Nathália C Campanella1, Eduardo Caetano Silva2, Gustavo Dix3, Fabiana de Lima Vazquez1, Flávia Escremim de Paula4, Gustavo N Berardinelli4, Marcelo Balancin5,6, Roger Chammas6, Rossana V Mendoza Lopez6, Henrique César S Silveira1, Vera Luiza Capelozzi5, Rui Manuel Reis7,8,9. 1. Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil. 2. Department of Pathology, Barretos Cancer Hospital, Barretos, Brazil. 3. Department of Surgery, Barretos Cancer Hospital, Barretos, Brazil. 4. Molecular Diagnostic Laboratory, Barretos Cancer Hospital, Barretos, Brazil. 5. Department of Pathology, Faculty of Medicine, University of São Paulo, São Paulo, Brazil. 6. Center for Translational Research in Oncology, Instituto do Câncer do Estado de São Paulo, São Paulo, Brazil. 7. Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil, ruireis.hcb@gmail.com. 8. Life and Health Sciences Research Institute (ICVS), Medical School, University of Minho, Braga, Portugal, ruireis.hcb@gmail.com. 9. ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal, ruireis.hcb@gmail.com.
Abstract
BACKGROUND: Malignant pleural mesothelioma (MPM) is a highly lethal disease comprising a heterogeneous group of tumors with challenging to predict biological behavior. The diagnosis is complex, and the histologic classification includes 2 major subtypes of MPM: epithelioid (∼60% of cases) and sarcomatous (∼20%). Its identification depends upon pathological investigation supported by clinical and radiological evidence and more recently ancillary molecular testing. Treatment options are currently limited, with no known targeted therapies available. OBJECTIVES: To elucidate the mutation profile of driver tumor suppressor and oncogenic genes in a cohort of Brazilian patients. METHODS: We sequenced 16 driver genes in a series of 43 Brazilian malignant mesothelioma (MM) patients from 3 distinct Brazilian centers. Genomic DNA was extracted from formalin-fixed paraffin-embedded tumor tissue blocks, and the TERT promoter region was amplified by PCR followed by direct capillary sequencing. The Illumina TruSight Tumor 15 was used to evaluate 250 amplicons from 15 genes associated with solid tumors (AKT1, GNA11, NRAS, BRAF, GNAQ, PDGFRA, EGFR, KIT, PIK3CA, ERBB2, KRAS, RET, FOXL2, MET,and TP53). Library preparation with the TruSight Tumor 15 was performed before sequencing at the MiSeq platform. Data analysis was performed using Sophia DDM software. RESULTS: Out of 43 MPM patients, 38 (88.4%) were epithelioid subtype and 5 (11.6%) were sarcomatoid histotype. Asbestos exposure was present in 15 (39.5%) patients with epithelioid MPM and 3 (60%) patients with sarcomatoid MPM. We found a TERT promoter mutation in 11.6% of MM, and the c.-146C>T mutation was the most common event. The next-generation sequencing was successful in 33 cases. A total of 18 samples showed at least 1 pathogenic, with a median of 1.8 variants, ranging from 1 to 6. The most mutated genes were TP53 and ERBB2 with 7 variants each, followed by NRAS BRAF, PI3KCA, EGFR and PDGFRA with 2 variants each. KIT, AKT1, and FOXL2 genes exhibited 1 variant each. Interestingly, 2 variants observed in the PDGFRA gene are classic imatinib-sensitive therapy. CONCLUSIONS: We concluded that Brazilian MPM harbor mutation in classic tumor suppressor and oncogenic genes, which might help in the guidance of personalized treatment of MPM.
BACKGROUND:Malignant pleural mesothelioma (MPM) is a highly lethal disease comprising a heterogeneous group of tumors with challenging to predict biological behavior. The diagnosis is complex, and the histologic classification includes 2 major subtypes of MPM: epithelioid (∼60% of cases) and sarcomatous (∼20%). Its identification depends upon pathological investigation supported by clinical and radiological evidence and more recently ancillary molecular testing. Treatment options are currently limited, with no known targeted therapies available. OBJECTIVES: To elucidate the mutation profile of driver tumor suppressor and oncogenic genes in a cohort of Brazilian patients. METHODS: We sequenced 16 driver genes in a series of 43 Brazilian malignant mesothelioma (MM) patients from 3 distinct Brazilian centers. Genomic DNA was extracted from formalin-fixed paraffin-embedded tumor tissue blocks, and the TERT promoter region was amplified by PCR followed by direct capillary sequencing. The Illumina TruSight Tumor 15 was used to evaluate 250 amplicons from 15 genes associated with solid tumors (AKT1, GNA11, NRAS, BRAF, GNAQ, PDGFRA, EGFR, KIT, PIK3CA, ERBB2, KRAS, RET, FOXL2, MET,and TP53). Library preparation with the TruSight Tumor 15 was performed before sequencing at the MiSeq platform. Data analysis was performed using Sophia DDM software. RESULTS: Out of 43 MPM patients, 38 (88.4%) were epithelioid subtype and 5 (11.6%) were sarcomatoid histotype. Asbestos exposure was present in 15 (39.5%) patients with epithelioid MPM and 3 (60%) patients with sarcomatoid MPM. We found a TERT promoter mutation in 11.6% of MM, and the c.-146C>T mutation was the most common event. The next-generation sequencing was successful in 33 cases. A total of 18 samples showed at least 1 pathogenic, with a median of 1.8 variants, ranging from 1 to 6. The most mutated genes were TP53 and ERBB2 with 7 variants each, followed by NRASBRAF, PI3KCA, EGFR and PDGFRA with 2 variants each. KIT, AKT1, and FOXL2 genes exhibited 1 variant each. Interestingly, 2 variants observed in the PDGFRA gene are classic imatinib-sensitive therapy. CONCLUSIONS: We concluded that Brazilian MPM harbor mutation in classic tumor suppressor and oncogenic genes, which might help in the guidance of personalized treatment of MPM.
Authors: Jenette Creaney; Ann-Marie Patch; Venkateswar Addala; Bruce W Robinson; Nicola Waddell; Sophie A Sneddon; Katia Nones; Ian M Dick; Y C Gary Lee; Felicity Newell; Ebony J Rouse; Marjan M Naeini; Olga Kondrashova; Vanessa Lakis; Apostolos Nakas; David Waller; Annabel Sharkey; Pamela Mukhopadhyay; Stephen H Kazakoff; Lambros T Koufariotis; Aimee L Davidson; Priya Ramarao-Milne; Oliver Holmes; Qinying Xu; Conrad Leonard; Scott Wood; Sean M Grimmond; Raphael Bueno; Dean A Fennell; John V Pearson Journal: Genome Med Date: 2022-05-30 Impact factor: 15.266
Authors: Rodrigo Cavagna; Flávia Escremim de Paula; Débora Sant'Anna; Iara Santana; Vinicius D da Silva; Eduardo C A da Silva; Carlos E Bacchi; José E Miziara; Josiane M Dias; Pedro De Marchi; Leticia F Leal; Rui M Reis Journal: JCO Glob Oncol Date: 2021-04
Authors: Diocésio Alves Pinto de Andrade; Luciane Sussuchi da Silva; Ana Carolina Laus; Marcos Alves de Lima; Gustavo Nóriz Berardinelli; Vinicius Duval da Silva; Graziela de Macedo Matsushita; Murilo Bonatelli; Aline Larissa Virginio da Silva; Adriane Feijó Evangelista; Jesus Paula Carvalho; Rui Manuel Reis; Ricardo Dos Reis Journal: Front Oncol Date: 2021-08-17 Impact factor: 6.244