Personalized oncogenomics: clinical experience with malignant peritoneal mesothelioma using whole genome sequencing

Our plain-English summary of Personalized oncogenomics: clinical experience with malignant peritoneal mesothelioma using whole genome sequencing, by B.S. Sheffield, A.V. Tinker, Y. Shen, et al (PloS One, 2015).

The study

• Authors: B.S. Sheffield, A.V. Tinker, Y. Shen, H. Hwang, H.H. Li-Chang, E. Pleasance, C. Ch'ng, A. Lum, J. Lorette, Y.J. McConnell, S. Sun, S.J. Jones, A.M. Gown, D.G. Huntsman, D.F. Schaeffer, A. Churg, S. Yip, J. Laskin, M.A. Marra
• Journal: PloS One
• Published: 2015;10(3):e0119689
• Type of article: Case report
• Cited by: 33 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This report described two women with primary peritoneal mesothelioma who took part in the Personalized OncoGenomics program at the British Columbia Cancer Agency in Vancouver, Canada. Neither had a reported history of asbestos exposure. The authors sequenced the whole genome of tumor samples and blood, measured gene activity in the tumors, and compared these results with how each patient responded to treatment. Both tumors carried mutations that disable the NF2 gene, and both showed high activity of the MET gene. Patient 1's tumor was epithelioid on biopsy. That patient responded poorly to therapy and died within 8 months of diagnosis. Patient 2's biopsy showed sarcomatoid mesothelioma. That patient was clinically well and disease free 14 months after surgery. In the protein-coding parts of genes, patient 2's two tumor samples together had 434 single-letter DNA changes, compared with 18 in patient 1's tumor. The authors concluded that a 'hypermutated' form of peritoneal mesothelioma may exist. They noted two cautions. Patient 2 had one more tumor sample tested than patient 1. And little is known about overall mutation rates in these tumors, which makes hypermutation hard to define strictly.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Report of two cases: clinical history plus whole genome sequencing, RNA expression profiling and targeted deep sequencing of tumor samples
• Who was studied: Two women with primary peritoneal mesothelioma in the Personalized OncoGenomics study at the British Columbia Cancer Agency, Vancouver, Canada. Patient 1 was a young woman and patient 2 a middle-aged woman. Dates are not given.
• Exposure: This was not a study of asbestos exposure. Neither patient had a reported history of asbestos exposure. The study examined tumor genetics and response to treatment.
• Main results:
  • Both patients' tumors had loss-of-function mutations in NF2. Both also shared a mutation in CNTNAP3B, whose significance the authors said was not clear.
  • High expression of the MET tyrosine kinase receptor was seen in both cases.
  • Patient 1: whole genome sequencing found a somatic frameshift mutation in NF2, plus changes in SOCS3, TET3 and TFPT. The BAP1 gene was normal in both tumor and blood.
  • Patient 1 (epithelioid histology on biopsy) responded poorly to therapy and died within 8 months of diagnosis. This therapy included everolimus, which was given on the basis of the molecular results.
  • Patient 2: mutations were found in SMO, TP53, NF2, LATS2 and NOTCH1. A CDKN2A mutation was found only in the chemotherapy-resistant right colon nodule.
  • Patient 2: 116 coding mutations were shared by both tumor samples, 151 were found only in the vaginal tumor, and 167 were found only in the pericolic tumor. The authors interpreted this as clonal divergence of the two tumor cell populations.
  • 18 single nucleotide variants were found in patient 1's tumor sample, compared with 434 in patient 2's two tumor samples. For patient 2, this 434 is the sum of coding variants: 116 shared plus 151 and 167 unique to each sample.
  • Mutation rates were 0.8 per megabase for patient 1 and 5.7 per megabase for patient 2. Under a colorectal cancer cutoff of more than 12 per megabase, neither case would count as hypermutated. Under a cutoff of more than 10,000 single nucleotide changes, patient 2 would count, with 16,329 coding and noncoding changes.
  • Patient 2's mutations were mostly cytosine-to-thymine changes, a signature the authors describe as linked to cytosine deamination. No chemotherapy-induced or DNA-repair deficiency signatures were identified.
  • Patient 2 (sarcomatoid histology on the vaginal biopsy) remained clinically well and disease free 14 months after surgery.
• The authors' conclusion: The authors concluded that their findings suggest a hypermutated form of peritoneal mesothelioma may exist, similar to forms described in some colorectal and lung cancers.
• Limitations the authors state:
  • When comparing mutation counts between the two patients, the authors note that patient 2 had an additional tumor sample analyzed.
  • Little is known about the overall mutation rate of peritoneal mesothelioma, which makes a strict definition of hypermutation difficult.
  • The genetic data did not explain why parts of patient 2's tumor responded to chemotherapy and other parts did not.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma, Peritoneal mesothelioma.

Medical terms in this study, explained in our Lexicon: Peritoneal Mesothelioma, Mesothelioma, CDKN2A, Sarcomatoid, Histology.

Related studies

• Establishment and mutation analysis of a novel malignant peritoneal mesothelioma cell line, TU-MM-1, using whole genome sequencing — N. Oumi, H. Itamochi, et al. (2016)
• Germline and somatic variant identification using BGISEQ-500 and HiSeq X Ten whole genome sequencing — A.M. Patch, K. Nones, et al. (2018)
• Whole exome and targeted deep sequencing identify genome-wide allelic loss and frequent SETDB1 mutations in malignant pleural mesotheliomas — H.C. Kang, H.K. Kim, et al. (2016)
• A Tumor-Specific Neo-Antigen Caused by a Frameshift Mutation in BAP1 Is a Potential Personalized Biomarker in Malignant Peritoneal Mesothelioma — J. Lai, Z. Zhou, et al. (2016)
• Immunohistochemistry for NF2, LATS1/2, and YAP/TAZ Fails to Separate Benign From Malignant Mesothelial Proliferations — B.S. Sheffield, J. Lorette, et al. (2016)
• Whole-exome sequencing reveals frequent genetic alterations in BAP1, NF2, CDKN2A, and CUL1 in malignant pleural mesothelioma — G. Guo, J. Chmielecki, et al. (2015)

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