Abstract 1897P
Background
Germline mutations in BAP1 and in other genes, such as BRCA2, CHEK2, CDKN2A or ATM, have been associated to hereditary predisposition to malignant pleural mesothelioma (MPM). We aim to characterize the genomic landscape in MPM patients at germline and somatic level.
Methods
We analyzed 22 consecutive patients with MPM by germline and somatic next generation sequencing (NGS). Blood DNA was sequenced using an ad hoc gene panel of 164 genes associated to hereditary cancer risk. Tumoral DNA and RNA were analyzed using the TSO500+ gene panel (Illumina®) with the aim of identifying somatic small variants, copy number alterations, microsatellite instability (MSI) and tumoral mutational burden (TMB).
Results
The mean age of subjects was 68 years and histology consisted of 20 epithelioid, 1 sarcomatoid and 1 atypical mesothelial hyperplasia. Seventeen patients had family history of cancer and 15 were exposed to asbestos. Three out of 22 MPM patients (13.6%) harbored germline likely-pathogenic (P) variants: 2 patients carried BAP1 [c.592dup p.(Glu198Glyfs*45) and c.3_6del p.(?)] and 1 carried BARD1 [c.998_999del p.(Ser333*)]. All three had family history of cancer (3 out of 17, 17.6%) and epithelioid histology. Tumor analysis confirmed germline mutations, and the most frequent somatic mutations were: BAP1, 22.7%; NF2, 22.7%; TP53, 13.6%; SETD2, 13.6% and LATS2, 4.5%. BAP1 and NF2 mutations were mutually exclusive, while SETD2 and LATS2 cooccurred with BAP1 and NF2 respectively. All but one sample had low TMB, and no evidence of MSI was detected.
Conclusions
This is the first study assessing both germline and somatic genetic alterations by NGS in MPM patients in our country. As 17.6% of MPM patients with family history of cancer were carriers of P germline mutations, we propose the implementation of mutational analysis of cancer susceptibility genes in all MPM cases with family history of cancer. Further validation in a larger cohort is ongoing.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Carlos III Health Institute (PI18/00920).
Disclosure
A. Teule: Advisory/Consultancy: Novartis; Advisory/Consultancy: Ipsen; Advisory/Consultancy: AAA; Advisory/Consultancy: Pfizer; Honoraria (institution): AstraZeneca. J. Brunet: Advisory/Consultancy: MSD; Advisory/Consultancy: AstraZeneca. E. Nadal: Advisory/Consultancy, Speaker Bureau/Expert testimony: BMS; Advisory/Consultancy, Speaker Bureau/Expert testimony: MSD; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self): Roche; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self): Pfizer; Advisory/Consultancy: Takeda; Advisory/Consultancy: Lilly; Advisory/Consultancy, Speaker Bureau/Expert testimony: Boehringer Ingelheim; Advisory/Consultancy, Speaker Bureau/Expert testimony: AstraZeneca. All other authors have declared no conflicts of interest.