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.

FrequentBRAFmutation in early-onset colorectal cancer in Taiwan: association with distinct clinicopathological and molecular features and poor clinical outcome

“…In recent years, we have encountered several BRAF -mutated CRCs in patients aged under 30 years, suggesting that this might be a common genetic change in EOCRC. However, the findings of studies in Western countries are in disagreement with our observation 8 9 18. Therefore, in this study, we analysed the molecular characteristics of EOCRC in Taiwan.…”

“…BRAF mutation rates in EOCRCs are lower than, or comparable with, those in older patients in two studies from the USA and one from France 8 9 18. Notably, in the studies of Chang et al and Kirzin et al , no BRAF mutation was detected in EOCRCs even though only microsatellite stable (MSS) tumours were considered 9 18. As early-onset MSI-H tumours are often associated with HNPCC and unlikely to have a BRAF mutation, exclusion of MSI-H tumours would probably increase the BRAF mutation rate.…”

Findings in young adults at colonoscopy from a hospital service database audit

“…SSA/P, being located in the proximal colon in young adults, are therefore unlikely to be the precursor lesion for most early-onset CRC. In support of this premise, somatic BRAF mutation, the molecular genetic hallmark of SSA/P, is relatively rare in CRC from young adults, being present at (3/45) 7% in a Norwegian study [16], 1/68 (2%) in a Spanish report [8], and in 0/39 (0%) from France [14]. Activating mutations in BRAF are present in 14–16% of all population-based CRC [28, 29].…”

Molecular approach to genetic and epigenetic pathogenesis of early-onset colorectal cancer

“…FAP cases are observed in less than 1% frequency in total CRC cases. Thus, 70% of all CRC and the majority of EOCRC cases are introduced in sporadic form [136][137][138] . Sporadic EOCRCs are classified into two major groups.…”

“…Both genetic and epigenetic inactivation of MMR genes result in a mutator phenotype, mutations in cancer related genes and CRC development [144] . Kirzin et al [137] identified CTNNB1 as one of the most over-expressed genes in MSS-young patients compared to MSS-old patients and this leads to an over-activation of beta catenin in sporadic EOCRC. In addition, FernandezRozadilla et al [145] determined a heterozygous deletion in the 10q22-q23 region involving BMPR1A gene of EOCRC cases with MMR proficiency.…”