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.
Highlights
Colorectal cancer (CRC) is most commonly seen in elderly adults with a median age at diagnosis of 70 years [1]
Rectal tumors were more abundant in sporadic Early onset CRC (EOCRC) (41% versus 8.3%, p = 7.4 e-04) with less frequent adenomas seen on resected specimens (8% versus 33%, p = 0.013)
The results of the present study suggest that sporadic EOCRC is a distinct clinical and molecular entity
Summary
Colorectal cancer (CRC) is most commonly seen in elderly adults with a median age at diagnosis of 70 years [1]. According to US registries the incidence of CRC in young adults is rising constantly, at a rate of 1.5% per year between 1992 and 2005 in adults aged 20–49 [2]. Individuals can be predisposed to EOCRC through heredity and inflammatory bowel diseases. The most well-defined hereditary forms of CRC are Lynch syndrome and familial adenomatous polyposis (FAP) that account for 2–4% and less than 1% of total CRC cases, respectively [3]. The relative contribution of inflammatory bowel diseases and FAP to EOCRC is modest since both conditions can be identified by their clinical features and managed by screening and prophylactic treatment according to established guidelines. Lynch syndrome does not display a specific phenotype and frequently leads to carcinoma, making up one-third of EOCRC cases [4]. The majority of EOCRC are sporadic cases that lack genetic markers indicating predisposition
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
