Exome sequencing reveals novel oncogenic mutations in early-onset sporadic rectal cancer
Bibliographic record
Abstract
Colorectal cancer (CRC) is an aging related disease with 72% of newly diagnosed cases aged 65 years or older (Cancer Registration Statistics, 2012). Past few decades of research from the West have identified aberrantly activated canonical Wnt/catenin signaling and microsatellite instability (MSI) as the major pathways driving CRC tumorigenesis. In India however majority of cases appear to belong to a younger age group with preponderance of rectal cancer. Molecular genetic screening of early-onset sporadic rectal cancer (EOSRC) performed earlier from our laboratory identified a significant proportion of EOSRC to be driven neither by aberrant Wnt signaling nor MSI. We performed whole exome sequencing of 27 tumor/normal pairs obtained from surgically resected rectal adenocarcinomas (microsatellite stable with no aberrant Wnt signaling) using the Illumina HiSeq 2500 platform. We identified recurrently mutated genes in EOSRC including known tumor suppressors (TSG) and oncogenes such as TP53, APC, KRAS, SMAD4 and PIK3CA. More importantly, we discovered mutations in uncharacterized TSGs and oncogenes such as ARID2, FAT3, FAT4, ZEB2 and TRPC7. These included putative oncogenic mutations in the zinc finger domains of ZEB2, a DNA-binding transcriptional repressor that promotes epithelial to mesenchymal transition in tumors. Functional work is underway to characterize the effect of these mutations on CRC tumor progression. APC mutations detected in this study were present in major population of cells, yet were not driving -catenin to the nucleus. This observation suggests -catenin degradation independent tumor suppressor function of APC, which is being validated.
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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 | 0.001 |
| 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 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| 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".