Virtual Library

Start Your Search

Francoise Galateau-Salle



Author of

  • +

    MS25 - Genetic and Prognostic Markers in Mesothelioma; Going Beyond the Histology Subtypes (ID 803)

    • Event: WCLC 2018
    • Type: Mini Symposium
    • Track: Mesothelioma
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/26/2018, 10:30 - 12:00, Room 206 AC
    • +

      MS25.02 - How Should P16, BAP1, and NF2 Mutations Be Integrated in Therapeutic Algorithms? (Now Available) (ID 11507)

      10:45 - 11:00  |  Presenting Author(s): Francoise Galateau-Salle

      • Abstract
      • Presentation
      • Slides

      Abstract

      Malignant mesothelioma (MM) is a rare cancer with a natural history of 7–9 months if untreated and a 5-year survival rate of less than 5% for the epithelioid and 0% for the biphasic and sarcomatoid types. MPM aggressiveness is strongly associated with histological differentiation (2017 -MESOPATH data). Up to now there are no curable available therapeutic options but patients treated with avastin, cisplatin, pemetrexed, or targeting angiogenesis (bevacizumab) may present a median longer survival by few months. However for epithelioid type depending of the TNM stage of the disease surgery remains a therapeutic option that may increase overall survival depending on the radiological volume and tumor thickness. Additionally, in 2017 the immune checkpoints inhibitors have been evaluated in unresectable malignant pleural mesothelioma [MPM] and recent preliminary data using immunotherapy combination have demonstrated a potential efficacy for second line therapy. Moreover, recent trials using drug that target the epigenome such as the enhancer of zest homolog 2(EZH2) was expected to bring the promise of a better survival for patient harboring BAP1 mutations.

      These data showed the extreme importance of an accurate histopathological diagnosis in the management of the patient and the urgent need of more effective treatments. The 2015 WHO classification have upgraded the histological diagnosis of MPM in separating the epithelioid from the non-epithelioid types for a better prognostication. The second most important challenge is the separation of benign reactive mesothelial hyperplasia and malignant epithelioid mesothelioma and the need of molecular markers to select the best treatment strategy at an early stage when the treatment can prevent the spread of the disease. In 2018, a recent IASLC-EURACAN multidisciplinary meeting in Lyon, France, reported the most common genomic advances in MPM that may change routine practice and management of patient.

      Development of genomic analysis has reported the most frequent genomic alterations observed in malignant pleural mesothelioma and new advances for diagnosis and prognostication. The genomic landscape of MPM rest on inactivating mutations in several tumor suppressors genes. CDKN2A (p16), BAP1 and NF2 are the three most frequent genomic alterations observed in MPM. BAP1 is a tumor suppressor gene located in chromosome band 3p2.1 that encodes BRCA1 -associated protein 1 which belongs to the ubiquitin C-terminal hydrolase subfamily of deubiquitinating enzymes removing ubiquitin from proteins and also from histone H2A which is important for coordination of cell proliferation. Moreover BAP1 enzymes bind to the BRCA1 protein via its RING finger domain and are involved in regulation of the cell cycle, cellular growth, regulation of DNA transcription, response to DNA damage and chromatin remodeling. BAP1 alterations follow the classic two hit paradigm so one mutant allele which is present in all cells just need the other mutant allele by somatic inactivation to trigger transformation. The mutational status of BAP1 can be very easily assessed by immunohistochemistry on biopsy tissue and cytology samples by showing a lack of nuclear staining with a positive control observed on the adjacent normal cells is very easy and accurate to perform. BAP1 loss of expression is observed in approximately 60% of MPM, mostly on the epithelioid type. BAP1 is one of the most important tumor suppressor genes which inactivation will contribute in treatment decision; first as a molecular marker for separating chronic pleuritis, or benign reactive atypical mesothelial hyperplasia from malignant pleural epithelioid mesothelioma allowing a diagnosis of in situ mesothelioma which may favor early treatment to prevent the spread of the disease; second, BAP1 loss which results from increased trimethylated histone H3 lysine 27 (H3K27me3, increased enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) expression and enhanced repression of polycomb repressive complex2 (PCR) targets. Preclinical models of EZH2 inhibition have showed a benefit in malignant pleural mesothelioma presenting BAP1 loss. A phase II clinical trials evaluating the EZH2 inhibitor tazemetostat in MPM is ongoing. Additionally, a new alternative splice isoform of BAP1 has been reported to regulate DNA damage response and to influence drug sensitivity. BAP1 loss play also a role in prognostication, these patients having a much better prognosis. Another driver mutation is the CDKN2A gene located in chromosome 9p21 encoding p14 ARF and p16 INK4a which through p14 ARF interacts with MDM2 leading to MDM2 degradation and activation of p53 . In consequence loss of p14 ARF favor cell survival. On the other way loss of p16 INK4a leads to inhibition of the retinoblastoma pathway and to cell progression. CDKN2A(p16) is observed by FISH analysis in nearly 50% of malignant pleural mesothelioma to more than 80% in sarcomatoid and desmoplastic mesothelioma A large number of publications have confirmed that CDKN2A(P16) homozygous deletion by FISH testing is an accurate marker of malignancy playing a major role in the separation of benign reactive mesothelial hyperplasia versus epithelioid malignant pleural mesothelioma and more interestingly in the separation of diffuse chronic pleural fibrosis from sarcomatoid MPM.

      Finally the last more common driver mutation, the neurofibromin 2 gene (NF2) located at chromosome 22q12 encodes the merlin protein which regulates the hippo pathway. Next generation sequencing has showed alterations in NF2 in 20 to 50% of MPLM and In consequence the loss of NF2 results in cell proliferation and survival. The potential utility of NF2 loss was evaluated using immunohistochemistry by Sheffield et al, showing that the incidence of NF2 immunohistochemical staining was not helpful for the diagnosis of mesothelioma with a sensitivity of 4%. However, recent investigation has showed that defactinib a focal adhesion kinase (FAK) inhibitor may have a potential action on the NF2 pathway for blocking cell survival.

      The diverse molecular events are not exclusive and it should be expected that additional mutations may play a role in treatment sensitivity. BAP1, NF2 and p16 are the main tumor suppressor genes involve in mesothelioma important to evaluate for diagnosis, prognostication and treatment decision. Therapeutic algorithms will be presented during the session.

      References

      Ladanyi M, Zauderer MG, Krug LM, Ito T, McMillan R, Bott M, Giancotti F. New strategies in pleural mesothelioma: BAP1 and NF2 as novel targets for therapeutic development and risk assessment.Clin Cancer Res. 2012 Sep 1;18(17):4485-90

      McCambridge AJ, Napolitano A, Mansfield AS, Fennell DA, Sekido Y, Nowak AK, Reungwetwattana T, Mao W, Pass HI, Carbone M, Yang H, Peikert T. Progress in the Management of Malignant Pleural Mesothelioma in 2017. J Thorac Oncol. 2018 May;13(5):606-623

      Churg A, Sheffield BS, Galateau-Salle F. New markers for separating benign from malignant mesothelial proliferations: are we there yet?Arch Pathol Lab Med. 2016;140(4):318–321.

      Sheffield BS, Hwang HC, Lee AF, et al. BAP1 immunohistochemistry and p16 FISH to separate benign from malignant mesothelial proliferations. Am J Surg Pathol. 2015;39(7):977–98

      Baumann F, Flores E, Napolitano A, Kanodia S, Taioli E, Pass H, Yang H, Carbone M. Mesothelioma patients with germline BAP1 mutations have 7-fold improved long-term survival. Carcinogenesis. 2015 Jan;36(1):76-81.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

    WS02 - Mesothelioma Workshop (ID 996)

    • Event: WCLC 2018
    • Type: Workshop
    • Track: Mesothelioma
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/23/2018, 08:00 - 11:15, Room 205 AC
    • +

      WS02.05 - Reliability of MM Diagnosis and Role of BAP1 Staining (Now Available) (ID 14749)

      08:45 - 09:00  |  Presenting Author(s): Francoise Galateau-Salle

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.