Abstract 1217: The <i>FAM72</i> gene family promotes cancer development by disabling the base excision repair system
Bibliographic record
Abstract
Abstract Genetic lesions are central contributors to cancer development and progression, and understanding the sources of these lesions will provide a better understanding of the mechanisms of carcinogenesis. Our previous work showed that the uncharacterized murine Fam72a gene promotes mutagenic DNA repair during antibody maturation by causing the degradation of Uracil DNA glycosylase 2 (UNG2), a component of the base excision repair (BER) system. Humans encode four almost identical paralogues of FAM72 called FAM72A-D, which are absent in all other mammalian genomes, including those of non-human primates. The role of these four paralogues in human biology is unknown. Intriguingly, a previous report showed that FAM72A is over-expressed in many cancers. Since FAM72A promotes mutagenesis by degradation of UNG2, we hypothesized that overexpression of the FAM72 gene family might promote cancer development and progression. Here we show that FAM72A-D is overexpressed in many human cancers and inversely correlates with UNG2 protein levels in tumorigenic tissue. However, FAM72A but not FAM72B-D causes degradation of UNG2. Consistent with this effect, FAM72 expression correlates with a higher mutation load in many tumor types. Since genetic mutations are associated with cancer development and progression, we tested whether FAM72 expression is associated with disease outcomes. Indeed, we found that high FAM72 expression was associated with poorer survival in several cancers. To directly test if Fam72a is sufficient to promote cancer, we generated transgenic mice that overexpress Fam72a in multiple tissues. We observed that Fam72a overexpression promotes increased colonic polyps in the Apcmin background compared to controls. These data show that the novel FAM72 gene family are drivers of cancer development in both mice and humans and advances our understanding of the underlying molecular mechanisms that precipitate cancer development and progression. This work is supported by a grant from the CIHR (PJT-180269). Citation Format: Yuqing Feng, Bhupesh Thakur, Jeffery Bruce, Sami Mamand, Melika Shirdarreh, Matthew Wong, Jennifer Silvester, Ming Han, Mohammad Kashem, Amin Zia, David Cescon, Tervor Pugh, Rossanna C. Pezo, Alberto Martin. The FAM72 gene family promotes cancer development by disabling the base excision repair system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1217.
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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) | 0.004 | 0.001 |
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".