185 results on '"Servant, N."'
Search Results
2. Combining immunotherapy with an epidrug in squamous cell carcinomas of different locations: rationale and design of the PEVO basket trial
- Author
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de Guillebon, E., Jimenez, M., Mazzarella, L., Betsou, F., Stadler, P., Peták, I., Jeannot, E., Chanas, L., Servant, N., Marret, G., Duso, B.A., Legrand, F., Kornerup, K.N., Bernhart, S.H., Balogh, G., Dóczi, R., Filotás, P., Curigliano, G., Bièche, I., Guérin, J., Dirner, A., Neuzillet, C., Girard, N., Borcoman, E., Larbi Chérif, L., Tresca, P., Roufai, D.B., Dupain, C., Scholl, S., André, F., Fernandez, X., Filleron, T., Kamal, M., and Le Tourneau, C.
- Published
- 2021
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3. Challenging single- and multi-probesets gene expression signatures of pathological complete response to neoadjuvant chemotherapy in breast cancer: Experience of the REMAGUS 02 phase II trial
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Valet, F., de Cremoux, P., Spyratos, F., Servant, N., Dujaric, M.E., Gentien, D., Lehmann-Che, J., Scott, V., Sigal-Zafrani, B., Mathieu, M.C., Bertheau, P., Guinebretière, J.M., Pierga, J.Y., Delaloge, S., Giacchetti, S., Brain, E., Tembo, O., Marty, M., and Asselain, B.
- Published
- 2013
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4. 2406P Phase II trial evaluating the efficacy of pembrolizumab combined with vorinostat in patients with recurrent and/or metastatic squamous cell carcinoma of the penis: Subgroup analysis of the PEVOsq basket trial
- Author
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Coquan, E., Gomez-Roca, C.A., Lambert, A., You, B., Vansteene, D., Bigot, F., Cousin, S., Ajgal, Z. Castel, Jeannot, E., Guerini Rocco, E., Frige, G., Mazzarella, L., Francisco, M., Servant, N., Halladjian, M., Kamal, M., Legrand, F., Jimenez, M., Cabarrou, B., and Le Tourneau, C.
- Published
- 2023
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5. 923P Phase II trial evaluating the efficacy of pembrolizumab combined with vorinostat in patients with recurrent and/or metastatic head & neck squamous cell carcinoma – subgroup analysis of the PEVOsq basket trial
- Author
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Le Tourneau, C., Ghiringhelli, F., Saada, E.B., Chaltiel, R., Vansteene, D., Durando, X., You, B., Borel, C., Bigot, F., Abdeddaim, C., Marret, G., Jeannot, E., Guerini Rocco, E., Frige, G., Servant, N., Dupain, C., Kamal, M., Legrand, F., Jimenez, M., and Filleron, T.
- Published
- 2023
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6. 864P Serial cell-free tumor DNA in prognosing survival in patients with head and neck squamous cell carcinoma treated with upfront surgery
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Marret, G., Lamy, C., Vacher, S., Ahmanache, L., Séné, M., Klijanienko, J., Martinat, C., Halladjian, M., Bronzini, T., Balsat, C., Sauvage, S., Martin, E., Rougier, G., Dubray Vautrin, A., Choussy, O., Masliah-Planchon, J., Servant, N., Bieche, I., Le Tourneau, C., and Kamal, M.
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- 2023
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7. ACTuDB, a new database for the integrated analysis of array-CGH and clinical data for tumors
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Hupé, P, La Rosa, P, Liva, S, Lair, S, Servant, N, and Barillot, E
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- 2007
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8. Amifostine and Dexrazoxane Enhance the Rapid Loss of Bone Mass and Further Deterioration of Vertebrae Architecture in Female Rats
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Mwale, F., Ciobanu, I., Demers, C.N., Antoniou, J., Héon, S., Servant, N., and Chalifour, L.E.
- Published
- 2005
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9. Gender-Dependent Reductions in Vertebrae Length, Bone Mineral Density and Content by Doxorubicin Are Not Reduced by Dexrazoxane in Young Rats: Effect on Growth Plate and Intervertebral Discs
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Mwale, F., Antoniou, J., Héon, S., Servant, N., Wang, C., Kirby, G. M., Demers, C. N., and Chalifour, L. E.
- Published
- 2005
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10. Isolated ‘idiopathic’ micropenis: hidden genetic defects?
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Paris, F., De Ferran, K., Bhangoo, A., Ten, S., Lahlou, N., Audran, F., Servant, N., Poulat, F., Philibert, P., and Sultan, C.
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- 2011
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11. 75P Tumor mutational burden in clinical routine practice: Identifying the right threshold?
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Dupain, C., Gutman, T., Girard, E., du Rusquec, P., Sablin, M-P., Tresca, P., Neuzillet, C., Vincent-Salomon, A., Antonio, S., Franck, C., Galut, M., Allory, Y., Cyrta, J., Guillou, I., Wong, J., Le Tourneau, C., Bièche, I., Servant, N., Kamal, M., and Masliah-Planchon, J.
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- 2021
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12. Testotoxicosis without Testicular Mass: Revealed by Peripheral Precocious Puberty and Confirmed by Somatic LHCGR Gene Mutation.
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Daussac, A., Barat, P., Servant, N., Yacoub, M., Missonier, S., Lavran, F, Gaspari, L., Sultan, C., and Paris, F.
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PRECOCIOUS puberty ,LEYDIG cells ,HORMONE receptors ,SOMATIC mutation ,GENES ,LUTEINIZING hormone receptors - Abstract
Purpose: Testotoxicosis is an autosomal dominant form of limited gonadotropin-independent precocious puberty in boys. It is caused by a heterozygous constitutively activating mutation of the LHCGR gene encoding the luteinizing/hormone receptor (LHR). Some twenty mutations of the LHCGR gene have been reported. Most of them are constitutive mutations isolated from blood leukocyte DNA, although others are somatic, found only in testicular tumoural tissue. In all the previously reported cases of these somatic mutations, the tumour, whether a nodular Leydig cell adenoma or hyperplasia, was easily visible on testicular ultrasonography. The aim of this study was to describe an unusual presentation of a patient with the clinical and hormonal characteristics of testotoxicosis but no well-circumscribed lesion at testicular ultrasonography. Materials and Methods: Molecular analysis of the LHCGR gene was performed by direct sequencing of DNA extracted from peripheral leucocytes and testicular biopsy. Results: Molecular analysis didn't find any LHR mutation in blood, whereas it revealed for the first time a somatic D578H mutation in testicular tissue despite no evidence of a nodular aspect at testis ultrasonography. Conclusions: This observation underlines the need to look for a somatic LHCGR gene mutation from the testicular biopsies of all boys with testotoxicosis with no constitutive LHCGR gene mutation identified from blood DNA, even in the absence of circumscribed testicular lesion at ultrasonography. In addition, based on the known link between LHR mutations and testicular tumourigenesis, yearly ultrasound monitoring of the testes should be considered for these patients. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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13. LINE-1 activity in facultative heterochromatin formation during X chromosome inactivation
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Chow JC, Ciaudo C, Fazzari MJ, Mise N, Servant N, Glass JL, Attreed M, Avner P, Wutz A, Barillot E, Greally JM, Voinnet O, Heard E, Servant N, Glass JL, Attreed M, Avner P, Wutz A, Barillot E, Greally JM, Voinnet O, and Heard E
- Published
- 2010
14. RNAi-dependent and independent control of LINE1 accumulation and mobility in mouse embryonic stem cells
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Ciaudo C, Jay F, Okamoto I, Chen CJ, Sarazin A, Servant N, Barillot E, Heard E, and Voinnet O.
- Published
- 2013
15. PO-497 Microtubule regulatory proteins as predictive biomarkers of taxane-based chemoresistance in breast cancer?
- Author
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Moindjie, H., Rodrigues-Ferreira, S., Dujaric, M.E., Servant, N., Asselain, B., Arnedos, M., Pierga, J.Y., André, F., and Nahmias, C.
- Published
- 2018
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16. 1268P - Retrospective analysis of a SHIVA01 trial cohort using functional mutational analysis successfully predicted treatment outcome
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Tarcic, G., Le Tourneau, C., Kamal, M., Edelheit, O., Barbash, Z., Vidne, M., Dureau, S., Miron, B., Callens, C., Servant, N., and Bieche, I.
- Published
- 2017
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17. 11LBA - Functional mutational analysis to assess the oncogenic activity of variant of uncertain significance (VUS) detected in patients included in the SHIVA trial
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Tarcic, G., Kamal, M., Edelheit, O., Barbash, Z., Vidne, M., Miron, B., Callens, C., Servant, N., Bièche, I., and Le Tourneau, C.
- Published
- 2016
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18. Integrating a Molecular Signature of Intrinsic Radiosensitivity Into the Classification of Breast Cancer
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Torres-Roca, J.F., Fulp, W.J., Naghavi, A.O., Servant, N., Bollet, M., van de Vijver, M.J., Harris, E.E., and Eschrich, S.A.
- Published
- 2014
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19. 1571PD - De Novo Mutation Detection from Ctdna Correlates with Variants Detected on Metastasis of Patients with Any Kind of Refractory Cancer from the Shiva Trial
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Pierga, J., Decraene, C., Bernard, V., Kamal, M., Blin, A., Rio Frio, T., Servant, N., Bidard, F.C., Paoletti, X., Stern, M., Lebofsky, R., and Le Tourneau, C.
- Published
- 2014
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20. Randomised proof-of-concept phase II trial comparing targeted therapy based on tumour molecular profiling vs conventional therapy in patients with refractory cancer: results of the feasibility part of the SHIVA trial.
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Le Tourneau, C, Paoletti, X, Servant, N, Bièche, I, Gentien, D, Rio Frio, T, Vincent-Salomon, A, Servois, V, Romejon, J, Mariani, O, Bernard, V, Huppe, P, Pierron, G, Mulot, F, Callens, C, Wong, J, Mauborgne, C, Rouleau, E, Reyes, C, and Henry, E
- Subjects
METASTASIS ,RANDOMIZED controlled trials ,BIOPSY ,CANCER diagnosis ,IMMUNOHISTOCHEMISTRY ,CANCER genetics - Abstract
Background:The SHIVA trial is a multicentric randomised proof-of-concept phase II trial comparing molecularly targeted therapy based on tumour molecular profiling vs conventional therapy in patients with any type of refractory cancer. Results of the feasibility study on the first 100 enrolled patients are presented.Methods:Adult patients with any type of metastatic cancer who failed standard therapy were eligible for the study. The molecular profile was performed on a mandatory biopsy, and included mutations and gene copy number alteration analyses using high-throughput technologies, as well as the determination of oestrogen, progesterone, and androgen receptors by immunohistochemistry (IHC).Results:Biopsy was safely performed in 95 of the first 100 included patients. Median time between the biopsy and the therapeutic decision taken during a weekly molecular biology board was 26 days. Mutations, gene copy number alterations, and IHC analyses were successful in 63 (66%), 65 (68%), and 87 (92%) patients, respectively. A druggable molecular abnormality was present in 38 patients (40%).Conclusions:The establishment of a comprehensive tumour molecular profile was safe, feasible, and compatible with clinical practice in refractory cancer patients. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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21. 114 Validation process of a gene-expression signature of local recurrences after breast-conserving treatments
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Bollet, M.A., Servant, N., Kreike, B., Halfwerk, H., Daoud, S., Lebigot, I., Bartelink, H., Fourquet, A., Sigal-Zafrani, B., and van de Vijver, M.J.
- Published
- 2010
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22. SP002 Bioinformatics analysis for real-time applications.
- Author
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Servant, N., Hupé, P., Kamal, M., LeTourneau, C., and Barillot, E.
- Published
- 2013
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23. Efficacy of molecularly targeted agents given in the randomised trial SHIVA01 according to the ESMO Scale for Clinical Actionability of molecular Targets.
- Author
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Moreira, A., Masliah-Planchon, J., Callens, C., Vacher, S., Lecerf, C., Frelaut, M., Borcoman, E., Torossian, N., Ricci, F., Hescot, S., Sablin, M.P., Tresca, P., Loirat, D., Melaabi, S., Trabelsi-Grati, O., Pierron, G., Gentien, D., Bernard, V., Vincent Salomon, A., and Servant, N.
- Subjects
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ALGORITHMS , *ANTINEOPLASTIC agents , *CANCER chemotherapy , *CELLULAR signal transduction , *METASTASIS , *MOLECULAR pathology , *SURVIVAL , *TUMORS , *RANDOMIZED controlled trials , *TREATMENT effectiveness , *RETROSPECTIVE studies , *DESCRIPTIVE statistics , *LOG-rank test , *PHARMACODYNAMICS - Abstract
A randomised trial SHIVA01 compared the efficacy of matched molecularly targeted therapy outside their indications based on a prespecified treatment algorithm versus conventional chemotherapy in patients with metastatic solid tumours who had failed standard of care. No statistical difference was reported between the two groups in terms of progression-free survival (PFS), challenging treatment algorithm. The European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of molecular Targets (ESCAT) recently defined criteria to prioritise molecular alterations (MAs) to select anticancer drugs. We aimed to retrospectively evaluate the efficacy of matched molecularly targeted agents (MTAs) given in SHIVA01 according to ESCAT tiers. MAs used in SHIVA01 were retrospectively classified into ESCAT tiers, and PFS and overall survival (OS) were compared using log-rank tests. One hundred fifty-three patients were treated with matched MTAs in SHIVA01. MAs used to allocate MTAs were classified into tiers II, IIIA, IIIB and IVA according to the ESCAT. Median PFS was 2.0 months in tier II, 3.1 in tier IIIA, 1.7 in tier IIIB and 3.2 in tier IVA (p = 0.13). Median OS in tier IIIB was worse than that in tiers II, IIIA and IVA (6.3 months versus 11.7, 11.2 and 12.1, p = 0.002). Most MAs used to allocate therapy in SHIVA01 were shown to improve outcomes in other tumour types (tier IIIA). Worst outcome was observed in patients treated based on another type of alteration than the one reported to improve outcomes (tier IIIB), highlighting the crucial impact of the type of the alterations beyond the gene and the signalling pathway. • Most alterations used to allocate therapy in SHIVA01 had low actionability according to the ESMO Scale for Clinical Actionability of molecular Targets. • Worst outcome was reported in patients treated based on another type of alteration than the one reported to improve outcome. • The results highlight the crucial impact of alterations type beyond the gene and/or the signalling pathway. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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24. 7 - Proffered Paper: Mechanical induction of the tumourogenic beta-catenin pathway by tumour growth pressure.
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Fernández-Sánchez, M.E., Barbier, S., Whitehead, J., Béalle, G., Michel, A., Latorre-Ossa, H., Rey, C., Fouassier, L., Claperon, A., Brullé, L., Girard, E., Servant, N., Rio-Frio, T., Marie, H., Lesieur, S., Housset, C., Gennisson, J.-L., Tanter, M., Ménager, C., and Fre, S.
- Published
- 2016
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25. The genomic and transcriptomic landscape of metastastic urothelial cancer.
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Loriot Y, Kamal M, Syx L, Nicolle R, Dupain C, Mensourri N, Duquesne I, Lavaud P, Nicotra C, Ngocamus M, Lacroix L, Tselikas L, Crehange G, Friboulet L, Castel-Ajgal Z, Neuzillet Y, Borcoman E, Beuzeboc P, Marret G, Gutman T, Wong J, Radvanyi F, Dureau S, Scoazec JY, Servant N, Allory Y, Besse B, Andre F, Le Tourneau C, Massard C, and Bieche I
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- Humans, Male, Female, Receptor, ErbB-2 genetics, Receptor, ErbB-2 metabolism, Urinary Bladder Neoplasms genetics, Urinary Bladder Neoplasms pathology, Nectins genetics, Nectins metabolism, Aged, Tuberous Sclerosis Complex 1 Protein genetics, Tuberous Sclerosis Complex 1 Protein metabolism, Cell Adhesion Molecules genetics, Cell Adhesion Molecules metabolism, Antigens, Neoplasm genetics, Antigens, Neoplasm metabolism, Class I Phosphatidylinositol 3-Kinases genetics, Class I Phosphatidylinositol 3-Kinases metabolism, Genomics, Middle Aged, APOBEC Deaminases genetics, APOBEC Deaminases metabolism, Urothelium pathology, Urothelium metabolism, Gene Expression Regulation, Neoplastic, Cytidine Deaminase genetics, Cytidine Deaminase metabolism, Neoplasm Metastasis genetics, Aged, 80 and over, Carcinoma, Transitional Cell genetics, Carcinoma, Transitional Cell pathology, Urologic Neoplasms genetics, Urologic Neoplasms pathology, Gene Expression Profiling methods, Receptor, Fibroblast Growth Factor, Type 3 genetics, Receptor, Fibroblast Growth Factor, Type 3 metabolism, Transcriptome, Mutation, Exome Sequencing
- Abstract
Metastatic urothelial carcinoma (mUC) is a lethal cancer, with limited therapeutic options. Large-scale studies in early settings provided critical insights into the genomic and transcriptomic characteristics of non-metastatic UC. The genomic landscape of mUC remains however unclear. Using Whole Exome (WES) and mRNA sequencing (RNA-seq) performed on metastatic biopsies from 111 patients, we show that driver genomic alterations from mUC were comparable to primary UC (TCGA data). APOBEC, platin, and HRD mutational signatures are the most prevalent in mUC, identified in 56%, 14%, and 9% of mUC samples, respectively. Molecular subtyping using consensus transcriptomic classification in mUC shows enrichment in neuroendocrine subtype. Paired samples analysis reveals subtype heterogeneity and temporal evolution. We identify potential therapeutic targets in 73% of mUC patients, of which FGFR3 (26%), ERBB2 (7%), TSC1 (7%), and PIK3CA (13%) are the most common. NECTIN4 and TACSTD2 are highly expressed regardless of molecular subtypes, FGFR3 alterations and sites of metastases., (© 2024. The Author(s).)
- Published
- 2024
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26. Methylation, Gene Expression, and Risk Genotypes at the TERT-CLPTM1L Locus in Cervical Cancer.
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Ramachandran D, Mao Q, Liao D, Kamal M, Schürmann P, Eisenblätter R, Geffers R, Balint B, Lecompte L, Servant N, Chérif LL, Lamy C, Baulande S, Legoix P, Le Tourneau C, Latouche A, Hillemanns P, Scholl S, and Dörk T
- Abstract
The reverse transcriptase subunit of telomerase, TERT, is frequently activated in high-grade dysplasia and invasive cancers of the uterine cervix. Telomerase activation through hypomethylation of the TERT promoter holds promise as a biomarker for cervical cancer progression, however, specific CpG sites involved in cervical cancer risk remain to be fully defined. A recent genome-wide association study on cervical cancer identified genetic polymorphisms at 5p13.33 (close to TERT-CLPTM1L) but the underlying mechanisms are undetermined. We investigated 529 CpG sites within the TERT promoter region and 3 CpG islands nearby, and 21 CpG sites within CLPTM1L in 190 bisulfite-converted cervical tumor DNA samples from BioRAIDs (NCT02428842). We identified eight CpG sites within TERT intron 2 where methylation was significantly associated with the genotypes of cervical cancer risk variants rs27070 and rs459961 in cervical tumors after multiple testing correction (p < 9.4 × 10E-5). Hypermethylation at chr5:1289663 correlated with decreased TERT mRNA levels. In an independent series of 188 normal or dysplastic cervical tissues, rare alleles of rs27070 and rs459961 were associated with low basal CLPTM1L levels and with the absence of TERT mRNA in HPV-negative samples, consistent with their proposed role as protective variants for cervical cancer. HPV infection was associated with increased CLPTM1L and TERT levels. Collectively, our results provide a link between cervical cancer risk variants, methylation, and gene expression and implicate both TERT and CLPTM1L as genes modulated by genomic background and HPV infection during cervical cancer development., (© 2024 Wiley Periodicals LLC.)
- Published
- 2024
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27. Copy number alterations in metastatic and early breast tumours: prognostic and acquired biomarkers of resistance to CDK4/6 inhibitors.
- Author
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Sablin MP, Gestraud P, Jonas SF, Lamy C, Lacroix-Triki M, Bachelot T, Filleron T, Lacroix L, Tran-Dien A, Jézéquel P, Mauduit M, Barros Monteiro J, Jimenez M, Michiels S, Attignon V, Soubeyran I, Driouch K, Servant N, Le Tourneau C, Kamal M, André F, and Bièche I
- Subjects
- Humans, Female, Prognosis, Neoplasm Metastasis, Protein Kinase Inhibitors therapeutic use, Polymorphism, Single Nucleotide, Middle Aged, Receptor, ErbB-2 genetics, Prospective Studies, Adult, Telomerase genetics, Aged, Breast Neoplasms genetics, Breast Neoplasms drug therapy, Breast Neoplasms pathology, Cyclin-Dependent Kinase 4 genetics, Cyclin-Dependent Kinase 4 antagonists & inhibitors, Cyclin-Dependent Kinase 6 genetics, Cyclin-Dependent Kinase 6 antagonists & inhibitors, Biomarkers, Tumor genetics, DNA Copy Number Variations, Drug Resistance, Neoplasm genetics
- Abstract
Background: Copy number alterations (CNA) are acquired during the evolution of cancers from their early stage to metastatic stage. This study aims at analysing the clinical value of the identified metastasis-associated CNAs both in metastatic breast cancers (mBCs) and early breast cancers (eBCs)., Methods: Single-nucleotide polymorphism (SNP)-array was performed on 926 biopsies from mBC patients, enrolled in SAFIR02-BREAST prospective trial. CNA profiles of eBCs from The Cancer Genome Atlas Breast Invasive Carcinoma (n = 770), Molecular Taxonomy of Breast Cancer International Consortium (n = 1620) and PACS04 trial (n = 243) cohorts were used as references for comparing mBCs and eBCs CNA profiles. Overall survival was the considered survival endpoint., Results: Among the twenty-one genes frequently altered in ER + /HER2- mBCs: focal amplification of TERT was associated with poor outcome in the ER + /HER2- mBC population. Among the ER + /HER2- mBCs patients for whom CDK4/6 inhibitors information before biopsies collection was available: we identified seven genes on post-treatment biopsies, including the cyclin-dependent kinase 4 (CDK4), which was amplified in 9.8% of the ER + /HER2- mBCs pretreated population, as compared to 1.5% in the ER + /HER2- mBCs unpretreated population (P = 2.82E-04) as well as the 3 eBC populations. CDK4 amplification was associated with poor outcome in the ER + /HER2- eBCs., Conclusions: This study provides insights into the biology of mBCs and identifies clinically useful genomic features for future improvement of breast cancer patient management., (© 2024. The Author(s).)
- Published
- 2024
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28. Metastatic renal cell carcinoma with occult primary: a multicenter prospective cohort.
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Jacquin N, Flippot R, Masliah-Planchon J, Grisay G, Brillet R, Dupain C, Kamal M, Guillou I, Gruel N, Servant N, Gestraud P, Wong J, Cockenpot V, Goncalves A, Selves J, Blons H, Rouleau E, Delattre O, Gervais C, Le Tourneau C, Bièche I, Allory Y, Albigès L, and Watson S
- Abstract
Metastatic carcinoma of presumed renal origin (rCUP) has recently emerged as a new entity within the heterogeneous entity of Cancers of Unknown Primary (CUP) but their biological features and optimal therapeutic management remain unknown. We report the molecular characteristics and clinical outcome of a series of 25 rCUP prospectively identified within the French National Multidisciplinary Tumor Board for CUP. This cohort strongly suggests that rCUP share similarities with common RCC subtypes and benefit from renal-tailored systemic treatment. This study highlights the importance of integrating clinical and molecular data for optimal diagnosis and management of CUP., (© 2024. The Author(s).)
- Published
- 2024
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29. VC-resist glioblastoma cell state: vessel co-option as a key driver of chemoradiation resistance.
- Author
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Pichol-Thievend C, Anezo O, Pettiwala AM, Bourmeau G, Montagne R, Lyne AM, Guichet PO, Deshors P, Ballestín A, Blanchard B, Reveilles J, Ravi VM, Joseph K, Heiland DH, Julien B, Leboucher S, Besse L, Legoix P, Dingli F, Liva S, Loew D, Giani E, Ribecco V, Furumaya C, Marcos-Kovandzic L, Masliantsev K, Daubon T, Wang L, Diaz AA, Schnell O, Beck J, Servant N, Karayan-Tapon L, Cavalli FMG, and Seano G
- Subjects
- Humans, Animals, Cell Line, Tumor, Mice, Chemoradiotherapy methods, Drug Resistance, Neoplasm, Gene Expression Regulation, Neoplastic, Radiation Tolerance, YAP-Signaling Proteins metabolism, Brain metabolism, Brain pathology, Proteomics, Glioblastoma metabolism, Glioblastoma pathology, Glioblastoma drug therapy, Glioblastoma genetics, Brain Neoplasms metabolism, Brain Neoplasms pathology, Brain Neoplasms drug therapy, Brain Neoplasms genetics
- Abstract
Glioblastoma (GBM) is a highly lethal type of cancer. GBM recurrence following chemoradiation is typically attributed to the regrowth of invasive and resistant cells. Therefore, there is a pressing need to gain a deeper understanding of the mechanisms underlying GBM resistance to chemoradiation and its ability to infiltrate. Using a combination of transcriptomic, proteomic, and phosphoproteomic analyses, longitudinal imaging, organotypic cultures, functional assays, animal studies, and clinical data analyses, we demonstrate that chemoradiation and brain vasculature induce cell transition to a functional state named VC-Resist (vessel co-opting and resistant cell state). This cell state is midway along the transcriptomic axis between proneural and mesenchymal GBM cells and is closer to the AC/MES1-like state. VC-Resist GBM cells are highly vessel co-opting, allowing significant infiltration into the surrounding brain tissue and homing to the perivascular niche, which in turn induces even more VC-Resist transition. The molecular and functional characteristics of this FGFR1-YAP1-dependent GBM cell state, including resistance to DNA damage, enrichment in the G2M phase, and induction of senescence/stemness pathways, contribute to its enhanced resistance to chemoradiation. These findings demonstrate how vessel co-option, perivascular niche, and GBM cell plasticity jointly drive resistance to therapy during GBM recurrence., (© 2024. The Author(s).)
- Published
- 2024
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30. Escape from X inactivation is directly modulated by levels of Xist non-coding RNA.
- Author
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Hauth A, Panten J, Kneuss E, Picard C, Servant N, Rall I, Pérez-Rico YA, Clerquin L, Servaas N, Villacorta L, Jung F, Luong C, Chang HY, Zaugg JB, Stegle O, Odom DT, Loda A, and Heard E
- Abstract
In placental females, one copy of the two X chromosomes is largely silenced during a narrow developmental time window, in a process mediated by the non-coding RNA Xist
1 . Here, we demonstrate that Xist can initiate X-chromosome inactivation (XCI) well beyond early embryogenesis. By modifying its endogenous level, we show that Xist has the capacity to actively silence genes that escape XCI both in neuronal progenitor cells (NPCs) and in vivo , in mouse embryos. We also show that Xist plays a direct role in eliminating TAD-like structures associated with clusters of escapee genes on the inactive X chromosome, and that this is dependent on Xist's XCI initiation partner, SPEN2 . We further demonstrate that Xist's function in suppressing gene expression of escapees and topological domain formation is reversible for up to seven days post-induction, but that sustained Xist up-regulation leads to progressively irreversible silencing and CpG island DNA methylation of facultative escapees. Thus, the distinctive transcriptional and regulatory topologies of the silenced X chromosome is actively, directly - and reversibly - controlled by Xist RNA throughout life., Competing Interests: COMPETING INTERESTS H.Y.C. is a co-founder of Accent Therapeutics, Boundless Bio, Cartography Biosciences, Orbital Therapeutics, and an advisor of 10x Genomics, Arsenal Biosciences, Chroma Medicine, Exai Bio, and Spring Discovery.- Published
- 2024
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31. p4EBP1 staining predicts outcome in ER-positive endocrine-resistant metastatic breast cancer patients treated with everolimus and exemestane.
- Author
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Vanacker H, Treilleux I, Schiffler C, Bieche I, Campone M, Patsouris A, Arnedos M, Cottu PH, Jacquin JP, Dalenc F, Pinton A, Servant N, Attignon V, Rouleau E, Morel A, Legrand F, Jimenez M, Andre F, and Bachelot T
- Subjects
- Humans, Female, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Androstadienes therapeutic use, Biomarkers, Receptor, ErbB-2 metabolism, Everolimus, Breast Neoplasms drug therapy, Breast Neoplasms genetics, Breast Neoplasms pathology
- Abstract
Background: To identify patients most likely to respond to everolimus, a mammalian target of rapamycin (mTOR) inhibitor, a prospective biomarker study was conducted in hormone receptor-positive endocrine-resistant metastatic breast cancer patients treated with exemestane-everolimus therapy., Methods: Metastatic tumor biopsies were processed for immunohistochemical staining (p4EBP1, PTEN, pAKT, LKB1, and pS6K). ESR1, PIK3CA and AKT1 gene mutations were detected by NGS. The primary endpoint was the association between the p4EBP1 expression and clinical benefit rate (CBR) at 6 months of everolimus plus exemestane treatment., Results: Of 150 patients included, 107 were evaluable for the primary endpoint. p4EBP1 staining above the median (Allred score ≥6) was associated with a higher CBR at 6 months (62% versus 40% in high-p4EBP1 versus low-p4EBP1, χ2 test, p = 0.026) and a longer progression-free survival (PFS) (median PFS of 9.2 versus 5.8 months in high-p4EBP1 versus low-p4EBP1; p = 0.02). When tested with other biomarkers, only p4EBP1 remained a significant predictive marker of PFS in multivariate analysis (hazard ratio, 0.591; p = 0.01)., Conclusions: This study identified a subset of patients with hormone receptor-positive endocrine-resistant metastatic breast cancer and poor outcome who would derive less benefit from everolimus and exemestane. p4EBP1 may be a useful predictive biomarker in routine clinical practice., Clinical Trial Registration: NCT02444390., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
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- 2024
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32. Tumor mutational burden assessment and standardized bioinformatics approach using custom NGS panels in clinical routine.
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Dupain C, Gutman T, Girard E, Kamoun C, Marret G, Castel-Ajgal Z, Sablin MP, Neuzillet C, Borcoman E, Hescot S, Callens C, Trabelsi-Grati O, Melaabi S, Vibert R, Antonio S, Franck C, Galut M, Guillou I, Halladjian M, Allory Y, Cyrta J, Romejon J, Frouin E, Stoppa-Lyonnet D, Wong J, Le Tourneau C, Bièche I, Servant N, Kamal M, and Masliah-Planchon J
- Subjects
- Humans, Mutation, High-Throughput Nucleotide Sequencing methods, Neoplasms genetics
- Abstract
Background: High tumor mutational burden (TMB) was reported to predict the efficacy of immune checkpoint inhibitors (ICIs). Pembrolizumab, an anti-PD-1, received FDA-approval for the treatment of unresectable/metastatic tumors with high TMB as determined by the FoundationOne®CDx test. It remains to be determined how TMB can also be calculated using other tests., Results: FFPE/frozen tumor samples from various origins were sequenced in the frame of the Institut Curie (IC) Molecular Tumor Board using an in-house next-generation sequencing (NGS) panel. A TMB calculation method was developed at IC (IC algorithm) and compared to the FoundationOne® (FO) algorithm. Using IC algorithm, an optimal 10% variant allele frequency (VAF) cut-off was established for TMB evaluation on FFPE samples, compared to 5% on frozen samples. The median TMB score for MSS/POLE WT tumors was 8.8 mut/Mb versus 45 mut/Mb for MSI/POLE-mutated tumors. When focusing on MSS/POLE WT tumor samples, the highest median TMB scores were observed in lymphoma, lung, endometrial, and cervical cancers. After biological manual curation of these cases, 21% of them could be reclassified as MSI/POLE tumors and considered as "true TMB high." Higher TMB values were obtained using FO algorithm on FFPE samples compared to IC algorithm (40 mut/Mb [10-3927] versus 8.2 mut/Mb [2.5-897], p < 0.001)., Conclusions: We herein propose a TMB calculation method and a bioinformatics tool that is customizable to different NGS panels and sample types. We were not able to retrieve TMB values from FO algorithm using our own algorithm and NGS panel., (© 2024. The Author(s).)
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- 2024
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33. Molecular underpinnings and environmental drivers of loss of heterozygosity in Drosophila intestinal stem cells.
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Al Zouabi L, Stefanutti M, Roumeliotis S, Le Meur G, Boumard B, Riddiford N, Rubanova N, Bohec M, Gervais L, Servant N, and Bardin AJ
- Subjects
- Animals, Humans, DNA Repair, Loss of Heterozygosity, Saccharomyces cerevisiae genetics, Stem Cells, Drosophila genetics, Recombination, Genetic genetics
- Abstract
During development and aging, genome mutation leading to loss of heterozygosity (LOH) can uncover recessive phenotypes within tissue compartments. This phenomenon occurs in normal human tissues and is prevalent in pathological genetic conditions and cancers. While studies in yeast have defined DNA repair mechanisms that can promote LOH, the predominant pathways and environmental triggers in somatic tissues of multicellular organisms are not well understood. Here, we investigate mechanisms underlying LOH in intestinal stem cells in Drosophila. Infection with the pathogenic bacteria, Erwinia carotovora carotovora 15, but not Pseudomonas entomophila, increases LOH frequency. Using whole genome sequencing of somatic LOH events, we demonstrate that they arise primarily via mitotic recombination. Molecular features and genetic evidence argue against a break-induced replication mechanism and instead support cross-over via double Holliday junction-based repair. This study provides a mechanistic understanding of mitotic recombination, an important mediator of LOH, and its effects on stem cells in vivo., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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34. Chromatin state transitions in the Drosophila intestinal lineage identify principles of cell-type specification.
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Josserand M, Rubanova N, Stefanutti M, Roumeliotis S, Espenel M, Marshall OJ, Servant N, Gervais L, and Bardin AJ
- Subjects
- Animals, Histones metabolism, Chromatin metabolism, Cell Lineage, Intestines, Cell Differentiation genetics, Drosophila metabolism, Drosophila Proteins genetics, Drosophila Proteins metabolism
- Abstract
Tissue homeostasis relies on rewiring of stem cell transcriptional programs into those of differentiated cells. Here, we investigate changes in chromatin occurring in a bipotent adult stem cells. Combining mapping of chromatin-associated factors with statistical modeling, we identify genome-wide transitions during differentiation in the adult Drosophila intestinal stem cell (ISC) lineage. Active, stem-cell-enriched genes transition to a repressive heterochromatin protein-1-enriched state more prominently in enteroendocrine cells (EEs) than in enterocytes (ECs), in which the histone H1-enriched Black state is preeminent. In contrast, terminal differentiation genes associated with metabolic functions follow a common path from a repressive, primed, histone H1-enriched Black state in ISCs to active chromatin states in EE and EC cells. Furthermore, we find that lineage priming has an important function in adult ISCs, and we identify histone H1 as a mediator of this process. These data define underlying principles of chromatin changes during adult multipotent stem cell differentiation., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2023
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35. Adaptive nanopore sequencing to determine pathogenicity of BRCA1 exonic duplication.
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Filser M, Schwartz M, Merchadou K, Hamza A, Villy MC, Decees A, Frouin E, Girard E, Caputo SM, Renault V, Becette V, Golmard L, Servant N, Stoppa-Lyonnet D, Delattre O, Colas C, and Masliah-Planchon J
- Subjects
- Female, Humans, Virulence, Genetic Predisposition to Disease, BRCA1 Protein genetics, BRCA2 Protein genetics, Genes, BRCA2, Exons, Germ-Line Mutation genetics, High-Throughput Nucleotide Sequencing methods, Nanopore Sequencing, Breast Neoplasms genetics
- Abstract
BRCA1 and BRCA2 are tumour suppressor genes that have been characterised as predisposition genes for the development of hereditary breast and ovarian cancers among other malignancies. The molecular diagnosis of this predisposition syndrome is based on the detection of inactivating variants of any type in those genes. But in the case of structural variants, functional consequences can be difficult to assess using standard molecular methods, as the precise resolution of their sequence is often impossible with short-read next generation sequencing techniques. It has been recently demonstrated that Oxford Nanopore long-read sequencing technology can accurately and rapidly provide genetic diagnoses of Mendelian diseases, including those linked to pathogenic structural variants. Here, we report the accurate resolution of a germline duplication event of exons 18-20 of BRCA1 using Nanopore sequencing with adaptive sampling target enrichment. This allowed us to classify this variant as pathogenic within a short timeframe of 10 days. This study provides a proof-of-concept that nanopore adaptive sampling is a highly efficient technique for the investigation of structural variants of tumour suppressor genes in a clinical context., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2023
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36. Virilization at puberty in adolescent girls may reveal a 46,XY disorder of sexual development.
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Bergougnoux A, Gaspari L, Soleirol M, Servant N, Soskin S, Rossignol S, Wagner-Mahler K, Bertherat J, Sultan C, Kalfa N, and Paris F
- Abstract
Although hyperandrogenism is a frequent cause of consultation in adolescent girls, more severe forms with virilization must lead to suspicion of an adrenal or ovarian tumor. However, they may also reveal a 46,XY disorder of sexual development (DSD). Here, we describe four adolescent girls referred for pubertal virilization and in whom we diagnosed a 46,XY DSD. We performed gene mutation screening by Sanger sequencing (all patients) and by next-generation sequencing (NGS) in patient #4. We identified new heterozygous NR5A1 gene variants in patients #1 and #2 and a homozygous SRD5A2 gene deletion in patient #3. Patient #4 received a diagnosis of complete androgen insensitivity in childhood; however, due the unusual pubertal virilization, we completed the gene analysis by NGS that revealed two heterozygous HSD17B3 variants. This work underlines the importance of considering the hypothesis of 46,XY DSD in adolescent girls with unexplained virilization at puberty.
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- 2023
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37. Imaging and multi-omics datasets converge to define different neural progenitor origins for ATRT-SHH subgroups.
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Lobón-Iglesias MJ, Andrianteranagna M, Han ZY, Chauvin C, Masliah-Planchon J, Manriquez V, Tauziede-Espariat A, Turczynski S, Bouarich-Bourimi R, Frah M, Dufour C, Blauwblomme T, Cardoen L, Pierron G, Maillot L, Guillemot D, Reynaud S, Bourneix C, Pouponnot C, Surdez D, Bohec M, Baulande S, Delattre O, Piaggio E, Ayrault O, Waterfall JJ, Servant N, Beccaria K, Dangouloff-Ros V, and Bourdeaut F
- Subjects
- Humans, Multiomics, SMARCB1 Protein genetics, Transcription Factors genetics, Diagnostic Imaging, Hedgehog Proteins genetics, Rhabdoid Tumor genetics, Brain Neoplasms genetics, Teratoma pathology
- Abstract
Atypical teratoid rhabdoid tumors (ATRT) are divided into MYC, TYR and SHH subgroups, suggesting diverse lineages of origin. Here, we investigate the imaging of human ATRT at diagnosis and the precise anatomic origin of brain tumors in the Rosa26-Cre
ERT2 ::Smarcb1flox/flox model. This cross-species analysis points to an extra-cerebral origin for MYC tumors. Additionally, we clearly distinguish SHH ATRT emerging from the cerebellar anterior lobe (CAL) from those emerging from the basal ganglia (BG) and intra-ventricular (IV) regions. Molecular characteristics point to the midbrain-hindbrain boundary as the origin of CAL SHH ATRT, and to the ganglionic eminence as the origin of BG/IV SHH ATRT. Single-cell RNA sequencing on SHH ATRT supports these hypotheses. Trajectory analyses suggest that SMARCB1 loss induces a de-differentiation process mediated by repressors of the neuronal program such as REST, ID and the NOTCH pathway., (© 2023. Springer Nature Limited.)- Published
- 2023
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38. Patient Derived Xenografts (PDX) Models as an Avatar to Assess Personalized Therapy Options in Uveal Melanoma: A Feasibility Study.
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Nemati F, de Koning L, Gentien D, Assayag F, Henry E, Ait Rais K, Pierron G, Mariani O, Nijnikoff M, Champenois G, Nicolas A, Meseure D, Gardrat S, Servant N, Hupé P, Kamal M, Le Tourneau C, Piperno-Neumann S, Rodrigues M, Roman-Roman S, Decaudin D, Mariani P, and Cassoux N
- Subjects
- Adult, Animals, Mice, Humans, Feasibility Studies, Heterografts, Mice, SCID, Recurrence, Neoplasm Recurrence, Local, Liver Neoplasms genetics
- Abstract
Uveal melanoma is the most common primary intraocular malignancy in adults. Up to 50% of UM patients develop metastatic disease, usually in the liver. When metastatic, the prognosis is poor, and few treatment options exist. Here, we investigated the feasibility of establishing patient-derived xenografts (PDXs) from a patient's tumor in order to screen for therapies that the patient could benefit from. Samples obtained from 29 primary tumors and liver metastases of uveal melanoma were grafted into SCID mice. PDX models were successfully established for 35% of primary patient tumors and 67% of liver metastases. The tumor take rate was proportional to the risk of metastases. PDXs showed the same morphology, the same GNAQ/11, BAP1, and SF3B1 mutations, and the same chromosome 3 and 8q status as the corresponding patient samples. Six PDX models were challenged with two compounds for 4 weeks. We show that, for 31% of patients with high or intermediate risk of metastasis, the timing to obtain efficacy results on PDX models derived from their primary tumors was compatible with the selection of the therapy to treat the patient after relapse. PDXs could thus be a valid tool ("avatar") to select the best personalized therapy for one third of patients that are most at risk of relapse.
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- 2023
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39. Multi-omics comparison of malignant and normal uveal melanocytes reveals molecular features of uveal melanoma.
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Gentien D, Saberi-Ansari E, Servant N, Jolly A, de la Grange P, Némati F, Liot G, Saule S, Teissandier A, Bourc'his D, Girard E, Wong J, Masliah-Planchon J, Narmanli E, Liu Y, Torun E, Goulancourt R, Rodrigues M, Gaudé LV, Reyes C, Bazire M, Chenegros T, Henry E, Rapinat A, Bohec M, Baulande S, M'kacher R, Jeandidier E, Nicolas A, Ciriello G, Margueron R, Decaudin D, Cassoux N, Piperno-Neumann S, Stern MH, Gibcus JH, Dekker J, Heard E, Roman-Roman S, and Waterfall JJ
- Subjects
- Humans, Melanocytes metabolism, DNA, Antigens, Neoplasm genetics, Multiomics, Melanoma pathology
- Abstract
Uveal melanoma (UM) is a rare cancer resulting from the transformation of melanocytes in the uveal tract. Integrative analysis has identified four molecular and clinical subsets of UM. To improve our molecular understanding of UM, we performed extensive multi-omics characterization comparing two aggressive UM patient-derived xenograft models with normal choroidal melanocytes, including DNA optical mapping, specific histone modifications, and DNA topology analysis using Hi-C. Our gene expression and cytogenetic analyses suggest that genomic instability is a hallmark of UM. We also identified a recurrent deletion in the BAP1 promoter resulting in loss of expression and associated with high risk of metastases in UM patients. Hi-C revealed chromatin topology changes associated with the upregulation of PRAME, an independent prognostic biomarker in UM, and a potential therapeutic target. Our findings illustrate how multi-omics approaches can improve our understanding of tumorigenesis and reveal two distinct mechanisms of gene expression dysregulation in UM., Competing Interests: Declaration of interests P.d.l.G. is a co-founder of Genosplice technology. A.J. and R.G. are employees of Genosplice technology. R.M. is the founder of Cell Environment., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2023
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40. Nivolumab plus chemoradiotherapy in locally-advanced cervical cancer: the NICOL phase 1 trial.
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Rodrigues M, Vanoni G, Loap P, Dubot C, Timperi E, Minsat M, Bazire L, Durdux C, Fourchotte V, Laas E, Pouget N, Castel-Ajgal Z, Marret G, Lesage L, Meseure D, Vincent-Salomon A, Lecompte L, Servant N, Vacher S, Bieche I, Malhaire C, Huchet V, Champion L, Kamal M, Amigorena S, Lantz O, Chevrier M, and Romano E
- Subjects
- Humans, Female, Nivolumab therapeutic use, B7-H1 Antigen, Programmed Cell Death 1 Receptor, Chemoradiotherapy, Uterine Cervical Neoplasms drug therapy, Lung Neoplasms drug therapy
- Abstract
Concurrent chemoradiotherapy (CRT) with blockade of the PD-1 pathway may enhance immune-mediated tumor control through increased phagocytosis, cell death, and antigen presentation. The NiCOL phase 1 trial (NCT03298893) is designed to determine the safety/tolerance profile and the recommended phase-II dose of nivolumab with and following concurrent CRT in 16 women with locally advanced cervical cancer. Secondary endpoints include objective response rate (ORR), progression free survival (PFS), disease free survival, and immune correlates of response. Three patients experience grade 3 dose-limiting toxicities. The pre-specified endpoints are met, and overall response rate is 93.8% [95%CI: 69.8-99.8%] with a 2-year PFS of 75% [95% CI: 56.5-99.5%]. Compared to patients with progressive disease (PD), progression-free (PF) subjects show a brisker stromal immune infiltrate, higher proximity of tumor-infiltrating CD3
+ T cells to PD-L1+ tumor cells and of FOXP3+ T cells to proliferating CD11c+ myeloid cells. PF show higher baseline levels of PD-1 and ICOS-L on tumor-infiltrating EMRA CD4+ T cells and tumor-associated macrophages, respectively; PD instead, display enhanced PD-L1 expression on TAMs, higher peripheral frequencies of proliferating Tregs at baseline and higher PD-1 levels at week 6 post-treatment initiation on CD4 and CD8 T cell subsets. Concomitant nivolumab plus definitive CRT is safe and associated with encouraging PFS rates. Further validation in the subset of locally advanced cervical cancer displaying pre-existing, adaptive immune activation is warranted., (© 2023. The Author(s).)- Published
- 2023
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41. A druggable copper-signalling pathway that drives inflammation.
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Solier S, Müller S, Cañeque T, Versini A, Mansart A, Sindikubwabo F, Baron L, Emam L, Gestraud P, Pantoș GD, Gandon V, Gaillet C, Wu TD, Dingli F, Loew D, Baulande S, Durand S, Sencio V, Robil C, Trottein F, Péricat D, Näser E, Cougoule C, Meunier E, Bègue AL, Salmon H, Manel N, Puisieux A, Watson S, Dawson MA, Servant N, Kroemer G, Annane D, and Rodriguez R
- Subjects
- Animals, Mice, Macrophages drug effects, Macrophages immunology, Macrophages metabolism, Macrophages pathology, NAD metabolism, Mitochondria drug effects, Mitochondria metabolism, Hydrogen Peroxide metabolism, Epigenesis, Genetic drug effects, Metformin analogs & derivatives, Oxidation-Reduction, Macrophage Activation drug effects, Macrophage Activation genetics, Copper metabolism, Inflammation drug therapy, Inflammation genetics, Inflammation immunology, Inflammation metabolism, Inflammation pathology, Signal Transduction drug effects, Cell Plasticity drug effects, Cell Plasticity genetics
- Abstract
Inflammation is a complex physiological process triggered in response to harmful stimuli
1 . It involves cells of the immune system capable of clearing sources of injury and damaged tissues. Excessive inflammation can occur as a result of infection and is a hallmark of several diseases2-4 . The molecular bases underlying inflammatory responses are not fully understood. Here we show that the cell surface glycoprotein CD44, which marks the acquisition of distinct cell phenotypes in the context of development, immunity and cancer progression, mediates the uptake of metals including copper. We identify a pool of chemically reactive copper(II) in mitochondria of inflammatory macrophages that catalyses NAD(H) redox cycling by activating hydrogen peroxide. Maintenance of NAD+ enables metabolic and epigenetic programming towards the inflammatory state. Targeting mitochondrial copper(II) with supformin (LCC-12), a rationally designed dimer of metformin, induces a reduction of the NAD(H) pool, leading to metabolic and epigenetic states that oppose macrophage activation. LCC-12 interferes with cell plasticity in other settings and reduces inflammation in mouse models of bacterial and viral infections. Our work highlights the central role of copper as a regulator of cell plasticity and unveils a therapeutic strategy based on metabolic reprogramming and the control of epigenetic cell states., (© 2023. The Author(s).)- Published
- 2023
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42. Correction to: Human papilloma virus (HPV) integration signature in Cervical Cancer: identification of MACROD2 gene as HPV hot spot integration site.
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Kamal M, Lameiras S, Deloger M, Morel A, Vacher S, Lecerf C, Dupain C, Jeannot E, Girard E, Baulande S, Dubot C, Kenter G, Jordanova ES, Berns EMJJ, Bataillon G, Popovic M, Rouzier R, Cacheux W, Le Tourneau C, Nicolas A, Servant N, Scholl SM, and Bièche I
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- 2023
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43. The mutational landscape of skull base and spinal chordomas and the identification of potential prognostic and theranostic biomarkers.
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Passeri T, Gutman T, Hamza A, Adle-Biassette H, Girard E, Beaurepere R, Tariq Z, Mariani O, Dahmani A, Bourneix C, Abbritti R, Driouch K, Bohec M, Servant N, Baulande S, Decaudin D, Guichard JP, Calugaru V, Feuvret L, Guinebretière JM, Champion L, Bièche I, Froelich S, Mammar H, and Masliah-Planchon J
- Subjects
- Humans, Prognosis, Precision Medicine, Retrospective Studies, Neoplasm Recurrence, Local genetics, Neoplasm Recurrence, Local pathology, Biomarkers, Skull Base pathology, Class I Phosphatidylinositol 3-Kinases genetics, Chordoma pathology, Spinal Neoplasms genetics, Skull Base Neoplasms pathology
- Abstract
Objective: Chordomas are rare bone neoplasms characterized by a high recurrence rate and no benefit from any approved medical treatment to date. However, the investigation of molecular alterations in chordomas could be essential to prognosticate, guide clinical decision-making, and identify theranostic biomarkers. The aim of this study was to provide a detailed genomic landscape of a homogeneous series of 64 chordoma samples, revealing driver events, theranostic markers, and outcome-related genomic features., Methods: The authors conducted whole-exome sequencing (WES), targeted next-generation sequencing, and RNA sequencing of 64 skull base and spinal chordoma samples collected between December 2006 and September 2020. Clinical, histological, and radiological data were retrospectively analyzed and correlated to genetic findings., Results: The authors identified homozygous deletions of CDKN2A/2B, PIK3CA mutations, and alterations affecting genes of SWI/SNF chromatin remodeling complexes (PBRM1 and ARID1A) as potential theranostic biomarkers. Using matched germline WES, they observed a higher frequency of a common genetic variant (rs2305089; p.(Gly177Asp)) in TBXT (97.8%, p < 0.001) compared to its distribution in the general population. PIK3CA mutation was identified as an independent biomarker of short progression-free survival (HR 10.68, p = 0.0008). Loss of CDKN2A/2B was more frequently observed in spinal tumors and recurrent tumors., Conclusions: In the current study, the authors identified driver events such as PBRM1 and PIK3CA mutations, TBXT alterations, or homozygous deletions of CDKN2A/2B, which could, for some, be considered potential theranostic markers and could allow for identifying novel therapeutic approaches. With the aim of a future biomolecular prognostication classification, alterations affecting PIK3CA and CDKN2A/2B could be considered as poor prognostic biomarkers.
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- 2023
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44. Post-transcriptional polyadenylation site cleavage maintains 3'-end processing upon DNA damage.
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Sfaxi R, Biswas B, Boldina G, Cadix M, Servant N, Chen H, Larson DR, Dutertre M, Robert C, and Vagner S
- Subjects
- DNA Damage, RNA Precursors genetics, RNA Precursors metabolism, Chromatin, Polyadenylation, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism
- Abstract
The recognition of polyadenylation signals (PAS) in eukaryotic pre-mRNAs is usually coupled to transcription termination, occurring while pre-mRNA is chromatin-bound. However, for some pre-mRNAs, this 3'-end processing occurs post-transcriptionally, i.e., through a co-transcriptional cleavage (CoTC) event downstream of the PAS, leading to chromatin release and subsequent PAS cleavage in the nucleoplasm. While DNA-damaging agents trigger the shutdown of co-transcriptional chromatin-associated 3'-end processing, specific compensatory mechanisms exist to ensure efficient 3'-end processing for certain pre-mRNAs, including those that encode proteins involved in the DNA damage response, such as the tumor suppressor p53. We show that cleavage at the p53 polyadenylation site occurs in part post-transcriptionally following a co-transcriptional cleavage event. Cells with an engineered deletion of the p53 CoTC site exhibit impaired p53 3'-end processing, decreased mRNA and protein levels of p53 and its transcriptional target p21, and altered cell cycle progression upon UV-induced DNA damage. Using a transcriptome-wide analysis of PAS cleavage, we identify additional pre-mRNAs whose PAS cleavage is maintained in response to UV irradiation and occurring post-transcriptionally. These findings indicate that CoTC-type cleavage of pre-mRNAs, followed by PAS cleavage in the nucleoplasm, allows certain pre-mRNAs to escape 3'-end processing inhibition in response to UV-induced DNA damage., (© 2023 The Authors. Published under the terms of the CC BY 4.0 license.)
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- 2023
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45. Intratumoral microbiome is driven by metastatic site and associated with immune histopathological parameters: An ancillary study of the SHIVA clinical trial.
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Hilmi M, Kamal M, Vacher S, Dupain C, Ibadioune S, Halladjian M, Sablin MP, Marret G, Ajgal ZC, Nijnikoff M, Salomon A, El Beaino Z, Servant N, Dureau S, Sokol H, Nicolle R, Le Tourneau C, Bieche I, and Neuzillet C
- Subjects
- Humans, RNA, Ribosomal, 16S genetics, Lung, Breast, Bacteria, B7-H1 Antigen, Microbiota
- Abstract
Background: Data on the role of the microbiota in cancer have accumulated in recent years, with particular interest in intratumoral bacteria. Previous results have shown that the composition of intratumoral microbiome is different depending on the type of primary tumour and that bacteria from the primary tumour could migrate to metastatic sites., Methods: Seventy-nine patients with breast, lung, or colorectal cancer and available biopsy samples from lymph node, lung, or liver site, treated in the SHIVA01 trial were analysed. We performed bacterial 16S rRNA gene sequencing on these samples to characterise the intratumoral microbiome. We assessed the association between microbiome composition, clinicopathological characteristics, and outcomes., Results: Microbial richness (Chao1 index), evenness (Shannon index) and beta-diversity (Bray Curtis distance) were associated with biopsy site (p = 0.0001, p = 0.03 and p < 0.0001, respectively) but not with primary tumour type (p = 0.52, p = 0.54 and p = 0.82, respectively). Furthermore, microbial richness was inversely associated with tumour-infiltrating lymphocytes (TILs, p = 0.02), and PD-L1 expression on immune cells (p = 0.03), or assessed by Tumor Proportion Score (TPS, p = 0.02) or Combined Positive Score (CPS, p = 0.04). Beta-diversity was also associated with these parameters (p < 0.05). Patients with lower intratumoral microbiome richness had shorter overall survival (p = 0.03) and progression-free survival (p = 0.02) in multivariate analysis., Conclusion: Biopsy site, rather than primary tumour type, was strongly associated with microbiome diversity. Immune histopathological parameters such as PD-L1 expression and TILs were significantly associated with alpha and beta-diversity supporting the cancer-microbiome-immune axis hypothesis., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
- Published
- 2023
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46. DNA methylation and hydroxymethylation characterize the identity of D1 and D2 striatal projection neurons.
- Author
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Marion-Poll L, Roussarie JP, Taing L, Dard-Dascot C, Servant N, Jaszczyszyn Y, Jordi E, Mulugeta E, Hervé D, Bourc'his D, Greengard P, Thermes C, and Girault JA
- Subjects
- Corpus Striatum, Neurons, Epigenomics, DNA Methylation, Interneurons
- Abstract
Neuronal DNA modifications differ from those in other cells, including methylation outside CpG context and abundant 5-hydroxymethylation whose relevance for neuronal identities are unclear. Striatal projection neurons expressing D1 or D2 dopamine receptors allow addressing this question, as they share many characteristics but differ in their gene expression profiles, connections, and functional roles. We compare translating mRNAs and DNA modifications in these two populations. DNA methylation differences occur predominantly in large genomic clusters including differentially expressed genes, potentially important for D1 and D2 neurons. Decreased gene body methylation is associated with higher gene expression. Hydroxymethylation differences are more scattered and affect transcription factor binding sites, which can influence gene expression. We also find a strong genome-wide hydroxymethylation asymmetry between the two DNA strands, particularly pronounced at expressed genes and retrotransposons. These results identify novel properties of neuronal DNA modifications and unveil epigenetic characteristics of striatal projection neurons heterogeneity., (© 2022. The Author(s).)
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- 2022
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47. Relevance of the TRIAP1/p53 axis in colon cancer cell proliferation and adaptation to glutamine deprivation.
- Author
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Nedara K, Reinhardt C, Lebraud E, Arena G, Gracia C, Buard V, Pioche-Durieu C, Castelli F, Colsch B, Bénit P, Rustin P, Albaud B, Gestraud P, Baulande S, Servant N, Deutsch E, Verbavatz JM, Brenner C, Milliat F, and Modjtahedi N
- Abstract
Human TRIAP1 (TP53-regulated inhibitor of apoptosis 1; also known as p53CSV for p53-inducible cell survival factor) is the homolog of yeast Mdm35, a well-known chaperone that interacts with the Ups/PRELI family proteins and participates in the intramitochondrial transfer of lipids for the synthesis of cardiolipin (CL) and phosphatidylethanolamine. Although recent reports indicate that TRIAP1 is a prosurvival factor abnormally overexpressed in various types of cancer, knowledge about its molecular and metabolic function in human cells is still elusive. It is therefore critical to understand the metabolic and proliferative advantages that TRIAP1 expression provides to cancer cells. Here, in a colorectal cancer cell model, we report that the expression of TRIAP1 supports cancer cell proliferation and tumorigenesis. Depletion of TRIAP1 perturbed the mitochondrial ultrastructure, without a major impact on CL levels and mitochondrial activity. TRIAP1 depletion caused extramitochondrial perturbations resulting in changes in the endoplasmic reticulum-dependent lipid homeostasis and induction of a p53-mediated stress response. Furthermore, we observed that TRIAP1 depletion conferred a robust p53-mediated resistance to the metabolic stress caused by glutamine deprivation. These findings highlight the importance of TRIAP1 in tumorigenesis and indicate that the loss of TRIAP1 has extramitochondrial consequences that could impact on the metabolic plasticity of cancer cells and their response to conditions of nutrient deprivation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Nedara, Reinhardt, Lebraud, Arena, Gracia, Buard, Pioche-Durieu, Castelli, Colsch, Bénit, Rustin, Albaud, Gestraud, Baulande, Servant, Deutsch, Verbavatz, Brenner, Milliat and Modjtahedi.)
- Published
- 2022
- Full Text
- View/download PDF
48. Deciphering High-Resolution 3D Chromatin Organization via Capture Hi-C.
- Author
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Hauth A, Galupa R, Servant N, Villacorta L, Hauschulz K, van Bemmel JG, Loda A, and Heard E
- Subjects
- Mice, Animals, Chromosome Mapping methods, High-Throughput Nucleotide Sequencing methods, Genomics methods, Chromatin genetics, Chromosomes
- Abstract
The spatial organization of the genome contributes to its function and regulation in many contexts, including transcription, replication, recombination, and repair. Understanding the exact causality between genome topology and function is therefore crucial and increasingly the subject of intensive research. Chromosome conformation capture technologies (3C) allow inferring the 3D structure of chromatin by measuring the frequency of interactions between any region of the genome. Here we describe a fast and simple protocol to perform Capture Hi-C, a 3C-based target enrichment method that characterizes the allele-specific 3D organization of megabased-sized genomic targets at high-resolution. In Capture Hi-C, target regions are captured by an array of biotinylated probes before downstream high-throughput sequencing. Thus, higher resolution and allele-specificity are achieved while improving the time-effectiveness and affordability of the technology. To demonstrate its strengths, the Capture Hi-C protocol was applied to the mouse X-inactivation center (Xic), the master regulatory locus of X-chromosome inactivation (XCI).
- Published
- 2022
- Full Text
- View/download PDF
49. Genomics to select treatment for patients with metastatic breast cancer.
- Author
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Andre F, Filleron T, Kamal M, Mosele F, Arnedos M, Dalenc F, Sablin MP, Campone M, Bonnefoi H, Lefeuvre-Plesse C, Jacot W, Coussy F, Ferrero JM, Emile G, Mouret-Reynier MA, Thery JC, Isambert N, Mege A, Barthelemy P, You B, Hajjaji N, Lacroix L, Rouleau E, Tran-Dien A, Boyault S, Attignon V, Gestraud P, Servant N, Le Tourneau C, Cherif LL, Soubeyran I, Montemurro F, Morel A, Lusque A, Jimenez M, Jacquet A, Gonçalves A, Bachelot T, and Bieche I
- Subjects
- DNA Mutational Analysis, Disease Progression, Female, Genes, BRCA1, Genes, BRCA2, Humans, Phthalazines therapeutic use, Piperazines therapeutic use, Breast Neoplasms drug therapy, Breast Neoplasms genetics, Breast Neoplasms pathology, Clinical Decision-Making methods, Genome, Human genetics, Genomics, Neoplasm Metastasis drug therapy, Neoplasm Metastasis genetics, Neoplasm Metastasis pathology
- Abstract
Cancer progression is driven in part by genomic alterations
1 . The genomic characterization of cancers has shown interpatient heterogeneity regarding driver alterations2 , leading to the concept that generation of genomic profiling in patients with cancer could allow the selection of effective therapies3,4 . Although DNA sequencing has been implemented in practice, it remains unclear how to use its results. A total of 1,462 patients with HER2-non-overexpressing metastatic breast cancer were enroled to receive genomic profiling in the SAFIR02-BREAST trial. Two hundred and thirty-eight of these patients were randomized in two trials (nos. NCT02299999 and NCT03386162) comparing the efficacy of maintenance treatment5 with a targeted therapy matched to genomic alteration. Targeted therapies matched to genomics improves progression-free survival when genomic alterations are classified as level I/II according to the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT)6 (adjusted hazards ratio (HR): 0.41, 90% confidence interval (CI): 0.27-0.61, P < 0.001), but not when alterations are unselected using ESCAT (adjusted HR: 0.77, 95% CI: 0.56-1.06, P = 0.109). No improvement in progression-free survival was observed in the targeted therapies arm (unadjusted HR: 1.15, 95% CI: 0.76-1.75) for patients presenting with ESCAT alteration beyond level I/II. Patients with germline BRCA1/2 mutations (n = 49) derived high benefit from olaparib (gBRCA1: HR = 0.36, 90% CI: 0.14-0.89; gBRCA2: HR = 0.37, 90% CI: 0.17-0.78). This trial provides evidence that the treatment decision led by genomics should be driven by a framework of target actionability in patients with metastatic breast cancer., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2022
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- View/download PDF
50. Human papilloma virus integration sites and genomic signatures in head and neck squamous cell carcinoma.
- Author
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Mainguené J, Vacher S, Kamal M, Hamza A, Masliah-Planchon J, Baulande S, Ibadioune S, Borcoman E, Cacheux W, Calugaru V, Courtois L, Crozes C, Deloger M, Girard E, Delord JP, Dubray-Vautrin A, Larbi Chérif L, Dupain C, Jeannot E, Klijanienko J, Lameiras S, Lecerf C, Modesto A, Nicolas A, Rouzier R, Saada-Bouzid E, Saintigny P, Sudaka A, Servant N, Le Tourneau C, and Bièche I
- Subjects
- Carcinogenesis, DNA, Genomics, Humans, Kruppel-Like Transcription Factors, Papillomaviridae genetics, Retrospective Studies, Squamous Cell Carcinoma of Head and Neck genetics, Alphapapillomavirus, Carcinoma, Squamous Cell genetics, Carcinoma, Squamous Cell pathology, Head and Neck Neoplasms genetics, Oncogene Proteins, Viral genetics, Oncogene Proteins, Viral metabolism, Papillomavirus Infections complications, Papillomavirus Infections genetics, Papillomavirus Infections pathology
- Abstract
A prevalence of around 26% of human papillomavirus (HPV) in head and neck squamous cell carcinoma (HNSCC) has been previously reported. HPV induced oncogenesis mainly involving E6 and E7 viral oncoproteins. In some cases, HPV viral DNA has been detected to integrate with the host genome and possibly contributes to carcinogenesis by affecting the gene expression. We retrospectively assessed HPV integration sites and signatures in 80 HPV positive patients with HNSCC, by using a double capture-HPV method followed by next-generation Sequencing. We detected HPV16 in 90% of the analyzed cohort and confirmed five previously described mechanistic signatures of HPV integration [episomal (EPI), integrated in a truncated form revealing two HPV-chromosomal junctions colinear (2J-COL) or nonlinear (2J-NL), multiple hybrid junctions clustering in a single chromosomal region (MJ-CL) or scattered over different chromosomal regions (MJ-SC) of the human genome]. Our results suggested that HPV remained episomal in 38.8% of the cases or was integrated/mixed in the remaining 61.2% of patients with HNSCC. We showed a lack of association of HPV genomic signatures to tumour and patient characteristics, as well as patient survival. Similar to other HPV associated cancers, low HPV copy number was associated with worse prognosis. We identified 267 HPV-human junctions scattered on most chromosomes. Remarkably, we observed four recurrent integration regions: PDL1/PDL2/PLGRKT (8.2%), MYC/PVT1 (6.1%), MACROD2 (4.1%) and KLF5/KLF12 regions (4.1%). We detected the overexpression of PDL1 and MYC upon integration by gene expression analysis. In conclusion, we identified recurrent targeting of several cancer genes such as PDL1 and MYC upon HPV integration, suggesting a role of altered gene expression by HPV integration during HNSCC carcinogenesis., (© 2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)
- Published
- 2022
- Full Text
- View/download PDF
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