The two single nucleotide polymorphisms in the H37/RBM5 tumour suppressor gene at 3p21.3 correlated with different subtypes of non-small cell lung cancers

Abstract

SummaryAllele loss and genetic alteration in chromosome 3p, particularly in 3p21.3 region, are the most frequent and the earliest genomic abnormalities found in lung cancer. Multiple 3p21.3 genes exhibit various degrees of tumour suppression activity suggesting that 3p21.3 genes may function as an integrated tumour suppressor region through their diverse biological activities. We have previously demonstrated growth inhibitory effects and tumour suppression mechanism of the H37/RBM5 gene which is one of the 19 genes residing in the 370kb minimal overlap region at 3p21.3. In the current study, in an attempt to find, if any, mutations in the H37 coding region in lung cancer cells, we compared nucleotide sequences of the entire H37 gene in tumour vs. adjacent normal tissues from 17 non-small cell lung cancer (NSCLC) patients. No mutations were detected, instead, we found the two silent single nucleotide polymorphisms (SNPs), C1138T and C2185T, within the coding region of the H37 gene. In addition, we found that specific allele types at these SNP positions are correlated with different histological subtypes of NSCLC; tumours containing heterozygous alleles (C+T) at these SNP positions are more likely to be associated with adenocarcinoma (AC) whereas homozygous alleles (either C or T) are associated with squamous cell carcinoma (SCC) (p=0.0098). We postulate that, these two silent polymorphisms may be in linkage disequilibrium (LD) with a disease causative allele in the 3p21.3 tumour suppressor region which is packed with a large number of important genes affecting lung cancer development. In addition, because of prevalent loss of heterozygosity (LOH) detected at 3p21.3 which precedes lung cancer initiation, these SNPs may be developed into a marker screening for the high risk individuals. Keywords lung cancer; H37/RBM5/Luca15; single nucleotide polymorphism; 3p21.3; tumour suppressor gene; linkage disequilibrium; loss of heterozygosity

Frequent 3p21 allelic loss and methylation-associated RASSF1A inactivation in non-small cell lung cancer and its clinical implication

“…3p21 allelic loss, as indicated by LOH at 2 or more adjacent markers, was detected in more than 50% of cases, with loss at individual locus occurring in 35.4%-46.1% of informative cases. This LOH frequency is consistent with those previously reported in other studies of 3p21 loss in NSCLC [14][15][16][17] . Statistically significant associations were observed in univariate analysis between 3p21 LOH and smoking history, tumor histological type, and patient gender, respectively, with a higher proportion of deletion, observed in SM compared to NS, SCC, and AD as well as in men compared with in women.…”

Whole-transcriptome microarray analysis reveals regulation of Rab4 by RBM5 in neurons

“…Given that endogenous mechanisms exist by which RBM5 activity could be decreased in humans - such as by microRNAs (miRNA) (Selbach et al, 2008), intronic antisense transcripts located within the RBM5 precursor mRNA (e.g. Je2) (Mourtada-Maarabouni et al, 2002, Rintala-Maki and Sutherland, 2009), other long non-coding RNAs (lncRNA) (Sehgal et al, 2014), and by RBM5 polymorphisms (Oh et al, 2007) - future studies are needed to examine if RBM5 similarly regulates Rab4a/SERT in human neurons.…”

Up-regulation of the proapoptotic caspase 2 splicing isoform by a candidate tumor suppressor, RBM5

“…RBM5 was originally identified as one of genes deleted in human lung cancer in the 3p21.3 chromosomal region (23) together with two single-nucleotide polymorphism changes (24). RBM5 expression is repressed in 70-80% of lung cancers (25).…”

“…RBM5 was originally identified as one of genes deleted in human lung cancer in the 3p21.3 chromosomal region (23) together with two single-nucleotide polymorphism changes (24). RBM5 expression is repressed in 70-80% of lung cancers (25). RBM5 overexpression causes cell cycle arrest, apoptosis, and inhibition of tumor growth (25)(26)(27)29), sensitizing cells to apoptosis induced by death receptor ligands, FAS, TNF-␣, and TRAIL (31,32).…”