Abstract 4350: Clonal selection and parallel evolution during leptomeningeal dissemination of human and mouse medulloblastoma result in bicompartmental disease
Bibliographic record
Abstract
Abstract Medulloblastoma metastasizes through the CSF in the leptomeningeal space to cover the brain and spinal cord. Mechanisms driving metastasis are currently unknown. It had been assumed that the primary tumor and its metastases share very similar biology. The Sleeping Beauty (SB) system is a novel functional genomics tool for cancer gene discovery. Ptch +/− mice develop localized medulloblastoma in 15% of cases, while ≈100% of Math1-SB11, SB transposon donor, Ptch +/− mice develop metastatic medulloblastoma. We sequenced over 158,000 insertion sites (Roche 454) from a series of >140 SB-induced primary medulloblastomas, as well as matched spinal and frontal lobe leptomeningeal metastases. Statistical analysis identified 359 commonly inserted genes (CIGs) in the primary tumors and 285 CIGs in the leptomeningeal metastases. Although primary tumors and their metastases always demonstrate a common transformed ancestor through sharing of identical clonal insertion sites, less than 10% of CIGs were found in both primary tumor and matched metastases. Matched spinal and frontal lobe metastases shared identical clonal insertions that were very highly subclonal in the primary tumor, suggesting that leptomeningeal dissemination arises only once, or from a single small subclonal population in the primary tumor. These data support the clonal selection model of metastasis, and suggest that MET-CIG insertions are acting as metastasis virulence genes. Similarity between metastases supports a model in which medulloblastoma is a bicompartmental disease (primary vs. metastases) that arises through parallel evolution in the two compartments. We validated our mouse model through copy number profiling of three matched trios of human medullolblastoma (primary and two metastases). In each case we demonstrate highly clonal regions of chromosomal gain/loss that are present in both metastatic samples, but are not apparent in the matched primary tumor. Similarly, profiling of promotor CpG island methylation in human primary medulloblastomas and matched metastases shows that within a given child the metastases are very similar to each other, but distinct from the primary tumor. PCR amplification was used to demonstrate a clonal 179 Kb deletion in a pair of human metastases, which was present in an extremely small subclone of the primary tumor, strongly supporting the clonal selection model during dissemination of human medulloblastoma. Our results support a model in which individual medulloblastomas metastases are similar to each other, but distinct from the primary tumor. This ‘bicompartmental model’ suggests a proximate reason for failure of current therapies, and that future clinical trials may need to address each compartment individually. 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 4350.
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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 | 0.001 | 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) | 0.001 | 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".