title: Proteomic signatures reveal a dualistic and clinically relevant classification of anal canal carcinoma.
abstract: Aetiologically linked to HPV infection, malignancies of the anal canal have substantially increased in incidence over the last 20 years. Although most anal squamous cell carcinomas (SCCs) respond well to chemoradiotherapy, about 30% of patients experience a poor outcome, for undetermined reasons. Despite cumulative efforts for discovering independent predictors of overall survival, both nodal status and tumour size are still the only reliable factors predicting patient outcome. Recent efforts have revealed that the biology of HPV-related lesions in the cervix is strongly linked to the originally infected cell population. To address the hypothesis that topography also influences both gene expression profile and behaviour of anal (pre)neoplastic lesions, we correlated both proteomic signatures and clinicopathological features of tumours arising from two distinct portions of the anal canal: the lower part (squamous zone) and the more proximal anal transitional zone. Although microdissected cancer cells appeared indistinguishable by morphology (squamous phenotype), unsupervised clustering analysis of the whole proteome significantly highlighted the heterogeneity that exists within anal canal tumours. More importantly, two region-specific subtypes of SCC were revealed. The expression profile (sensitivity/specificity) of several selected biomarkers (keratin filaments) further confirmed the subclassification of anal (pre)cancers based on their cellular origin. Less commonly detected compared to their counterparts located in the squamous mucosa, SCCs originating in the transitional zone more frequently displayed a poor or basaloid differentiation, and were significantly correlated with reduced disease-free and overall survivals. Taken together, we present direct evidence that anal canal SCC comprises two distinct entities with different cells of origin, proteomic signatures, and survival rates. This study forms the basis for a dualistic classification of anal carcinoma, with implications for management, outcome expectations, and possibly therapy. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
authors.affiliation: Laboratory of Experimental Pathology, GIGA-Cancer, University of Liège, Liège, Belgium.
authors.forename: Michael
authors.initials: M
authors.lastname: Herfs
authors.affiliation: Mass Spectrometry Laboratory, Systems Biology and Chemical Biology, GIGA-Research, University of Liège, Liège, Belgium.
authors.forename: Rémi
authors.initials: R
authors.lastname: Longuespée
authors.affiliation: Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Quick
authors.affiliation: Laboratory of Experimental Pathology, GIGA-Cancer, University of Liège, Liège, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Roncarati
authors.affiliation: Laboratory of Experimental Pathology, GIGA-Cancer, University of Liège, Liège, Belgium.
authors.forename: Meggy
authors.initials: M
authors.lastname: Suarez-Carmona
authors.affiliation: Laboratory of Experimental Pathology, GIGA-Cancer, University of Liège, Liège, Belgium.
authors.forename: Pascale
authors.initials: P
authors.lastname: Hubert
authors.affiliation: Laboratory of Experimental Pathology, GIGA-Cancer, University of Liège, Liège, Belgium.
authors.forename: Alizée
authors.initials: A
authors.lastname: Lebeau
authors.affiliation: Laboratory of Experimental Pathology, GIGA-Cancer, University of Liège, Liège, Belgium.
authors.forename: Diane
authors.initials: D
authors.lastname: Bruyere
authors.affiliation: Mass Spectrometry Laboratory, Systems Biology and Chemical Biology, GIGA-Research, University of Liège, Liège, Belgium.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Mazzucchelli
authors.affiliation: Mass Spectrometry Laboratory, Systems Biology and Chemical Biology, GIGA-Research, University of Liège, Liège, Belgium.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Smargiasso
authors.affiliation: Mass Spectrometry Laboratory, Systems Biology and Chemical Biology, GIGA-Research, University of Liège, Liège, Belgium.|GIGA Proteomic Facility, University of Liège, Liège, Belgium.
authors.forename: Dominique
authors.initials: D
authors.lastname: Baiwir
authors.affiliation: Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: Keith
authors.initials: K
authors.lastname: Lai
authors.affiliation: Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Dunn
authors.affiliation: Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: Fabiola
authors.initials: F
authors.lastname: Obregon
authors.affiliation: Department of Pathology, Division of Women's and Perinatal Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Yang
authors.affiliation: Mass Spectrometry Laboratory, Systems Biology and Chemical Biology, GIGA-Research, University of Liège, Liège, Belgium.
authors.forename: Edwin De
authors.initials: E
authors.lastname: Pauw
authors.affiliation: Department of Pathology, Division of Women's and Perinatal Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Crum
authors.affiliation: Laboratory of Experimental Pathology, GIGA-Cancer, University of Liège, Liège, Belgium.
authors.forename: Philippe
authors.initials: P
authors.lastname: Delvenne
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001003:Anal Canal / Q000473:pathology / Q000821:virology; D001005:Anus Neoplasms / Q000145:classification* / Q000473:pathology / Q000821:virology; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000145:classification* / Q000473:pathology / Q000821:virology; D002584:Cervix Uteri / Q000473:pathology / Q000821:virology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D027383:Papillomaviridae / Q000502:physiology*; D040901:Proteomics
chemical_list: D014408:Biomarkers, Tumor
keywords: HPV; anal cancer; gastrointestinal malignancies; histopathology; proteomic analysis