Abstract 1590: BRM and BRM polymorphisms applications for target therapy
Bibliographic record
Abstract
Abstract BRM is a catalytic subunit of the SWI/SNF chromatin remodeling complex, which regulates the expression and function of key cellular proteins and signal transduction pathways, many of which have anticancer functions. BRM is lost in 15-25% of many solid tumor types. BRM is specifically tied to Rb function in that Rb-mediated growth arrest is thwarted by the loss of BRM, but restored when BRM expression is restored. Despite this observation, BRM null mice did not develop tumors, indicating that BRM is not a classic tumor suppressor protein. However, cells from these animals display distinct cell cycle abnormalities, and when these mice are exposed to carcinogens, they develop larger and 10-fold more tumors. Unlike many other anticancer proteins, however, BRM is reversibly silenced, and when it is re-expressed in BRM-deficient cell lines, growth is substantially inhibited. To understand how BRM is silenced, we sequenced the BRM promoter and found two 6-7bp inserts, so called insertion/deletion polymorphisms (IDPs). We sequenced DNA from 160 Caucasian individuals, and found that the frequency of the two polymorphism sites were approximately 20%, 50%, and 30% for the homozygous, heterozygous and wild type states respectively. In comparison, a set of 10 BRM-deficient cell lines were found to be homozygous for one or both of these polymorphic sites, while a set of 12 BRM-positive cell lines showed the opposite frequency of these IDPs_that is, almost all were wild type for both sites. From these observations, it appears that these polymorphic sites correlate with the loss of BRM. We next analyzed the presence or absence of these polymorphic sites in both BRM-positive and BRM-negative tumors. We found that the BRM-negative tumors were essentially uniformly homozygous for both polymorphic sites while the BRM-positive tumors demonstrated a distribution similar to those seen in the normal population. Because BRM appears to be a tumor susceptible gene, we hypothesize that BRM polymorphism causes the loss of BRM which then indicates a predisposition to cancer. To test this hypothesis, we are conducting a case control study and found that the ratio for lung cancer risk was 1.6 and 2.2 for the presence of one and both polymorphic sites respectively. Since BRM is silenced in cancer cells, we next determined the impact of pharmacologically restoring BRM. We next applied two BRM inducing compounds to two BRM-deficient cell lines. The application of these compounds resulted in the induction of several BRM-dependent genes indicting that the induced BRM is functional and has caused the cells to undergo growth arrest. Both of these observations were BRM-dependent because these effects could be blocked with either antiBRM shRNAi or dominant negative BRM. These findings have broad and novel implications for cancer treatment, as they show that it may it be possible to restore BRM and target treatment to the preferred patient population by simply genotyping patients. 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 1590.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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) | 0.000 | 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 teacher head, 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".