The role of SMAD4 in early‐onset colorectal cancer

Abstract

Objective Chromosomal loss within the region of 18q and loss of SMAD4 expression have been reported to be frequent somatic events during colorectal cancer tumour progression; however, their associations with age at onset have not been widely studied. Method We analysed 109 tumours from a population-based case-family study based on colorectal cancers diagnosed before the age of 45 years. These patients with early-onset colorectal cancer had been previously screened for germ-line mismatch repair gene mutations, microsatellite instability (that included the mononucleotide repeat in TGFβRII) and somatic k-ras mutations. We measured SMAD4 protein expression using immunohistochemistry and SMAD4 copy number using quantitative real-time PCR. Results Loss of SMAD4 protein expression was observed in 27/109 (25%) of cancers tested and was more commonly observed in rectal tumours (15/41, 36%) when compared with tumours arising in the colon (11/66, 17%) (P = 0.04). There was no association between SMAD4 protein expression and TGFβR11 mutation status, SMAD4 copy number, family history, MSI status, tumour stage or grade. Conclusion Loss of SMAD4 expression is a common feature of early-onset colorectal tumours as it is in colorectal cancers diagnosed in other age-groups. Taken together, the molecular pathways (genetic and epigenetic) now known to be involved in early-onset colorectal cancer only explain a small proportion of the disease and require further exploration.

Loss of p15INK4bExpression in Colorectal Cancer is Linked to Ethnic Origin

“…This is supported by the methylation data on colorectal cancers of Chinese (Xu et al, 2004) and Japanese origin (Ishiguro et al, 2006). the tumors examined of both Egyptian and Finnish origin consistent with the published literature (Royce et al, 2010;Ahn et al, 2011). SMAD4 is a potential upstream inducer of p15 INK4b (see introduction).…”

SMAD4 protein expression and cell proliferation in colorectal adenocarcinomas

“…The results of our study suggest that in colorectal adenocarcinomas, the loss of SMAD4 nuclear expression, [23,[28][29][30][31][32]. In the present study, we investigated a 'homogeneous' group of invasive adenocarcinomas.…”

“…Similar to other reported data [28,30], we observed that loss of SMAD4 nuclear expression was infrequent and showed a tendency to relate to aberrant MMR protein expression (p=0.08). However, a complete lack of correlation between SMAD4 expression and presence of microsatellite instability has been reported in early onset colorectal cancer [29] and in inflammatory bowel disease-associated colorectal adenocarcinomas [52]. Events other than abnormal SMAD4 signalling, such as TGFβRII mutation, could be related to abnormal TGFβ signalling in tumours lacking the MMR protein [66][67][68].…”

Targeting the ERK pathway reduces liver metastasis of Smad4-inactivated colorectal cancer

“…2,13 Loss of SMAD4 has been reported to occur in 9-67% of CRC and is associated with advanced disease, metastasis and poor prognosis of CRC. 13,[20][21][22][23] It has been proposed that loss of Smad4 may contribute to functional shift of TGF-β from tumor suppressor to tumor promoter. 24,25 Notably, overactivation of TGF-β induced MEK/ERK and p38-MAPK pathways are involved in malignancy promotion and drug resistance of colon cancer.…”