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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; HR PIK3CA  = 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., (© 2023 UICC.)

Anal squamous cell carcinoma (ASCC) is a rare tumour, but its incidence is increasing. Standard chemoradiotherapy fails to cure 20% of patients and no targeted therapy is currently approved for recurrent ASCC. The PI3K/Akt/mTOR pathway is frequently altered in this poorly characterised carcinoma . IGF2 was identified here as a key factor in ASCC oncogenesis, as IGF2 was shown to play a crucial role in the PI3K pathway with frequent (~60%) and mutually exclusive genomic alterations in IGF2, IGF1R, PTEN and PIK3CA genes. We also demonstrated that IGF2 expression is mainly due to cancer-associated fibroblasts and that IGF2 secreted by cancer-associated fibroblasts from ASCC samples promotes proliferation of a human ASCC cell line via IGF2 paracrine signalling. Altogether, these results highlight the key role of the IGF2/PI3K axis, and the major role of cancer-associated fibroblasts in tumour growth via IGF2 secretion, suggesting a major role of IGF2/IGF1R inhibitors in ASCC therapies., (© 2019 UICC.)

Background: A better understanding of the molecular profile of anal squamous cell carcinomas (ASCCs) is necessary to consider new therapeutic approaches, and the identification of prognostic and predictive factors for response to treatment., Methods: We retrospectively analysed tumours from ASCC patients for mutational analysis of KRAS, NRAS, HRAS, BRAF, PIK3CA, MET, TP53 and FBXW7 genes by HRM and Sanger sequencing analysis., Results: Specimens from 148 patients were analysed: 96 treatment-naive tumours and 52 recurrences after initial radiotherapy (RT) or chemoradiotherapy (CRT). Mutations of KRAS, PIK3CA, FBXW7 and TP53 genes were present in 3 (2.0%), 30 (20.3%), 9 (6.1%) and 7 tumours (4.7%), respectively. The distribution of the mutations was similar between treatment-naive tumours and recurrences, except for TP53 mutations being more frequent in recurrences (P=0.0005). In patients treated with abdominoperineal resection (APR) after relapse (n=38, median follow-up of 18.2 years), overall survival (OS) was significantly correlated with HPV16 status (P=0.048), gender (P=0.045) and PIK3CA mutation (P=0.037). The PIK3CA status retained its prognostic significance in Cox multivariate regression analysis (P=0.025)., Conclusions: Our study identified PIK3CA mutation as an independent prognostic factor in patients who underwent APR for ASCC recurrence, suggesting a potential benefit from adjuvant treatment and the evaluation of targeted therapies with PI3K/Akt/mTor inhibitors in PIK3CA-mutated patients.