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PROJET MSICARE

Détection de l’Instabilité Microsatellitaire dans les Cancers Humains Défectifs en Réparation des Erreurs de Réplication de l’ADN (Tumeurs MSI) par Séquençage de Nouvelle Génération (NGS)

Ce projet est porté par l’Inserm UMRS 938 – Centre de Recherche Saint-Antoine (CRSA).

CONTEXT

Mismatch repair (MMR) deficient tumors display a molecular phenotype referred to as MSI (for Microsatellite Instability). MSI status was recently shown to predict clinical benefit from immune checkpoint inhibitors (ICI) in patients. These observations and others have led to international guidelines recommending universal MSI screening of all newly diagnosed tumors regardless of the primary tissue of origin. Today, molecular methods using PCR to detect the MSI phenotype are not very efficient, except in canonical tumor locations (colon, stomach). They do not allow to adapt to the current clinical situation which requires that this biomarker be reliably identified in pan-cancer and even in liquid biopsies (blood, others), in particular at the metastatic stage. Thus, the acquisition of a simple, reliable, highly sensitive and specific molecular method for diagnosing MSI in pan-cancer is today an urgent unmet clinical need. In the present project, we want to propose a bioinformatics algorithm, namely MSICare, as a high-performance diagnostic tool for the diagnosis of MSI in in pan-Cancer using next generation sequencing (NGS). Thanks to an exceptional clinical network and a unique genomic expertise in the field of MSI cancer research, our team has the possibility to propose the construction of such a tool in a short time (3 years) within the framework of an ambitious project based on the screening of a very large number of perfectly annotated normal and tumor samples coming from numerous primary locations. Importantly, some refinements of this diagnostic algorithm will be considered in the project, so that it will be able to identify the MSI status of a tumor sample without reference to matching healthy tissue, which is a major technological milestone in the clinic. Finally, we intend to implement this algorithm so that it will also be efficient to detect MSI on circulating tumor DNA, outside the primary tumor site (blood sample).

OBJECTIVES

In brief, the aims of the present project are as follows:

  1. To demonstrate that MSICare is performant to diagnose MSI in pan-cancer from the analysis of paired tumor and matched normal DNAs (Primary objective 1, PO1). The level of genomic instability is highly variable in dMMR tumors. It depends in part on the MMR gene defect (e.g. low level of MSI in MSH6-deficient [dMSH6] tumors) and the tissue origin of the cancer (e.g. low instability in dMMR glioblastomas compared to gastrointestinal tumors) 33. Thus, MSICare thresholds for detecting MSI in tumors will have to take into account the tumor origin and dMMR setting;
  2. To design an optimized MSICare tool for identifying MSI in samples (ctDNA, primary tumors) without referencing to matched normal DNAs whenever possible (primary objective 2, PO2). As previously done with the pentaplex, the reference to healthy tissue to detect MSI in tumor DNA can be dispensed with if a prior analysis of the polymorphism of each microsatellite in human populations. The opportunity to detect MSI from the isolated tumor DNA by NGS will offer the possibility of an easier detection of this biomarker in cancer patients, like for other tumor biomarkers that are currently detected in clinical oncology by NGS without analysis of the corresponding healthy DNA. This will simplify the sample circuit, limit identity control problems and reduce costs, and will facilitate as mentioned above the integration of MSI detection using NGS in clinical routine at a time when the search for other somatic biomarkers in human cancers does not require the use of normal DNA;
  3. To demonstrate that MSICare is also effective for detecting MSI in liquid biopsies from the analysis of circulating tumor DNAs (ctDNAs, primary objective 3, PO3). The invasive nature and specific prerequisite of MSI- PCR and MMR-IHC tests might hinder their application when surgery is not an option or when the tumor tissues are insufficient. The application of NGS, which is highly sensitive, in combination with liquid biopsy to extract ctDNA whenever possible, therefore, presents an interesting possibility that we plan to explore. Moreover, post-diagnosis MSI testing is today more and more recommended for both hereditary syndrome screening as well as prognosis and treatment implications in MSI cancer patients, especially in the metastatic settings for detection of resistance and/or relapse in patients treated with ICI (fore review, see 11).

Overall, the envisioned application of this translational research program is to design a new bioinformatics software which will allow optimal detection of MSI in pan-Cancer, including tumors where this phenotype is scarce and/or difficult to diagnose using the current molecular standard approach (MSI PCR). Primary endpoints will be sensitivity, specificity, positive and negative predictive values. If accuracy is validated, the use of the new MSICare software will represent a major breakthrough for precision medicine of patients with MSI/dMMR tumors in pan-cancer, especially in metastatic settings to improve the prescription of ICI.

RESULTS

During this first year, we made a special effort to recruit the cohorts needed to develop the program. At the 3 sites (Paris, Toulouse, Lille), a prospective search for dMMR/MSI cases of interest was intensively carried out in panCancer. Several new recruitments have been made for this phase, which will continue (see financial appendix). Today, we are in a position to plan a complete bioinformatic analysis of cohorts from the colon, stomach and endometrium (more than 1,200 dMMR/MSI tumors overall for these 3 primary tumor locations) which were sequenced both by WES and using a targeted MSIDiag panel (441 Micorsatellite Markers, cf. Ratovomanana et al., Gastroenterology 2021). In addition, we have made significant progress towards the aim of being able to analyze MSI instability in tumors without the need for corresponding healthy tissue. Finally, we were able to use ctDNA (circulating tumor DNA) samples to analyze the possibility of validating MSI status in the blood of patients with metastatic colorectal cancer (NIPICOL cohort). These very significant advances enable us to envisage the possibility of publishing these results in the near future, particularly for the colon site (i.e., publication of the algorithm without associated healthy tissue and navalization analysis in ctDNA). We can also reasonably expect to publish our results for gastric and endometrial sites shortly. Importantly, the MSICare tool has also been used in 2023 in the context of other work from the team already accepted for publication (Ratovomanana et al., Ann Oncol 2023, IF 54) or submitted (Jonchere et al., submitted to Genome Biology, IF 18).

It is worth noting that in connection with the development of this research program, we have founded the startUp MSInsight, which has purchased a license to exploit the MSIcare panCancer patent. This biotech company will be a key factor in helping us to capitalize on the academic work carried out by the Inserm team, thanks to the financial support of the MSDAvenir foundation.`

Very importantly, this year was also used to draft the regulatory part of our program (research protocol, patient information note, MR004 context outside the Jaer law, etc.).

RECENT PUBLICATIONS

  1. Ratovomanana T, Nicolle R, Cohen R, Diehl A, Siret A, Letourneur Q, Buhard O, Perrier A, Guillerm E, Coulet F, Cervera P, Benusiglio P, Labrèche K, Colle R, Collura A, Despras E, Le Rouzic P, Renaud F, Cros J, Alentorn A, Touat M, Ayadi M, Bourgoin P, Prunier C, Tournigand C, Fouchardière C, Tougeron D, Jonchère V, Bennouna J, de Reynies A, Fléjou JF, Svrcek M, André T, Duval A. Prediction of response to immune checkpoint blockade in patients with metastatic colorectal cancer with microsatellite instability. Ann Oncol. 2023 Aug;34(8):703-713. doi: 10.1016/j.annonc.2023.05.010. Epub 2023 Jun 1.PMID: 37269904 Free PMC article 
  2. Benusiglio PR, Elder F, Touat M, Perrier A, Sanson M, Colas C, Guerrini-Rousseau L, Tran DT, Trabelsi N, Carpentier C, Marie Y, Adam C, Bernier M, Cazals-Hatem D, Mokhtari K, Tran S, Mathon B, Capelle L, Dhooge M, Idbaih A, Alentorn A, Houillier C, Dehais C, Hoang-Xuan K, Cuzzubbo S, Carpentier A, Duval A, Coulet F, Bielle F. Mismatch Repair Deficiency and Lynch Syndrome Among Adult Patients With Glioma. JCO Precis Oncol. 2023 May;7:e2200525. doi: 10.1200/PO.22.00525.PMID: 37262394
  3. Vibert R, Hasnaoui J, Perrier A, Lefebvre A, Colas C, Dhooge M, Basset N, Chansavang A, Desseignes C, Duval A, Farelly S, Hamzaoui N, Laurent-Puig P, Metras J, Moliere D, Muleris M, Netter J, Touat M, Bielle F, Labreche K, Nicolle R, Perkins G, Warcoin M, Coulet F, Benusiglio PR. Lynch syndrome: influence of additional susceptibility variants on cancer risk. Eur J Hum Genet. 2023 Sep;31(9):1078-1082. doi: 10.1038/s41431-023-01367-z. Epub 2023 Apr 24.PMID: 37088804 Free PMC article
  4. Colle R, Lonardi S, Cachanado M, Overman MJ, Elez E, Fakih M, Corti F, Jayachandran P, Svrcek M, Dardenne A, Cervantes B, Duval A, Cohen R, Pietrantonio F, André T. BRAF V600E/RAS Mutations and Lynch Syndrome in Patients With MSI-H/dMMR Metastatic Colorectal Cancer Treated With Immune Checkpoint Inhibitors. Oncologist. 2023 Apr 6:oyad082. doi: 10.1093/oncolo/oyad082. Online ahead of print.PMID: 37023721 Free PMC article
  5. Dorard C, Madry C, Buhard O, Toifl S, Didusch S, Ratovomanana T, Letourneur Q, Dolznig H, Garnett MJ, Duval A, Baccarini M. RAF1 contributes to cell proliferation and STAT3 activation in colorectal cancer independently of microsatellite and KRAS status. Oncogene. 2023 May;42(20):1649-1660. doi: 10.1038/s41388-023-02683-w. Epub 2023 Apr 5.PMID: 37020037 
  6. Hernández-Verdin I, Akdemir KC, Ramazzotti D, Caravagna G, Labreche K, Mokhtari K, Hoang-Xuan K, Peyre M, Bielle F, Touat M, Idbaih A, Duval A, Sanson M, Alentorn A. Pan-cancer landscape of AID-related mutations, composite mutations, and their potential role in the ICI response. NPJ Precis Oncol. 2022 Dec 1;6(1):89. doi: 10.1038/s41698-022-00331-2.PMID: 36456685 Free PMC article.
  7. Noel K, Bokhari A’, Bertrand R, Renaud F, Bourgoin P, Cohen R, Svrcek M, Joly AC, Duval A, Collura A. Consequences of the Hsp110DE9 mutation in tumorigenesis and the 5- fluorouracil-based chemotherapy response in Msh2-deficient mice. Cell Mol Life Sci. 2022 Jun 1;79(6):332. doi: 10.1007/s00018-022-04293-3.PMID: 35648235 
  8. Favier A, Varinot J, Uzan C, Duval A, Brocheriou I, Canlorbe G. The Role of Immunohistochemistry Markers in Endometrial Cancer with Mismatch Repair Deficiency: A Systematic Review. Cancers (Basel). 2022 Aug 3;14(15):3783. doi: 10.3390/cancers14153783.PMID: 35954447 Free PMC article.
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