Pathogenic alterations in PIK3CA and KMT2C are frequent and independent prognostic factors in anal squamous cell carcinoma treated with salvage abdominoperineal resection

• Published in: International journal of cancer Vol. 154; no. 3; pp. 504 - 515
• Main Authors: Hamza, Abderaouf, Masliah‐Planchon, Julien, Neuzillet, Cindy, Lefèvre, Jérémie H., Svrcek, Magali, Vacher, Sophie, Bourneix, Christine, Delaye, Matthieu, Goéré, Diane, Dartigues, Peggy, Samalin, Emmanuelle, Hilmi, Marc, Lazartigues, Julien, Girard, Elodie, Emile, Jean‐François, Rigault, Eugénie, Dangles‐Marie, Virginie, Rioux‐Leclercq, Nathalie, Fouchardière, Christelle, Tougeron, David, Casadei‐Gardini, Andrea, Mariani, Pascale, Peschaud, Frédérique, Cacheux, Wulfran, Lièvre, Astrid, Bièche, Ivan
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.02.2024; Wiley Subscription Services, Inc; Wiley
• Series: International Journal of Cancer
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Biomarkers; Cancer; cancer genomics; Cell cycle; Chromatin remodeling; Clinical trials; Gastric cancer; gastrointestinal cancer; Genetic analysis; Genomic analysis; genomic biomarkers; HPV associated cancer; Human papillomavirus; Life Sciences; Medical prognosis; Medical research; Multivariate analysis; next‐generation sequencing; p53 Protein; Patients; Precision medicine; Squamous cell carcinoma; Surgical techniques; TOR protein; Tumors; cancer genomics; precision medicine; next-generation sequencing; genomic biomarkers; HPV associated cancer; gastrointestinal cancer; Oncology; Cancer Research
• ISSN: 0020-7136; 1097-0215; 1097-0215
• DOI: 10.1002/ijc.34781

The management of anal squamous cell carcinoma (ASCC) has yet to experience the transformative impact of precision medicine. Conducting genomic analyses may uncover novel prognostic biomarkers and offer potential directions for the development of targeted therapies. To that end, we assessed the prognostic and theragnostic implications of pathogenic variants identified in 571 cancer‐related genes from surgical samples collected from a homogeneous, multicentric French cohort of 158 ASCC patients who underwent abdominoperineal resection treatment. Alterations in PI3K/AKT/mTOR, chromatin remodeling, and Notch pathways were frequent in HPV‐positive tumors, while HPV‐negative tumors often harbored variants in cell cycle regulation and genome integrity maintenance genes (e.g., frequent TP53 and TERT promoter mutations). In patients with HPV‐positive tumors, KMT2C and PIK3CA exon 9/20 pathogenic variants were associated with worse overall survival in multivariate analysis (Hazard ratio (HR)KMT2C = 2.54, 95%CI = [1.25,5.17], P value = .010; HRPIK3CA = 2.43, 95%CI = [1.3,4.56], P value = .006). Alterations with theragnostic value in another cancer type was detected in 43% of patients. These results suggest that PIK3CA and KMT2C pathogenic variants are independent prognostic factors in patients with ASCC with HPV‐positive tumors treated by abdominoperineal resection. And, importantly, the high prevalence of alterations bearing potential theragnostic value strongly supports the use of genomic profiling to allow patient enrollment in precision medicine clinical trials. What's new? To develop personalized therapies for anal squamous cell carcinoma (ASCC), researchers need to learn more about the genomics of the disease. Here, the authors examined pathogenic variants in 571 cancer‐related genes identified in surgical samples collected form patients with ASCC. They found that more than 40% of patients carried mutations known to be targetable in other cancers. In patients with HPV‐positive tumors, pathogenic variants in KMT2C and PIK3CA were associated with worse overall survival. These results support genomic profiling to identify patients for clinical trials of targeted therapies.