Surein Arulananda1, Bibhusal Thapa1, Marzena Walkiewicz2, Giada V Zapparoli3, David S Williams4, Alexander Dobrovic5, Thomas John6. 1. Cancer Immuno-Biology Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia; School of Cancer Medicine, La Trobe University, Heidelberg, Victoria, Australia. 2. Cancer Immuno-Biology Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia. 3. Translational Genomics and Epigenomics Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia. 4. School of Cancer Medicine, La Trobe University, Heidelberg, Victoria, Australia; Department of Pathology, University of Melbourne, Parkville, Victoria, Australia. 5. School of Cancer Medicine, La Trobe University, Heidelberg, Victoria, Australia; Translational Genomics and Epigenomics Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia; Department of Pathology, University of Melbourne, Parkville, Victoria, Australia. 6. Cancer Immuno-Biology Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia; School of Cancer Medicine, La Trobe University, Heidelberg, Victoria, Australia; Department of Medical Oncology, Olivia Newton-John Cancer and Wellness Centre, Heidelberg, Victoria, Australia. Electronic address: Tom.John@onjcri.org.au.
Abstract
INTRODUCTION: Malignant pleural mesothelioma is an aggressive malignancy with limited systemic therapy options. Promising results have been reported with use of anti-programmed cell death 1 therapy; however, its benefits appear to be confined to a subgroup of patients. Microsatellite instability (MSI) results from the inactivation of DNA mismatch repair genes and results in a high tumor mutational burden, a phenomenon that has not been seen with mesothelioma. MSI and protein absence have been shown to correlate in colorectal cancer, such that most centers have adopted immunohistochemistry (IHC) to screen for MSI-high colorectal cancers. We profiled a large cohort of patients with mesothelioma to determine the rate of negative IHC staining results the four common mismatch repair proteins. DESIGN: A tissue microarray comprising 335 patients with malignant pleural mesothelioma were used. IHC for the four common mismatch repair proteins (mutL homolog 1; PMS1 homolog 2, mismatch repair system component; mutS homolog 2; and mutS homolog 6) was performed. Programmed death ligand 1 IHC staining with the E1L3N clone was also performed. DNA was isolated from IHC equivocal samples and analyzed for microsatellite instability by using the Promega MSI Analysis System (version 1.2, Promega, Madison, WI). RESULTS: Of the patients profiled, 329 had intact mismatch repair proteins by IHC. Six samples with IHC testing results indicating absent mismatch repair protein were analyzed for MSI and confirmed to be negative. Of the six IHC-negative samples, five were negative for programmed death ligand 1 staining and one sample had more than 5% staining. CONCLUSION: In this large retrospective series, we were unable to identify any patients with malignant pleural mesothelioma with microsatellite instability. Response to anti-programmed cell death 1-based immunotherapy may be driven by other mechanisms.
INTRODUCTION:Malignant pleural mesothelioma is an aggressive malignancy with limited systemic therapy options. Promising results have been reported with use of anti-programmed cell death 1 therapy; however, its benefits appear to be confined to a subgroup of patients. Microsatellite instability (MSI) results from the inactivation of DNA mismatch repair genes and results in a high tumor mutational burden, a phenomenon that has not been seen with mesothelioma. MSI and protein absence have been shown to correlate in colorectal cancer, such that most centers have adopted immunohistochemistry (IHC) to screen for MSI-high colorectal cancers. We profiled a large cohort of patients with mesothelioma to determine the rate of negative IHC staining results the four common mismatch repair proteins. DESIGN: A tissue microarray comprising 335 patients with malignant pleural mesothelioma were used. IHC for the four common mismatch repair proteins (mutL homolog 1; PMS1 homolog 2, mismatch repair system component; mutS homolog 2; and mutS homolog 6) was performed. Programmed death ligand 1 IHC staining with the E1L3N clone was also performed. DNA was isolated from IHC equivocal samples and analyzed for microsatellite instability by using the Promega MSI Analysis System (version 1.2, Promega, Madison, WI). RESULTS: Of the patients profiled, 329 had intact mismatch repair proteins by IHC. Six samples with IHC testing results indicating absent mismatch repair protein were analyzed for MSI and confirmed to be negative. Of the six IHC-negative samples, five were negative for programmed death ligand 1 staining and one sample had more than 5% staining. CONCLUSION: In this large retrospective series, we were unable to identify any patients with malignant pleural mesothelioma with microsatellite instability. Response to anti-programmed cell death 1-based immunotherapy may be driven by other mechanisms.
Authors: Yurong Song; Shaneen S Baxter; Lisheng Dai; Chelsea Sanders; Sandra Burkett; Ryan N Baugher; Stephanie D Mellott; Todd B Young; Heidi E Lawhorn; Simone Difilippantonio; Baktiar Karim; Yuwaraj Kadariya; Ligia A Pinto; Joseph R Testa; Robert H Shoemaker Journal: Cancers (Basel) Date: 2022-06-24 Impact factor: 6.575
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