"Genetic determinants of tumor microenvironment in high grade serous ovarian carcinomas (2021-11-STERN_RODRIGUES)" project details

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2021-11-STERN_RODRIGUES

Genome-wide Association study (GWAS); Ovarian carcinoma, Tumor micro-environment; Cancer-associated Fibroblast; Immune reaction

Genetic determinants of tumor microenvironment in high grade serous ovarian carcinomas

Director(s) and team

Marc-Henri STERN & Manuel RODRIGUES

DNA Repair and Uveal Melanoma

Abstract

Description of the PhD thesis project
Half of patients with high-grade serous ovarian carcinomas (HGSC) will suffer recurrence in < 2 years. Immune checkpoint inhibitors (ICI) have shown a limited clinical activity, while HGSC is frequently associated with immune cell infiltration.  

It is crucial to identify the patients that will benefit from ICI, and to understand the mechanisms of resistance to circumvent them. Composition of the tumor microenvironment (TME), including tumor-infiltrating lymphocytes (TILs) and Cancer-associated Fibroblasts (CAFs), was found highly heterogeneous with immune-suppressive and stimulatory subsets. Constitutional genetic variants have been associated with different immune responses.  

Tumor genetic aberrations may also contribute to TME: high tumor mutation burden is associated with response to ICI, and BRCA1/2 inactivation (~50% HGSC) activates the cGAS-GAMP-STING pathway, inducing an interferon response. Intra-tumor and inter-individual heterogeneity of TME in complex association with tumor and patient genetic background defines puzzling landscape of HGSC to decipher in this project.  

We hypothesize that constitutional variants and/or tumor genetic and genomic explain largely the composition of TME.  

Objective 1: exploring the correlation between TILs/CAF infiltrations and genetic constitutional variants.
Objective 2: exploring the correlation between TILs/CAF infiltrations and somatic genetic alterations.
Objective 3: integrating constitutional and somatic variants to create a model predicting TME heterogeneity.  

Objectives 1 and 2 will consist in:
(i) estimating the correlation between these factors and TME composition in two datasets: the ~600 cases from TCGA used as discovery set and an in-house validation set consisting of ~150 HGSC characterized samples and,
(ii) unraveling cellular processes implicated in the regulation of TME composition,
(iii) retrospectively explore these factors as potential biomarkers of response to immune checkpoints in clinical trials.

International, interdisciplinary & intersectoral aspects of the project
Longstanding collaboration with the NCI-NIH, with outstanding expertise in GWAS. M. Machiela, expert in the field, will mentor the PhD student for analyses. Visits will be proposed to NCI-NIH.  

Longstanding experience of the team in developing molecular and bioinformatics tools for diagnostic and biomarkers, with 7 patents, one licensed to Myriad Genetics and commercialized as MyChoiceHRD. P. Korman, Vice President International at Myriad Genetics will guide the PhD student and advice for valorization.  

Project linking biology, medicine and mathematics. Our team includes two MD-PhD, one being medical oncologist responsible for clinical trials in gynecology, and a senior scientist, T. Popova, with a strong background in mathematics and expertise in bioinformatics and data mining.

Recent publications
1. Derrien AC, Rodrigues M, Eeckhoutte A, Dayot S, Houy A, Mobuchon L, Gardrat S, Lequin D, Ballet S, Pierron G, Alsafadi S, Mariani O, El-Marjou A, Matet A, Colas C, Cassoux N, Stern MH. Germline MBD4 mutations and predisposition to uveal melanoma. J Natl Cancer Inst. 2020 Apr 1:djaa047. PMID: 32239153.  

2. Rodrigues M, Mobuchon L, Houy A, Fiévet A, Gardrat S, Barnhill RL, Popova T, Servois V, Rampanou A, Mouton A, Dayot S, Raynal V, Galut M, Putterman M, Tick S, Cassoux N, Roman-Roman S, Bidard FC, Lantz O, Mariani P, Piperno-Neumann S, Stern MH. Outlier response to anti-PD1 in uveal melanoma reveals germline MBD4 mutations in hypermutated tumors. Nat Commun. 2018; 9:1866. PMID: 29760383.  

3.  Mobuchon L, Battistella A, Bardel C, Scelo G, Renoud A, Houy A, Cassoux N, Milder M, Cancel-Tassin G, Cussenot O, Delattre O, Besse C, Boland A, Deleuze JF, Cox DG, Stern MH. A GWAS in uveal melanoma identifies risk polymorphisms in the CLPTM1L locus. NPJ Genom Med, 2017; 2(1). PMID: 28781888.  

4. Mobuchon L, Battistella A, Bardel C, Scelo G, Renoud A, Houy A, Cassoux N, Milder M, Cancel-Tassin G, Cussenot O, Delattre O, Besse C, Boland A, Deleuze JF, Cox DG, Stern MH. A GWAS in uveal melanoma identifies risk polymorphisms in the CLPTM1L locus. NPJ Genom Med, 2017; 2(1). PMID: 28781888.  

5. Popova T, Manié E, Boeva V, Battistella A, Goundiam O, Smith NK, Mueller CR, Raynal V, Mariani O, Sastre-Garau X, Stern MH. Ovarian cancers harboring inactivating mutations in CDK12 display a distinct genomic instability pattern characterized by large tandem duplications. Cancer Research, 2016; 76:1882. PMID: 26787835

Requirements to apply for the PhD thesis project

As the project is mainly based on bioinformatics and biostatistics analyses, we expect a bioinformatic and biostastic strong background of the candidate, together with good background and interest in oncogenesis and genetics.

The EuReCa Program is in English.

For more information about the eligibility criteria, please check the EuReCa webpage