Personalized Oncogenomics: Clinical Experience with Malignant Peritoneal Mesothelioma Using Whole Genome Sequencing

Abstract

Peritoneal mesothelioma is a rare and sometimes lethal malignancy that presents a clinical challenge for both diagnosis and management. Recent studies have led to a better understanding of the molecular biology of peritoneal mesothelioma. Translation of the emerging data into better treatments and outcome is needed. From two patients with peritoneal mesothelioma, we derived whole genome sequences, RNA expression profiles, and targeted deep sequencing data. Molecular data were made available for translation into a clinical treatment plan. Treatment responses and outcomes were later examined in the context of molecular findings. Molecular studies presented here provide the first reported whole genome sequences of peritoneal mesothelioma. Mutations in known mesothelioma-related genes NF2, CDKN2A, LATS2, amongst others, were identified. Activation of MET-related signaling pathways was demonstrated in both cases. A hypermutated phenotype was observed in one case (434 vs. 18 single nucleotide variants) and was associated with a favourable outcome despite sarcomatoid histology and multifocal disease. This study represents the first report of whole genome analyses of peritoneal mesothelioma, a key step in the understanding and treatment of this disease.

Personalized Oncogenomics in the Management of Gastrointestinal Carcinomas—Early Experiences from a Pilot Study

“…A pilot project aimed to address the frequency with which clinically informative results might be obtained through the application of whole-genome analysis. The pog program currently represents the largest precision medicine endeavor in Canada, and it has resulted in the first genomic definitions of rare cancer types such as peritoneal mesothelioma 8 and, in the present report, appendiceal adenocarcinoma. Patients with incurable advanced cancers, good performance status, and limited remaining conventional treatment options are eligible for enrolment.…”

Malignant Peritoneal Mesothelioma Masquerades as Peritoneal Metastasis on 18F-FDG PET/CT Scans; a Rare Diagnosis that Should Not Be Missed

“…Loculated ascites with scalloping to the liver surface was best visualized in contrast-enhanced CT image (e), which showed minimal increased uptake (f, arrow), consistent with malignant ascites. Hypometabolic right pleural effusion without pleural lesion was considered benign causes (f, arrowhead) of PCKD and MPM have been reported [11] but none was found to be related to each other; however, detailed exploration is needed in further studies.…”

Next-Generation Sequencing Approaches in Cancer: Where Have They Brought Us and Where Will They Take Us?

“…Such studies can also reveal critical aspects of tumour biology, contributing to our more general knowledge of tumour mechanisms and behaviour. For instance, the Personal OncoGenomics (POG) initiative at the British Columbia Cancer Agency is a project that aims to gauge whether in-depth genomic data can be successfully used to guide clinical decision-making while also cataloguing genomic and transcriptomic information for hundreds of cancer patients [ 198 , 199 , 200 , 201 ]. Though this project is, to our knowledge, the only one that addresses precision oncology measures at the whole-genome scale, other groups have also published similar reports.…”

“…At the time of publication, 34 weeks following the beginning of therapy, the patient continued to show response and remained nearly asymptomatic. In the most recent POG study, Sheffield et al [ 199 ] reported the characterization of clinically and molecularly dissimilar peritoneal mesothelioma tumours from two patients. This study generated the first whole-genome sequencing data for this rare, relatively poorly understood cancer type.…”