The chromatin remodelling component SMARCB1/INI1 influences the metastatic behavior of colorectal cancer through a gene signature mapping to chromosome 22

Abstract

BackgroundINI1 (Integrase interactor 1), also known as SMARCB1, is the most studied subunit of chromatin remodelling complexes. Its role in colorectal tumorigenesis is not known.MethodsWe examined SMARCB1/INI1 protein expression in 134 cases of colorectal cancer (CRC) and 60 matched normal mucosa by using tissue microarrays and western blot and categorized the results according to mismatch repair status (MMR), CpG island methylator phenotype, biomarkers of tumor differentiation CDX2, CK20, vimentin and p53. We validated results in two independent data sets and in cultured CRC cell lines.ResultsHerein, we show that negative SMARCB1/INI1 expression (11% of CRCs) associates with loss of CDX2, poor differentiation, liver metastasis and shorter patients’ survival regardless of the MMR status or tumor stage. Unexpectedly, even CRCs displaying diffuse nuclear INI1 staining (33%) show an adverse prognosis and vimentin over-expression, in comparison with the low expressing group (56%). The negative association of SMARCB1/INI1-lack of expression with a metastatic behavior is enhanced by the TP53 status. By interrogating global gene expression from two independent cohorts of 226 and 146 patients, we confirm the prognostic results and identify a gene signature characterized by SMARCB1/INI1 deregulation. Notably, the top genes of the signature (BCR, COMT, MIF) map on the long arm of chromosome 22 and are closely associated with SMARCB1/INI1.ConclusionOur findings suggest that SMARCB1/INI1-dysregulation and genetic hot-spots on the long arm of chromosome 22 might play an important role in the CRC metastatic behavior and be clinically relevant as novel biomarkers.

Comprehensive evaluation of coding region point mutations in microsatellite‐unstable colorectal cancer

“…Loss of expression of SMARCB1 has been reported in colorectal adenocarcinomas and has been associated with higher histological grade, larger tumor size, poor overall survival, MSI, and the BRAF V600E mutation (Wang et al , ). Another CRC study has reported low expression of SMARCB1 to associate with poor differentiation, liver metastasis, and poorer survival regardless of the MMR status or tumor stage (Pancione et al , ).…”

Cancer-related CD15/FUT4 overexpression decreases benefit to agents targeting EGFR or VEGF acting as a novel RAF-MEK-ERK kinase downstream regulator in metastatic colorectal cancer

“…An independent cohort, named as validation series II consisting of 140 stage I-IV primary CRCs collected consecutively was then evaluated [ 21 , 22 ]. They represented a continuous, unselected TMAs cohort of patients with molecular, histopathological and clinical findings (OS) recruited during the period 2003–2009.…”

“…The gene-specific copy number was calculated according to the standard curve and normalized to the amount of cDNA (ng) in the reaction. All PCR reactions were performed in triplicate and expression levels were computed as reported [ 20 , 21 , 27 ].…”

The clinical perspectives of CDX2 expression in colorectal cancer: A qualitative systematic review

“…MUC2, MUC5AC, and MUC6 [51]. Furthermore, loss of CDX2 expression was associated with decreased expression of SMARCB1/ INI1 À a subunit of the chromatin remodeling complex À which might lead to change in transcription of several genes [53]. …”