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

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State: Public
Version: Final published version
Serval ID
serval:BIB_B0252FC96268
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
A dualistic model of primary anal canal adenocarcinoma with distinct cellular origins, etiologies, inflammatory microenvironments and mutational signatures: implications for personalised medicine.
Journal
British journal of cancer
Author(s)
Herfs M., Roncarati P., Koopmansch B., Peulen O., Bruyere D., Lebeau A., Hendrick E., Hubert P., Poncin A., Penny W., Piazzon N., Monnien F., Guenat D., Mougin C., Prétet J.L., Vuitton L., Segers K., Lambert F., Bours V., de Leval L., Valmary-Degano S., Quick C.M., Crum C.P., Delvenne P.
ISSN
1532-1827 (Electronic)
ISSN-L
0007-0920
Publication state
Published
Issued date
05/2018
Peer-reviewed
Oui
Volume
118
Number
10
Pages
1302-1312
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
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.
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.
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.
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.
Keywords
Adenocarcinoma/genetics, Adenocarcinoma/pathology, Adult, 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, Male, Middle Aged, Mutation, Precision Medicine, Prognosis, Programmed Cell Death 1 Receptor/genetics, Tumor Microenvironment/genetics
Pubmed
Web of science
Open Access
Yes
Create date
02/05/2018 14:52
Last modification date
20/08/2019 16:19
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