Author of

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  MA23 - Preclinical Models and Genetics of Malignant Pleural Mesothelioma (ID 353)

  • Event: WCLC 2019
  • Type: Mini Oral Session
  • Track: Mesothelioma
  • Presentations: 1
  • Now Available
  • Moderators:Ramon Palmero Sánchez, Raphael Bueno
  • Coordinates: 9/10/2019, 14:30 - 16:00, Copenhagen (1980)

  • 32426

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    MA23.10 - Low Number of Mutations and Frequent Co-Deletions of CDKN2A and IFN Type I Characterize Malignant Pleural Mesothelioma (Now Available) (ID 1627)

    14:30 - 16:00  |  Author(s): Shir Kiong Lu
    • Abstract
    • Presentation
    • Slides

    Background
    

    Malignant pleural mesothelioma (MPM) is an aggressive tumour with dismal prognosis and overall survival.

    To expand our understanding of molecular background of MPM and to identify novel targetable aberrations we report an integrated genomic analysis of 121 tumour samples.

    Method
    

    Fresh-frozen tumour samples (obtained from Mesobank UK,the BLF funded Mick Knighton Mesothelioma Tissue Bank, Respiratory BRU Biobank Diagnostic Archive, Royal Brompton Hospital and an Imperial College London prospective study) were analysed by whole exome sequencing (WES, n=50), SNP genotyping (n=118) and targeted capture sequencing (n=119) for 57 genes.

    Sequencing libraries were prepared using Target Enrichment Systems for the Illumina Multiplexed Sequencing platform. Somatic mutations were called using VarScan after recalibration of alignments by Genome Analysis Toolkit (GATK). SNP genotyping was performed with the Human Infinium Omni-Express-Exome v1.3/1.4 Bead Chips arrays. Segmentation and copy number calling was performed using a combination of Allelic specific copy number analysis of tumour (ASCAT), DNACopy and GISTIC softwares.

    Result
    

    Analysis of WES paired samples revealed a median of 31 non-synonymous somatic mutations per tumour, lower than melanoma (315 somatic mutations) or lung cancer (187.5 for squamous and 158 for adenocarcinoma), two types of tumours linked to known carcinogen exposure.

    Investigation of copy number showed significant frequent deletion (q-value>0.05) of 9p21 locus where CDKN2A, MTAP and IFN type I genes are located. Deletion of CDKN2A was seen in 71/121 patients with homozygous deletion in 58/71 patients. Homozygous co-deletion of CDKN2A and IFN type I was seen in 38/58 patients, homozygous codeletion with MTAP in 49/58 patients while 37 patients showed all three as homozygous co-deleted.

    Patients with CDKN2A and IFN type I deletions had worse overall survival compared with the CDKN2A wild type and patients CDKN2A only deleted patients (median 8.3 months vs 13.1 months, p-value=0.016).

    Deletion of 3p21.1 locus and mutations in BAP1 were detected in 54.5% of the patients, making BAP1 the second most commonly altered gene. RB1 (13q14.2) was commonly altered mainly by deletion in 25.6% of the patients. NF2 and TP53 were affected by mutations in 19.8% and 7.4% of the patients, repectively. Patients with mutations in TP53 had worse overall survival compared with TP53 wild type patients (p-value=0.0005).

    Conclusion
    

    Co-deletion of CDKN2A, MTAP and IFN type I genes could have therapeutic implications for the patients. Deletion of IFN type I may have direct implications for patient responses to immunotherapy. In the contex of multiple vulnerabilities, the presence of both CDKN2A and RB1 loss might define an important group of patients susceptible to CDK4/6i targeted therapies.

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