Genomic and transcriptomic analysis of a diffuse pleural mesothelioma patient-derived xenograft library

Our plain-English summary of Genomic and transcriptomic analysis of a diffuse pleural mesothelioma patient-derived xenograft library, by M. Offin, J.L. Sauter, S.E. Tischfield, et al (Genome Medicine, 2022).

The study

• Authors: M. Offin, J.L. Sauter, S.E. Tischfield, J.V. Egger, S. Chavan, N.S. Shah, P. Manoj, K. Ventura, V. Allaj, E. de Stanchina, W. Travis, M. Ladanyi, A. Rimner, V.W. Rusch, P.S. Adusumilli, J.T. Poirier, M.G. Zauderer, C.M. Rudin, T. Sen
• Journal: Genome Medicine
• Published: 2022;14(1):127
• Cited by: 5 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Diffuse pleural mesothelioma (DPM) is an aggressive malignancy that, despite recent treatment advances, has unacceptably poor outcomes. Therapeutic research in DPM is inhibited by a paucity of preclinical models that faithfully recapitulate the human disease.

Methods: We established 22 patient-derived xenografts (PDX) from 22 patients with DPM and performed multi-omic analyses to deconvolute the mutational landscapes, global expression profiles, and molecular subtypes of these PDX models and compared features to those of the matched primary patient tumors. Targeted next-generation sequencing (NGS; MSK-IMPACT), immunohistochemistry, and histologic subtyping were performed on all available samples. RNA sequencing was performed on all available PDX samples. Clinical outcomes and treatment history were annotated for all patients. Platinum-doublet progression-free survival (PFS) was determined from the start of chemotherapy until radiographic/clinical progression and grouped into < or ≥ 6 months.

Results: PDX models were established from both treatment naïve and previously treated samples and were noted to closely resemble the histology, genomic landscape, and proteomic profiles of the parent tumor. After establishing the validity of the models, transcriptomic analyses demonstrated overexpression in WNT/β-catenin, hedgehog, and TGF-β signaling and a consistent suppression of immune-related signaling in PDXs derived from patients with worse clinical outcomes.

Conclusions: These data demonstrate that DPM PDX models closely resemble the genotype and phenotype of parental tumors, and identify pathways altered in DPM for future exploration in preclinical studies.

© 2022. The Author(s).

In plain English

This laboratory study, by researchers at Memorial Sloan Kettering Cancer Center in New York, grew tumor samples from patients with diffuse pleural mesothelioma in mice to create 'patient-derived xenograft' models. Of 75 attempts, 22 models (29%) were established from 22 patients between 2014 and 2018. In 14 of the 22 patients (63%), the patient reported classic occupational asbestos exposure; the study did not examine asbestos further. The authors compared the mouse tumors with the patients' original tumors using microscopy, protein staining and gene sequencing. Paired samples matched in predominant tissue pattern in 7 of 11 epithelioid cases, and in BAP1 protein status in 14 of 14 pairs. CDKN2A/B gene changes matched less often. In gene-activity analyses, models from patients with shorter survival or shorter benefit from platinum chemotherapy showed more activity in WNT/beta-catenin, hedgehog and NOTCH pathways and less activity in immune-related pathways. The authors concluded that the models closely resemble the parent tumors. They noted the small sample size and that the mice lacked normal immune systems, which could alter the results.

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: Laboratory study creating patient-derived xenograft (PDX) models of diffuse pleural mesothelioma in mice and comparing them with the patients' tumors by histology, immunohistochemistry, targeted gene sequencing (MSK-IMPACT) and RNA sequencing, linked to patients' clinical outcomes
• Who was studied: 22 patients with diffuse pleural mesothelioma at Memorial Sloan Kettering Cancer Center, New York, identified December 2013 through May 2018. Median age was 70 (range 33 to 81) and 19 (86%) were male. Tumor types were 15 epithelioid, 5 biphasic and 2 sarcomatoid.
• Exposure: Asbestos was not the subject of the study. Table 1 records classic self-reported occupational asbestos exposure as yes for 14 patients (63%), no for 5 (23%) and unknown for 3 (14%). The analyses grouped models by tumor subtype, by benefit from platinum-based chemotherapy (progression-free survival under vs at least 6 months), by overall survival (under vs at least 2 years) and by OncoCast-MPM risk group.
• Main results:
  • In the 11 paired epithelioid patient and PDX samples, the predominant architectural pattern matched in 64% (7/11).
  • In the same 11 paired epithelioid samples, nuclear grade matched in 64% (7/11).
  • For the non-epithelioid tumors, 3 of the 5 available pairs (60%) showed matching histology.
  • BAP1 protein status matched in 100% (14/14) of paired patient and PDX samples. Other markers matched as follows: WT1 86% (12/14), mesothelin 77% (10/13), PD-L1 100% (14/14) and VISTA 67% (8/12).
  • Gene sequencing of 19 paired samples showed high agreement for somatic alterations, including BAP1 and NF2, but CDKN2A/B alterations agreed less often.
  • In the patient samples, BAP1 alterations were found in 26% and NF2 alterations in 53%. A previous study by the same group in 194 patients found BAP1 in 32% and NF2 in 25%.
  • Comparing epithelioid with non-epithelioid PDX models, 364 genes were differentially expressed.
  • PDX models from patients with shorter progression-free survival on platinum doublet treatment, and from patients with shorter overall survival, showed enrichment of WNT/beta-catenin, hedgehog and NOTCH signaling pathways and suppression of immune activation pathways.
  • Median overall survival of the 22 patients was 17.4 months (range 6.2 to 50.8 months). 16 patients (73%) had died at last follow-up.
• The authors' conclusion: The authors concluded that the PDX models closely resemble the genotype and phenotype of the patients' tumors and identify pathways altered in diffuse pleural mesothelioma for future preclinical study. They also wrote that their data suggest immune suppression is associated with worse outcomes.
• Limitations the authors state:
  • The models are kept in immune-incompetent mice. The authors wrote that the lack of an intact immune system could change the expression profiles seen in the models.
  • The authors stated that the small sample size and unequal numbers of each histologic subtype could have affected the gene expression results.
  • The authors attributed the lack of a survival difference between OncoCast-MPM risk groups to the small numbers in each group.
  • Tumor necrosis could not be assessed because many patients were treated before tissue sampling.
  • Not all PDX samples could be included in the tissue microarray used for comparison.

Topics

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

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Next-Generation Sequencing (NGS), Immunohistochemistry, Progression-Free Survival, Chemotherapy, Histology.

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