Brooj Abro1, Madhurima Kaushal2, Ling Chen3, Robert Wu4, Louis P Dehner1, John D Pfeifer1, Mai He5. 1. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63010, USA. 2. Institute of Informatics, Washington University School of Medicine, St. Louis, MO 63110, USA. 3. Division of Biostatistics, Washington University School of Medicine, St. Louis, MO 63110, USA. 4. Penn State College of Medicine, Hershey, PA 17033, USA. 5. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63010, USA. Electronic address: maihe@wustl.edu.
Abstract
INTRODUCTION: Malignant rhabdoid tumor (MRT) is a rare, aggressive pediatric tumor of nuclear lineage. It is mainly characterized by germline or somatic SMARCB1 (INI1) driver mutations. To characterize the potential for immunotherapy in untreated and treated MRT, current study investigated tumor mutational burden (TMB) and other biomarkers in MRT. MATERIAL AND METHODS: Normal-tumor paired whole exome sequencing (WES) and/or immunohistochemistry (IHC) of DNA mismatch repair (MMR) proteins, PD-L1, PD-1 and CD8 were performed in 16 cases, some with both primary and relapsed tumor. RESULTS: Five cases subjected to WES demonstrated germline SMARCB1 (INI1) mutations. TMB was 0.7-1.07/Mb in 4 of the 5 primary untreated tumors, and 33.81/Mb in one case with pathogenic MMR, POLD, and POLE mutations. Ten cases tested for MMR status by IHC showed retained nuclear expression of the proteins. Eight of the 16 cases (8/16, 50%) showed membranous expression of PD-L1 in 10-70% of tumor cells (tumor proportion score, TPS). Nine cases (9/16, 56.3%) showed high (>2/HPF) tumor infiltrating lymphocytes with PD-1 staining ranging 10-60%, correlating with tumor PD-L1 staining (p < 0.0001). Between post-treatment metastatic tumors and the pre-treatment primary tumors, TMB was similar while PD-L1 TPS was similar or lower. CONCLUSION: MRT has a low TMB. Nonetheless, because a subset of MRT cases have a PD-L1 TPS greater than the cutoff for checkpoint therapy in other malignancies, the utility of immune checkpoint inhibitors should be studied in this patient population.
INTRODUCTION:Malignant rhabdoid tumor (MRT) is a rare, aggressive pediatric tumor of nuclear lineage. It is mainly characterized by germline or somatic SMARCB1 (INI1) driver mutations. To characterize the potential for immunotherapy in untreated and treated MRT, current study investigated tumor mutational burden (TMB) and other biomarkers in MRT. MATERIAL AND METHODS: Normal-tumor paired whole exome sequencing (WES) and/or immunohistochemistry (IHC) of DNA mismatch repair (MMR) proteins, PD-L1, PD-1 and CD8 were performed in 16 cases, some with both primary and relapsed tumor. RESULTS: Five cases subjected to WES demonstrated germline SMARCB1 (INI1) mutations. TMB was 0.7-1.07/Mb in 4 of the 5 primary untreated tumors, and 33.81/Mb in one case with pathogenic MMR, POLD, and POLE mutations. Ten cases tested for MMR status by IHC showed retained nuclear expression of the proteins. Eight of the 16 cases (8/16, 50%) showed membranous expression of PD-L1 in 10-70% of tumor cells (tumor proportion score, TPS). Nine cases (9/16, 56.3%) showed high (>2/HPF) tumor infiltrating lymphocytes with PD-1 staining ranging 10-60%, correlating with tumorPD-L1 staining (p < 0.0001). Between post-treatment metastatic tumors and the pre-treatment primary tumors, TMB was similar while PD-L1 TPS was similar or lower. CONCLUSION: MRT has a low TMB. Nonetheless, because a subset of MRT cases have a PD-L1 TPS greater than the cutoff for checkpoint therapy in other malignancies, the utility of immune checkpoint inhibitors should be studied in this patient population.
Authors: Laura M Williamson; Craig M Rive; Daniela Di Francesco; Emma Titmuss; Hye-Jung E Chun; Scott D Brown; Katy Milne; Erin Pleasance; Anna F Lee; Stephen Yip; Daniel G Rosenbaum; Martin Hasselblatt; Pascal D Johann; Marcel Kool; Melissa Harvey; David Dix; Daniel J Renouf; Robert A Holt; Brad H Nelson; Martin Hirst; Steven J M Jones; Janessa Laskin; Shahrad R Rassekh; Rebecca J Deyell; Marco A Marra Journal: NPJ Precis Oncol Date: 2021-12-20
Authors: Zahra Alipour; Kris Ann P Schultz; Ling Chen; Anne K Harris; Ivan A Gonzalez; John Pfeifer; D Ashley Hill; Mai He; Louis P Dehner Journal: Pediatr Dev Pathol Date: 2021-07-15
Authors: Natasha Rekhtman; Joseph Montecalvo; Jason C Chang; Deepu Alex; Ryan N Ptashkin; Ni Ai; Jennifer L Sauter; Brie Kezlarian; Achim Jungbluth; Patrice Desmeules; Amanda Beras; Justin A Bishop; Andrew J Plodkowski; Mrinal M Gounder; Adam J Schoenfeld; Azadeh Namakydoust; Bob T Li; Charles M Rudin; Gregory J Riely; David R Jones; Marc Ladanyi; William D Travis Journal: J Thorac Oncol Date: 2019-11-18 Impact factor: 15.609