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Caractérisation anatomo-clinique et phénotypique des adénocarcinomes canalaires du pancréas avec instabilité des microsatellites

Renato Micelli Lupinacci 1
1 Inserm UMR_S 938 - Pathologies biliaires, fibrose et cancer du foie
CR Saint-Antoine - Centre de Recherche Saint-Antoine, CHU Saint-Antoine [AP-HP]
Abstract : Pancreatic ductal adenocarcinoma (PDAC) is a major health problem in France and around the world. PDAC is developed mainly from two precursor lesions: pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasm (IPMN). There are several molecular mechanisms underlying pancreatic oncogenesis. Particularly, we were interested in the MSI (MicroSatellite Instability) which is due to a defective DNA Mismatch Repair (MMR) system, which normally functions to recognize and repair erroneous insertions, deletions, and mis-incorporation of bases that can arise during DNA replication and recombination. The MSI phenotype was first described in the familial cancer condition known as Lynch syndrome (LS), where the MMR genes MLH1, MSH2, MSH6 or PMS2 harbor germline mutations. Interest in MSI tumors has recently increased after studies have highlighted the concomitant expression of multiple active immune checkpoint (ICK) markers including PD-1 and PD-L1 and the role of the MSI status to predict clinical benefit from immune checkpoint blockade. A Our results indicate that the MSI phenotype occurs in PDAC with a frequency of 1-2%. Our data showed that IHC using antibodies against the four MMR proteins was more sensitive for the assessment of MSI status than PCR-based methods. In addition, we demonstrate for the first time a statistically significant positive association between MSI and IPMNs in PDAC. MSI PDAC, including IPMN, are unlikely to be sporadic since they display molecular features that are usually observed in LS-related neoplasms. Also, our results highlight that an MSI-driven immunogenic pathway to cancer is active in MSI PDACs but suggest that MSI-driven somatic events may be tissue-specific. We observed a stronger lymphocytic tumor infiltration by activated TCD8 cells in MSI PDAC compared to MSS PDAC and found a positive association between PD-L1 expression and MSI status, suggesting that MSI PDAC could be responsive to ICK blockade therapy.
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Submitted on : Thursday, March 1, 2018 - 11:56:08 AM
Last modification on : Sunday, October 25, 2020 - 2:40:28 PM
Long-term archiving on: : Wednesday, May 30, 2018 - 1:12:16 PM


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  • HAL Id : tel-01720460, version 1


Renato Micelli Lupinacci. Caractérisation anatomo-clinique et phénotypique des adénocarcinomes canalaires du pancréas avec instabilité des microsatellites. Cancer. Université Pierre et Marie Curie - Paris VI, 2017. Français. ⟨NNT : 2017PA066311⟩. ⟨tel-01720460⟩



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