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