Genetic profile and functional proteomics of anal squamous cell carcinoma: proposal for a molecular classification

Abstract

Carcinoma anal de cèl·lules escamoses; Biologia molecular; Proteòmica

Anal squamous cell carcinoma; Molecular biology; Proteomics

Carcinoma anal de células escamosas; Biología molecular; Proteómica

Anal squamous cell carcinoma is a rare tumor. Chemo-radiotherapy yields a 50% 3-year relapse-free survival rate in advanced anal cancer, so improved predictive markers and therapeutic options are needed. High-throughput proteomics and whole-exome sequencing were performed in 46 paraffin samples from anal squamous cell carcinoma patients. Hierarchical clustering was used to establish groups de novo. Then, probabilistic graphical models were used to study the differences between groups of patients at the biological process level. A molecular classification into two groups of patients was established, one group with increased expression of proteins related to adhesion, T lymphocytes and glycolysis; and the other group with increased expression of proteins related to translation and ribosomes. The functional analysis by the probabilistic graphical model showed that these two groups presented differences in metabolism, mitochondria, translation, splicing and adhesion processes. Additionally, these groups showed different frequencies of genetic variants in some genes, such as ATM, SLFN11 and DST. Finally, genetic and proteomic characteristics of these groups suggested the use of some possible targeted therapies, such as PARP inhibitors or immunotherapy.

This study was supported by the Instituto de Salud Carlos III, Spanish Economy and Competitiveness Ministry, Spain and co-sponsored by the FEDER program, “Una forma de hacer Europa” (PI15/01310), a Roche Farma grant, Cátedra UAM-Amgen and a grant of Grupo Español Multidisciplinar en Cáncer Digestivo (GEMCAD1403). LT-F is supported by the Spanish Economy and Competitiveness Ministry (DI-15–07614). GP-V is supported by the Consejería de Educación, Juventud y Deporte of Comunidad de Madrid (IND2017/BMD7783); AZ-M is supported by Jesús Antolín Garciarena fellowship from IdiPAZ. The authors have declared a conflict of interest. JAFV and AG-P are shareholders in Biomedica Molecular Medicine SL. LT-F and GP-V are employees of Biomedica Molecular Medicine SL. JC has received honoraria for scientific consulting (as speaker and advisory roles) from Novartis, Pfizer, Ipsen, Exelixis, Bayer, Eisai, Advanced Accelerator Applications, Amgen, Sanofi and Merck Serono and research support from Eisai, Novartis, Ipsen, Astrazeneca, Pfizer and Advanced Accelerator Applications. IG has received honoraria and/or travel expenses from Roche, Sanofi, Merck, Servier, Amgen and Sirtflex, and for advisory role from Merck and Sanofi. JF has received consulting and advisory honoraria from Amgen, Ipsen, Eissai, Merck, Roche and Novartis; research funding from Merck, and travel and accommodation expenses from Amgen and Servier. The other authors declare no conflicts of interest.