Abstract 2012: Recurrent rearrangements of NAALADL2 in prostate, breast, cervical, head and neck and lung squamous cell carcinoma
Notice bibliographique
Résumé
Abstract Prostate cancer is a heterogeneous disease with unique molecular aberrations present in patient sub-groups. Distinct prostate cancer molecular changes have been shown to associate with specific clinical outcomes, suggesting the potential of molecular markers as diagnostic and prognostic biomarkers for prostate cancer. Recurrent ETS family gene fusions, BRAF and SPINK1 overexpression account for about 50-60% of the prostate cancer cases. Genetic aberrations in the remaining 40-50% of the cases is not known. Our attempt to identify new molecular markers in prostate cancer led to the identification of NAALADL2 gene shown to be associated with aggressive prostate cancer. In this study, we carried out a comprehensive analysis of genomic changes of NAALADL2 in prostate and other solid cancers by analyzing copy number changes and gene expression using TCGA next generation RNA sequencing data. We observed recurrent amplification, rearrangement, deletion, mutations and over-expression of NAALADL2 in prostate cancer cases. Notably, we observed mutually exclusive aberrations in NAALADL2 when compared to other cases with known prostate cancer aberrations including ETS gene fusions, indicating NAALADL2 as a distinct molecular sub-set of prostate cancer. Independent validation by fluorescent in situ hybridization (FISH) analysis using break apart probe for NAALADL2 on 874 prostate cancer revealed recurrent amplification and rearrangements in about 8% (71/874) [PN1] of the cases with higher prevalence in Caucasian American than African American cases. Based on these results, we explored prostate cancer TGCA gene fusion database and identified additional cases with gene fusions involving NAALADL2. We selected one of the gene fusions identified in the TCGA database involving NAALADL2-PIK3CA and conducted in vitro functional characterization studies and showed its oncogenic properties. Gene expression microarray analysis of RWPE1 cells transfected with NAALADL2-PIK3CA showed dysregulation of genes involved in cancer related pathways, further suggesting a role for NAALADL2-PIK3CA in prostate cancer development. Based on these studies, we explored the incidence of NAALADL2 gene fusion in other solid cancers including lung squamous cell cancer (LUSC), ovarian cancer, head and neck cancer, cervical cancer and breast cancer shown to have recurrent gene fusions identified in the TCGA gene fusion database. Notably, recurrent rearrangements and amplification are seen in a large subset (45%) of LUSC patients, but not in lung adenocarcinoma, suggesting that NAALADL2 could be developed as a novel biomarker in LUSC. Further validation studies using FISH in our independent cohort of LUSC and breast cancer patients including 79 patients from Ghana confirmed recurrent rearrangements and amplification in a subset of cases. In conclusion, similar to ERG, BRAF and FGFR genes, we show recurrent gene fusions of NAALADL2 across multiple solid cancer with potential applications as a pan cancer molecular marker for cancer diagnosis and a potential target for drug development. Citation Format: Pavithra D. Arachchige, Shannon Carskadon, James Hu, Justin Fernando, Darshan S. Chandrashekar, Nilesh S. Gupta, Sean R. Williamson, Dhananjay A. Chitale, Craig G. Rogers, James O. Peabody, Mani Menon, Tarek A. Bismar, Evelyn Jiagge, Sooryanarayana Varambally, Nallasivam Palanisamy. Recurrent rearrangements of NAALADL2 in prostate, breast, cervical, head and neck and lung squamous cell carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2012.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».