Translational research

Circulating biomarkers.

In collaboration with O. Lantz and the Circulating Tumor Biomarker group led by F.-C. Bidard, we developed several methods for ctDNA detection in different cancer types  ADDIN EN.CITE.DATA (1-12). Patents : 62331585, 173059205, 183052778.

 

Biomarkers of Homologous Recombination Deficiency (HRD ou BRCAness)

We have identified a signature of genomic instability related to the inactivation of HR (HR deficiency or HRD, also known as BRCAness), most often by inactivation of BRCA1 or BRCA2 (13); published patents: 123056483 and 61913637; exclusive licensing with Myriad Genetics, USA). This signature measures Large Scale State Transition (LST), the large number of which sign HRD. We have shown that LSTs correspond to inter-chromosomal translocations, developed a predictive signature of BRCA2 mutations, and confirmed the diagnostic interest of the LST signature in independent series of breast and ovarian cancers  ADDIN EN.CITE.DATA (14-26). This LST signature is part of the MyChoice HRD test from Myriad Genetics, the only FDA-approved test for HRD. Recent developments include adapting the LST signature from shallow Whole Genome Sequencing, for affordable and robust clinical diagnosis (27). Thanks to our expertise in HRD detection, we are participating to ancillary studies of several clinical trials, including Neopembrov, ROCSan, RadioPARP and TOPOLOGY.

 

Neoepitopes non conventionnels

In collaboration with S. Amigorena’s and O. Lantz’s teams, Inserm U932, we developed bioinformatics pipelines for analyzing aberrant transcripts and predicting public neo-epitopes (shared by tumors carrying similar phenotypes) (28). Patents : 19306064, 183058809 et 20305477. This work opens possible vaccinal strategies in this dismal disease.

 

T-Cell Prolymphocytic Leukemia

We discovered JAK2 and JAK3 mutations in this rare leukemia (29). We then participated to European collaboration led by M. Herling (Köln, Germany) and S. Mustjoki (Helsinki, Finland) on the molecular characterization and therapeutic development in this dismal leukemia (30-32).

 

1.   Silveira AB, Bidard FC, Kasperek A, et al. High-Accuracy Determination of Microsatellite Instability Compatible with Liquid Biopsies. Clin Chem 2020;66(4):606-613.

2.   Bidard FC, Kiavue N, Ychou M, et al. Circulating Tumor Cells and Circulating Tumor DNA Detection in Potentially Resectable Metastatic Colorectal Cancer: A Prospective Ancillary Study to the Unicancer Prodige-14 Trial. Cells 2019;8(6).

3.   Decraene C, Silveira AB, Bidard FC, et al. Multiple Hotspot Mutations Scanning by Single Droplet Digital PCR. Clin Chem 2018;64(2):317-328.

4.   Decraene C, Bortolini Silveira A, Michel M, et al. Single Droplet Digital Polymerase Chain Reaction for Comprehensive and Simultaneous Detection of Mutations in Hotspot Regions. J Vis Exp 2018; 10.3791/58051(139).

5.   Cabel L, Proudhon C, Romano E, et al. Clinical potential of circulating tumour DNA in patients receiving anticancer immunotherapy. Nat Rev Clin Oncol 2018;15(10):639-650.

6.   Riva F, Bidard FC, Houy A, et al. Patient-Specific Circulating Tumor DNA Detection during Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer. Clin Chem 2017;63(3):691-699.

7.   Saliou A, Bidard FC, Lantz O, et al. Circulating tumor DNA for triple-negative breast cancer diagnosis and treatment decisions. Expert Rev Mol Diagn 2016;16(1):39-50.

8.   Riva F, Dronov OI, Khomenko DI, et al. Clinical applications of circulating tumor DNA and circulating tumor cells in pancreatic cancer. Mol Oncol 2016;10(3):481-93.

9.   Madic J, Kiialainen A, Bidard FC, et al. Circulating tumor DNA and circulating tumor cells in metastatic triple negative breast cancer patients. Int J Cancer 2015;136(9):2158-65.

10. Lebofsky R, Decraene C, Bernard V, et al. Circulating tumor DNA as a non-invasive substitute to metastasis biopsy for tumor genotyping and personalized medicine in a prospective trial across all tumor types. Mol Oncol 2015;9(4):783-90.

11. Bidard FC, Madic J, Mariani P, et al. Detection rate and prognostic value of circulating tumor cells and circulating tumor DNA in metastatic uveal melanoma. Int J Cancer 2014;134(5):1207-13.

12. Madic J, Piperno-Neumann S, Servois V, et al. Pyrophosphorolysis-activated polymerization detects circulating tumor DNA in metastatic uveal melanoma. Clin Cancer Res 2012;18(14):3934-41.

13. Popova T, Manie E, Rieunier G, et al. Ploidy and large-scale genomic instability consistently identify basal-like breast carcinomas with BRCA1/2 inactivation. Cancer Res 2012;72(21):5454-62.

14. Jdey W, Thierry S, Popova T, et al. Micronuclei Frequency in Tumors Is a Predictive Biomarker for Genetic Instability and Sensitivity to the DNA Repair Inhibitor AsiDNA. Cancer Res 2017;77(16):4207-4216.

15. Manie E, Popova T, Battistella A, et al. Genomic hallmarks of homologous recombination deficiency in invasive breast carcinomas. Int J Cancer 2016;138(4):891-900.

16. Weigelt B, Ng CK, Shen R, et al. Corrigendum: metastatic breast carcinomas display genomic and transcriptomic heterogeneity. Mod Pathol 2015;28(4):607.

17. Goundiam O, Gestraud P, Popova T, et al. Histo-genomic stratification reveals the frequent amplification/overexpression of CCNE1 and BRD4 genes in non-BRCAness high grade ovarian carcinoma. Int J Cancer 2015;137(8):1890-900.

18. Curtit E, Benhamo V, Gruel N, et al. First description of a sporadic breast cancer in a woman with BRCA1 germline mutation. Oncotarget 2015;6(34):35616-24.

19. Gruel N, Benhamo V, Bhalshankar J, et al. Polarity gene alterations in pure invasive micropapillary carcinomas of the breast. Breast Cancer Res 2014;16(3):R46.

20. Pecuchet N, Popova T, Manie E, et al. Loss of heterozygosity at 13q13 and 14q32 predicts BRCA2 inactivation in luminal breast carcinomas. Int J Cancer 2013;133(12):2834-42.

21. Natrajan R, Mackay A, Lambros MB, et al. A whole-genome massively parallel sequencing analysis of BRCA1 mutant oestrogen receptor-negative and -positive breast cancers. J Pathol 2012;227(1):29-41.

22. Gentric G, Kieffer Y, Mieulet V, et al. PML-Regulated Mitochondrial Metabolism Enhances Chemosensitivity in Human Ovarian Cancers. Cell Metab 2019;29(1):156-173 e10.

23. Golmard L, Castera L, Krieger S, et al. Contribution of germline deleterious variants in the RAD51 paralogs to breast and ovarian cancers. Eur J Hum Genet 2017;25(12):1345-1353.

24. Coussy F, El-Botty R, Chateau-Joubert S, et al. BRCAness, SLFN11, and RB1 loss predict response to topoisomerase I inhibitors in triple-negative breast cancers. Sci Transl Med 2020;12(531).

25. Labidi-Galy SI, Olivier T, Rodrigues M, et al. Location of Mutation in BRCA2 Gene and Survival in Patients with Ovarian Cancer. Clin Cancer Res 2018;24(2):326-333.

26. Golmard L, Delnatte C, Lauge A, et al. Breast and ovarian cancer predisposition due to de novo BRCA1 and BRCA2 mutations. Oncogene 2016;35(10):1324-7.

27. Eeckhoutte A, Houy A, Manie E, et al. ShallowHRD: detection of homologous recombination deficiency from shallow whole genome sequencing. Bioinformatics 2020;36(12):3888-3889.

28. Bigot J, Lalanne AI, Lucibello F, et al. Splicing patterns in SF3B1 mutated uveal melanoma generate shared immunogenic tumor-specific neo-epitopes. Cancer Discov 2021; 10.1158/2159-8290.CD-20-0555.

29. Bellanger D, Jacquemin V, Chopin M, et al. Recurrent JAK1 and JAK3 somatic mutations in T-cell prolymphocytic leukemia. Leukemia 2014;28(2):417-9.

30. Wahnschaffe L, Braun T, Timonen S, et al. JAK/STAT-Activating Genomic Alterations Are a Hallmark of T-PLL. Cancers (Basel) 2019;11(12).

31. Schrader A, Crispatzu G, Oberbeck S, et al. Actionable perturbations of damage responses by TCL1/ATM and epigenetic lesions form the basis of T-PLL. Nat Commun 2018;9(1):697.

32. Andersson EI, Putzer S, Yadav B, et al. Discovery of novel drug sensitivities in T-PLL by high-throughput ex vivo drug testing and mutation profiling. Leukemia 2018;32(3):774-787.