Investigating genetic aberrations in metastatic gastric cancer and in primary renal cell carcinoma
Bibliographic record
Abstract
The advent of next-generation sequencing (NGS) has substantially contributed to our understanding of underlying factors of different cancers. In the first chapter of this thesis, I used NGS (whole-exome sequencing (WES)) to investigate genetic abnormalities associated with metastatic gastric cancer. In the second chapter of this thesis, I used NGS data (targeted sequencing) to investigate association between mutational status of PBRM1 (the second most commonly mutated gene in renal cancer) and clinical variables of affected patients. I have also extended my work to analyze function of PBRM1 in an in vitro model of renal cancer.Chapter-1: Gastric cancer is one of the leading causes of cancer related death worldwide accounting for over 2000 deaths/year in Canada. Peritoneal metastasis is the most common site of gastric cancer progression after curative intent surgery and is the leading cause of death. Metastasis to this site represents a significant challenge in patient management and there is limited knowledge about the underlying factors. We have performed WES of patient-matched trio samples including normal DNA, primary gastric cancer, and peritoneal metastasis from five unrelated patients in order to identify somatic mutations associated with the metastasis. We found several genes recurrently mutated in these tumors including known cancer-related genes such as KRAS, TP53 and CDH1. Moreover, our analysis revealed additional potentially interesting genes including DSG1, SPTA1 and HMCN1. Our findings highlight a heterogeneous mutational pattern in gastric cancer peritoneal metastasis, and provide the first catalogue of somatic mutations in this entity.Chapter-2: Clear cell renal cell carcinoma (ccRCC) is the most prevalent type of renal cell carcinoma. PBRM1 (polybromo-1) is the second most commonly mutated gene affected in about 40% of ccRCC cases after VHL (Von Hippel-Lindau, mutated in about 70% of patients). Molecular mechanisms by which deficiency of PBRM1 contribute to ccRCC are not fully understood despite the high prevalence of PBRM1 mutations in ccRCC. Our lab has previously shown that tumors with mutated PBRM1 harbor larger number of somatic mutations compared to those without PBRM1 mutations. We have also shown that tumors exhibiting a mutational signature compatible to the exposure of Aristolochic Acid (AA) (which induces A>T mutations) showed higher rate of truncating mutations in PBRM1. However, these PBRM1 mutations were not due to AA exposure. These findings suggest that PBRM1 deficiency may at least partly contribute to the dysregulation of response to DNA damage and apoptosis. I examined this hypothesis in 786-O cell line model of ccRCC by analyzing cell proliferation and apoptosis following modulation of PBRM1 expression in combination with treatment with AA. Our results indicate that PBRM1 deficiency impairs induction of AA-related apoptosis in 786-O cell line. This suggests that PBRM1 may be involved in response to environmental stress such as toxic agents including DNA-damage inducers.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| 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) | 0.002 | 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".