title: Sporadic early-onset colorectal cancer is a specific sub-type of cancer: a morphological, molecular and genetics study.
abstract: Sporadic early onset colorectal carcinoma (EOCRC) which has by definition no identified hereditary predisposition is a growing problem that remains poorly understood. Molecular analysis could improve identification of distinct sub-types of colorectal cancers (CRC) with therapeutic implications and thus can help establish that sporadic EOCRC is a distinct entity. From 954 patients resected for CRC at our institution, 98 patients were selected. Patients aged 45-60 years were excluded to help define "young" and "old" groups. Thirty-nine cases of sporadic EOCRC (patients ≤ 45 years with microsatellite stable tumors) were compared to both microsatellite stable tumors from older patients (36 cases, patients>60 years) and to groups of patients with microsatellite instability. Each group was tested for TP53, KRAS, BRAF, PIK3CA mutations and the presence of a methylator phenotype. Gene expression profiles were also used for pathway analysis. Compared to microsatellite stable CRC from old patients, sporadic EOCRC were characterized by distal location, frequent synchronous metastases and infrequent synchronous adenomas but did not have specific morphological characteristics. A familial history of CRC was more common in sporadic EOCRC patients despite a lack of identified hereditary conditions (p = 0.013). Genetic studies also showed the absence of BRAF mutations (p = 0.022) and the methylator phenotype (p = 0.005) in sporadic EOCRC compared to older patients. Gene expression analysis implicated key pathways such as Wnt/beta catenin, MAP Kinase, growth factor signaling (EGFR, HGF, PDGF) and the TNFR1 pathway in sporadic EOCRC. Wnt/beta catenin signaling activation was confirmed by aberrant nuclear beta catenin immunostaining (p = 0.01). This study strongly suggests that sporadic EOCRC is a distinct clinico-molecular entity presenting as a distal and aggressive disease associated with chromosome instability. Furthermore, several signaling pathways including the TNFR1 pathway have been identified as potential biomarkers for both the diagnosis and treatment of this disease.
authors.affiliation: Centre de Recherche en Cancérologie de Toulouse, Unité Mixte de Recherche, 1037 INSERM - Université Toulouse III, Toulouse, France; Department of Surgery, Centre Hospitalier Universitaire de Toulouse, Toulouse, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Kirzin
authors.affiliation: "Cartes d'Identité des Tumeurs" Program, Ligue Nationale Contre le Cancer, Paris, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Marisa
authors.affiliation: Centre de Recherche en Cancérologie de Toulouse, Unité Mixte de Recherche, 1037 INSERM - Université Toulouse III, Toulouse, France; Department of Oncology, Centre Hospitalier Universitaire de Toulouse, Toulouse, France.
authors.forename: Rosine
authors.initials: R
authors.lastname: Guimbaud
authors.affiliation: "Cartes d'Identité des Tumeurs" Program, Ligue Nationale Contre le Cancer, Paris, France.
authors.forename: Aurélien
authors.initials: A
authors.lastname: De Reynies
authors.affiliation: Laboratoire de Biochimie Biologie Moléculaire, Hôpitaux Universitaires de Hautepierre, Strasbourg, France.
authors.forename: Michèle
authors.initials: M
authors.lastname: Legrain
authors.affiliation: Bases Moléculaires de la réponse aux xénobiotiques, Université Paris Descartes, INSERM, UMR-S775, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Laurent-Puig
authors.affiliation: Centre de Recherche en Cancérologie de Toulouse, Unité Mixte de Recherche, 1037 INSERM - Université Toulouse III, Toulouse, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Cordelier
authors.affiliation: Department of Surgery, Centre Hospitalier Universitaire de Toulouse, Toulouse, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Pradère
authors.affiliation: Department of Oncology, Centre Hospitalier Universitaire de Toulouse, Toulouse, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Bonnet
authors.affiliation: Centre de Recherche en Cancérologie de Toulouse, Unité Mixte de Recherche, 1037 INSERM - Université Toulouse III, Toulouse, France.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Meggetto
authors.affiliation: Department of Surgery, Centre Hospitalier Universitaire de Toulouse, Toulouse, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Portier
authors.affiliation: Centre de Recherche en Cancérologie de Toulouse, Unité Mixte de Recherche, 1037 INSERM - Université Toulouse III, Toulouse, France; Department of Pathology, Centre Hospitalier Universitaire de Toulouse, Toulouse, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Brousset
authors.affiliation: Centre de Recherche en Cancérologie de Toulouse, Unité Mixte de Recherche, 1037 INSERM - Université Toulouse III, Toulouse, France; Department of Pathology, Centre Hospitalier Universitaire de Toulouse, Toulouse, France.
authors.forename: Janick
authors.initials: J
authors.lastname: Selves
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D016000:Cluster Analysis; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D044127:Epigenesis, Genetic; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D015398:Signal Transduction; D059467:Transcriptome; D051176:beta Catenin / Q000378:metabolism
chemical_list: D051176:beta Catenin
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