number analysis of the 10q23 region in the metastatic dataset identified PTEN and both flanking genomic regions as the most prominent deletion. Furthermore, the smallest overlapping region of deletion is a partial deletion of the PTEN gene and maps specifically to the BAC that is located at 89.66 - 89.84 Mb. One of the downstream consequences of the deletion acquisition and concomitant loss of PTEN functional activity is the activation of the AKT pathway. Elevated levels of activated AKT leads to the initiation of tumor promoting pathways, including proliferation, survival, and genomic instability, contributing to additional genomic aberrations such as formation of TMPRSS2:ETS fusion genes and loss of the second PTEN allele. These findings draw attention to the impact characterization of PTEN genomic loss, and complementary or independent candidate flanking genes involved will have on CaP. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 320.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".