Utility of CYP2D6 copy number variants as prognostic biomarker in localized anal squamous cell carcinoma.

Autor: Trilla-Fuertes L; Molecular Oncology Lab, Hospital Universitario La Paz-IdiPAZ, Madrid, Spain., Gámez-Pozo A; Molecular Oncology Lab, Hospital Universitario La Paz-IdiPAZ, Madrid, Spain.; Biomedica Molecular Medicine SL, Madrid, Spain., Nogué M; Spanish Multidisciplinary Group of Digestive Cancer, Barcelona, Spain.; Medical Oncology Service, Hospital de Granollers, Barcelona, Spain., Busquier I; Spanish Multidisciplinary Group of Digestive Cancer, Barcelona, Spain.; Medical Oncology Service, Hospital Provincial de Castellón, Castellón, Spain., Arias F; Spanish Multidisciplinary Group of Digestive Cancer, Barcelona, Spain.; Radiotherapy Oncology Service, Complejo Hospitalario de Navarra, Navarra, Spain., López-Campos F; Spanish Multidisciplinary Group of Digestive Cancer, Barcelona, Spain.; Radiotherapy Oncology Service, Hospital Ramón y Cajal, Madrid, Spain., Fernández-Montes A; Spanish Multidisciplinary Group of Digestive Cancer, Barcelona, Spain.; Medical Oncology Service, Complejo Hospitalario Universitario de Ourense, Ourense, Spain., Ruiz A; Spanish Multidisciplinary Group of Digestive Cancer, Barcelona, Spain.; Medical Oncology Service, Hospital Universitario Puerta de Hierro Majadahonda, IDIPHISA, Madrid, Spain., Velázquez C; Spanish Multidisciplinary Group of Digestive Cancer, Barcelona, Spain.; Medical Oncology Service, Hospital Miguel Servet, Zaragoza, Spain., Martín-Bravo C; Medical Oncology Service, Hospital Costa del Sol, Málaga, Spain., Pérez-Ruiz E; Unidad de Gestión Clínica Intercentros de Oncología Médica, Hospitales Universitarios Regional y Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga, Hospitales Universitarios Regional y Virgen de la Victoria, Málaga, Spain., Asensio E; Spanish Multidisciplinary Group of Digestive Cancer, Barcelona, Spain.; Medical Oncology Service, Hospital General Universitario de Elche, Elche, Spain., Hernández-Yagüe X; Spanish Multidisciplinary Group of Digestive Cancer, Barcelona, Spain.; Medical Oncology Service, Instituto Catalán de Oncología-Girona, Girona, Spain., Rodrigues A; Spanish Multidisciplinary Group of Digestive Cancer, Barcelona, Spain.; Medical Oncology Service, Hospital Universitario de Salamanca, Salamanca, Spain., Ghanem I; Spanish Multidisciplinary Group of Digestive Cancer, Barcelona, Spain.; Medical Oncology Service, Hospital Universitario La Paz, Madrid, Spain., López-Vacas R; Molecular Oncology Lab, Hospital Universitario La Paz-IdiPAZ, Madrid, Spain., Hafez A; Biotechvana SL, Parque Científico de Madrid, Madrid, Spain., Arias P; Pharmacogenetics Lab, Institute of Medical and Molecular Genetics-INGEMM, La Paz University Hospital-IdiPAZ, Autonomous University of Madrid, Madrid, Spain., Dapía I; Pharmacogenetics Lab, Institute of Medical and Molecular Genetics-INGEMM, La Paz University Hospital-IdiPAZ, Autonomous University of Madrid, Madrid, Spain., Solís M; Bioinformatics Unit, Institute of Medical and Molecular Genetics-INGEMM, La Paz University Hospital-IdiPAZ, Madrid, Spain., Dittmann A; Functional Genomics Center Zurich, University of Zurich/ETH Zurich, Zurich, Switzerland., Ramos R; Genomics Unit, Parque Científico de Madrid, Madrid, Spain., Llorens C; Biotechvana SL, Parque Científico de Madrid, Madrid, Spain., Maurel J; Spanish Multidisciplinary Group of Digestive Cancer, Barcelona, Spain.; Medical Oncology Department, Hospital Clínic of Barcelona, Translational Genomics and Targeted Therapeutics in Solid Tumors Group, IDIBAPS, University of Barcelona, Barcelona, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain., Campos-Barros Á; Institute of Medical and Molecular Genetics, IdiPAZ, Hospital Universitario La Paz/CIBERER Unit 753, ISCIII, Madrid, Spain., Fresno Vara JÁ; Molecular Oncology Lab, Hospital Universitario La Paz-IdiPAZ, Madrid, Spain.; Biomedica Molecular Medicine SL, Madrid, Spain.; Biomedical Research Networking Center on Oncology-CIBERONC, ISCIII, Madrid, Spain., Feliu J; Spanish Multidisciplinary Group of Digestive Cancer, Barcelona, Spain.; Medical Oncology Service, Hospital Universitario La Paz, Madrid, Spain.; Biomedical Research Networking Center on Oncology-CIBERONC, ISCIII, Madrid, Spain.; Cátedra UAM-Amgen, Universidad Autónoma de Madrid, Madrid, Spain.
Jazyk: angličtina
Zdroj: Cancer [Cancer] 2023 Aug 15; Vol. 129 (16), pp. 2581-2592. Date of Electronic Publication: 2023 Apr 25.
DOI: 10.1002/cncr.34797
Abstrakt: Background: Anal squamous cell carcinoma (ASCC) is an infrequent tumor whose treatment has not changed since the 1970s. The aim of this study is the identification of biomarkers allowing personalized treatments and improvement of therapeutic outcomes.
Methods: Forty-six paraffin tumor samples from ASCC patients were analyzed by whole-exome sequencing. Copy number variants (CNVs) were identified and their relation to disease-free survival (DFS) was studied and validated in an independent retrospective cohort of 101 ASCC patients from the Multidisciplinary Spanish Digestive Cancer Group (GEMCAD). GEMCAD cohort proteomics allowed assessing the biological features of these tumors.
Results: On the discovery cohort, the median age was 61 years old, 50% were males, stages I/II/III: 3 (7%)/16 (35%)/27 (58%), respectively, median DFS was 33 months, and overall survival was 45 months. Twenty-nine genes whose duplication was related to DFS were identified. The most representative was duplications of the CYP2D locus, including CYP2D6, CYP2D7P, and CYP2D8P genes. Patients with CYP2D6 CNV had worse DFS at 5 years than those with two CYP2D6 copies (21% vs. 84%; p < .0002, hazard ratio [HR], 5.8; 95% confidence interval [CI], 2.7-24.9). In the GEMCAD validation cohort, patients with CYP2D6 CNV also had worse DFS at 5 years (56% vs. 87%; p = .02, HR = 3.6; 95% CI, 1.1-5.7). Mitochondria and mitochondrial cell-cycle proteins were overexpressed in patients with CYP2D6 CNV.
Conclusions: Tumor CYP2D6 CNV identified patients with a significantly worse DFS at 5 years among localized ASCC patients treated with 5-fluorouracil, mitomycin C, and radiotherapy. Proteomics pointed out mitochondria and mitochondrial cell-cycle genes as possible therapeutic targets for these high-risk patients.
Plain Language Summary: Anal squamous cell carcinoma is an infrequent tumor whose treatment has not been changed since the 1970s. However, disease-free survival in late staged tumors is between 40% and 70%. The presence of an alteration in the number of copies of CYP2D6 gene is a biomarker of worse disease-free survival. The analysis of the proteins in these high-risk patients pointed out mitochondria and mitochondrial cell-cycle genes as possible therapeutic targets. Therefore, the determination of the number of copies of CYP2D6 allows the identification of anal squamous carcinoma patients with a high-risk of relapse that could be redirected to a clinical trial. Additionally, this study may be useful to suggest new treatment strategies to increase current therapy efficacy.
(© 2023 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)
Databáze: MEDLINE
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