PURPOSE: Malignant phyllodes tumors (MPT) are exceptionally rare, and the genomic drivers of these tumors are still being elucidated. We performed comprehensive genomic profiling (CGP) of MPT to identify genomic alterations that will inform approaches to targeted therapy for patients with MPT, including relapsed, refractory, and metastatic disease. METHODS: DNA was extracted from formalin-fixed, paraffin-embedded samples from 24 consecutive patient cases of MPT. CGP was performed using a hybrid capture, adaptor ligation-based next generation sequencing assay to a high, uniform coverage (mean, 582×). Tumor mutational burden (TMB) was calculated from a minimum of 1.14 Mb of sequenced DNA as previously described and reported as mutations/Mb. The results were analyzed for all classes of genomic alterations, including short variants (SV; base substitutions, small insertions, and deletions), rearrangements, and copy number changes, including amplifications and homozygous deletions. RESULTS: The 24 cases of MPT included 15 patients with localized and 9 with metastatic disease. The median TMB was 2.7 mut/Mb, and no cases had a TMB > 10 mut/Mb. 20 out of 24 cases were evaluable for microsatellite status, and all were microsatellite stable. The most commonly mutated genes were TP53 (58.3%), TERT-promoter (57.9%), NF1 (45.8%), MED12 (45.8%), CDKN2A/B (33.3%), and MLL2 (33.3%). Targetable kinase fusions including KIAA1549-BRAF or FGFR3-TACC3 were identified in 2/24 (8.3%) tumors. CONCLUSIONS: This study identifies clinically relevant genomic alterations that suggest novel targeted therapy approaches for patients with MPT.
PURPOSE:Malignant phyllodes tumors (MPT) are exceptionally rare, and the genomic drivers of these tumors are still being elucidated. We performed comprehensive genomic profiling (CGP) of MPT to identify genomic alterations that will inform approaches to targeted therapy for patients with MPT, including relapsed, refractory, and metastatic disease. METHODS: DNA was extracted from formalin-fixed, paraffin-embedded samples from 24 consecutive patient cases of MPT. CGP was performed using a hybrid capture, adaptor ligation-based next generation sequencing assay to a high, uniform coverage (mean, 582×). Tumor mutational burden (TMB) was calculated from a minimum of 1.14 Mb of sequenced DNA as previously described and reported as mutations/Mb. The results were analyzed for all classes of genomic alterations, including short variants (SV; base substitutions, small insertions, and deletions), rearrangements, and copy number changes, including amplifications and homozygous deletions. RESULTS: The 24 cases of MPT included 15 patients with localized and 9 with metastatic disease. The median TMB was 2.7 mut/Mb, and no cases had a TMB > 10 mut/Mb. 20 out of 24 cases were evaluable for microsatellite status, and all were microsatellite stable. The most commonly mutated genes were TP53 (58.3%), TERT-promoter (57.9%), NF1 (45.8%), MED12 (45.8%), CDKN2A/B (33.3%), and MLL2 (33.3%). Targetable kinase fusions including KIAA1549-BRAF or FGFR3-TACC3 were identified in 2/24 (8.3%) tumors. CONCLUSIONS: This study identifies clinically relevant genomic alterations that suggest novel targeted therapy approaches for patients with MPT.
Authors: Fresia Pareja; Arnaud Da Cruz Paula; Melissa P Murray; Timothy Hoang; Rodrigo Gularte-Mérida; David Brown; Edaise M da Silva; Ana Paula Martins Sebastiao; Dilip D Giri; Britta Weigelt; Jorge S Reis-Filho; Edi Brogi Journal: J Clin Pathol Date: 2018-11-22 Impact factor: 3.411
Authors: Coren A Milbury; James Creeden; Wai-Ki Yip; David L Smith; Varun Pattani; Kristi Maxwell; Bethany Sawchyn; Ole Gjoerup; Wei Meng; Joel Skoletsky; Alvin D Concepcion; Yanhua Tang; Xiaobo Bai; Ninad Dewal; Pei Ma; Shannon T Bailey; James Thornton; Dean C Pavlick; Garrett M Frampton; Daniel Lieber; Jared White; Christine Burns; Christine Vietz Journal: PLoS One Date: 2022-03-16 Impact factor: 3.240
Authors: Alyssa J Penning; Alyaa Al-Ibraheemi; Michael Michal; Brandon T Larsen; Soo-Jin Cho; Christina M Lockwood; Vera A Paulson; Yajuan J Liu; Lukáš Plank; Karen Fritchie; Carol Beadling; Tanaya L Neff; Christopher L Corless; Erin R Rudzinski; Jessica L Davis Journal: Mod Pathol Date: 2021-04-13 Impact factor: 8.209