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• W4366991870 abstract "Abstract 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." @default.
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• W4366991870 date "2023-04-25" @default.
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• W4366991870 title "Utility of <i>CYP2D6</i> copy number variants as prognostic biomarker in localized anal squamous cell carcinoma" @default.
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• W4366991870 doi "https://doi.org/10.1002/cncr.34797" @default.
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