A dualistic model of primary anal canal adenocarcinoma with distinct cellular origins, etiologies, inflammatory microenvironments and mutational signatures: implications for personalised medicine

Autor: Philippe Delvenne, Frédéric Lambert, Nathalie Piazzon, Séverine Valmary-Degano, Elodie Hendrick, Vincent Bours, Aurélie Poncin, Jean-Luc Prétet, Christiane Mougin, Lucine Vuitton, Karin Segers, Olivier Peulen, David Guenat, Patrick Roncarati, Franck Monnien, Benjamin Koopmansch, Diane Bruyère, Pascale Hubert, Laurence de Leval, William Penny, Michael Herfs, Alizée Lebeau, Christopher P. Crum, Charles M. Quick
Jazyk: angličtina
Rok vydání: 2018
Předmět:
0301 basic medicine
Neuroblastoma RAS viral oncogene homolog
Adult
Male
Cancer Research
Programmed Cell Death 1 Receptor
Adenocarcinoma/genetics
Adenocarcinoma/pathology
Aged
Aged
80 and over
Anus Neoplasms/genetics
Anus Neoplasms/pathology
B7-H1 Antigen/genetics
ErbB Receptors/genetics
Female
Gene Expression Regulation
Neoplastic/drug effects
Humans
Inflammation/genetics
Inflammation/pathology
Kaplan-Meier Estimate
Lymphocytes
Tumor-Infiltrating/pathology
Middle Aged
Mutation
Precision Medicine
Prognosis
Programmed Cell Death 1 Receptor/genetics
Tumor Microenvironment/genetics
Adenocarcinoma
medicine.disease_cause
Article
B7-H1 Antigen
03 medical and health sciences
0302 clinical medicine
Immune system
Lymphocytes
Tumor-Infiltrating
Tumor Microenvironment
Medicine
Gastrointestinal cancer
Inflammation
business.industry
FOXP3
Anal canal
medicine.disease
Anus Neoplasms
Anal canal adenocarcinoma
3. Good health
ErbB Receptors
Gene Expression Regulation
Neoplastic
030104 developmental biology
medicine.anatomical_structure
Oncology
030220 oncology & carcinogenesis
Anal gland
Cancer research
KRAS
business
Zdroj: British Journal of Cancer
British journal of cancer, vol. 118, no. 10, pp. 1302-1312
ISSN: 1532-1827
0007-0920
Popis: Background Primary adenocarcinoma of the anal canal is a rare and aggressive gastrointestinal disease with unclear pathogenesis. Because of its rarity, no clear clinical practice guideline has been defined and a targeted therapeutic armamentarium has yet to be developed. The present article aimed at addressing this information gap by in-depth characterising the anal glandular neoplasms at the histologic, immunologic, genomic and epidemiologic levels. Methods In this multi-institutional study, we first examined the histological features displayed by each collected tumour (n = 74) and analysed their etiological relationship with human papillomavirus (HPV) infection. The intratumoural immune cell subsets (CD4, CD8, Foxp3), the expression of immune checkpoints (PD-1, PD-L1), the defect in mismatch repair proteins and the mutation analysis of multiple clinically relevant genes in the gastrointestinal cancer setting were also determined. Finally, the prognostic significance of each clinicopathological variable was assessed. Results Phenotypic analysis revealed two region-specific subtypes of anal canal adenocarcinoma. The significant differences in the HPV status, density of tumour-infiltrating lymphocytes, expression of immune checkpoints and mutational profile of several targetable genes further supported the separation of these latter neoplasms into two distinct entities. Importantly, anal gland/transitional-type cancers, which poorly respond to standard treatments, displayed less mutations in downstream effectors of the EGFR signalling pathway (i.e., KRAS and NRAS) and demonstrated a significantly higher expression of the immune inhibitory ligand-receptor pair PD-1/PD-L1 compared to their counterparts arising from the colorectal mucosa. Conclusions Taken together, the findings reported in the present article reveal, for the first time, that glandular neoplasms of the anal canal arise by HPV-dependent or independent pathways. These etiological differences leads to both individual immune profiles and mutational landscapes that can be targeted for therapeutic benefits.
Databáze: OpenAIRE
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