Association of Caucasian-identified variants with colorectal cancer risk in Singapore Chinese

Background: Genome-wide association studies (GWAS) in Caucasians have identified fourteen index single nucleotide polymorphisms (iSNPs) that influence colorectal cancer (CRC) risk. Methods: We investigated the role of eleven iSNPs or surrogate SNPs (sSNPs), in high linkage disequilibrium (LD, r2≥0.8) and within 100 kb vicinity of iSNPs, in 2,000 age- and gender-matched Singapore Chinese (SCH) cases and controls. Results: Only iSNP rs6983267 at 8q24.21 and sSNPs rs6695584, rs11986063, rs3087967, rs2059254, and rs7226855 at 1q41, 8q23.3, 11q23.1, 16q22.1 and 18q21.1 respectively showed evidence of association with CRC risk, with odds ratios (OR) ranging from 1.13 to 1.40. sSNP rs827401 at 10p14 was associated with rectal cancer risk (OR = 0.74, 95% CI 0.63-0.88) but not disease prognosis (OR = 0.91, 95% CI 0.69-1.20). Interestingly, sSNP rs3087967 at 11q23.1 was associated with CRC risk in men (OR = 1.34, 95% CI 1.14-1.58) but not women (OR = 1.07, 95% CI: 0.88-1.29), suggesting a gender-specific role. Half of the Caucasian-identified variants, including the recently fine-mapped BMP pathway loci, BMP4, GREM1, BMP2 and LAMA 5, did not show any evidence for association with CRC in SCH (OR ~1; p-value >0.1). Comparing the results of this study with that of the Northern and Hong Kong Chinese, only variants at chromosomes 8q24.21, 10p14, 11q23.1 and 18q21.1 were replicated in at least two out of the three Chinese studies. Conclusions: The contrasting results between Caucasians and Chinese could be due to different LD patterns and allelic frequencies or genetic heterogeneity. The results suggest that additional common variants contributing to CRC predisposition remained to be identified. © 2012 Thean et al

Enhancer-derived long non-coding RNAs CCAT1 and CCAT2 at rs6983267 has limited predictability for early stage colorectal carcinoma metastasis

Up-regulation of long non-coding RNAs (lncRNAs), colon-cancer associated transcript (CCAT) 1 and 2, was associated with worse prognosis in colorectal cancer (CRC). Nevertheless, their role in predicting metastasis in early-stage CRC is unclear. We measured the expression of CCAT1, CCAT2 and their oncotarget, c-Myc, in 150 matched mucosa-tumour samples of early-stage microsatellite-stable Chinese CRC patients with definitive metastasis status by multiplex real-time RT-PCR assay. Expression of CCAT1, CCAT2 and c-Myc were significantly up-regulated in the tumours compared to matched mucosa (p < 0.0001). The expression of c-Myc in the tumours was significantly correlated to time to metastasis [hazard ratio = 1.47 (1.10–1.97)] and the risk genotype (GG) of rs6983267, located within CCAT2. Expression of c-Myc and CCAT2 in the tumour were also significantly up-regulated in metastasis-positive compared to metastasis-negative patients (p = 0.009 and p = 0.04 respectively). Nevertheless, integrating the expression of CCAT1 and CCAT2 by the Random Forest classifier did not improve the predictive values of ColoMet19, the mRNA-based predictor for metastasis previously developed on the same series of tumours. The role of these two lncRNAs is probably mitigated via their oncotarget, c-Myc, which was not ranked high enough previously to be included in ColoMet19

Chromosome 19q13 disruption alters expressions of <i>CYP2A7</i>, <i>MIA</i> and <i>MIA-RAB4B</i> lncRNA and contributes to FAP-like phenotype in <i>APC</i> mutation-negative familial colorectal cancer patients - Fig 4

<p><b>Relative quantitation of (A) <i>MIA</i> (B) <i>MIA-RAB4B</i> (C) <i>PIM2</i> and (D) <i>TAOK1</i> transcripts in the polyps normalized to matched mucosa of 344 and 421 respectively.</b><i>MIA-RAB4B</i> is the read-through lncRNAs of <i>MIA</i> and <i>RAB4B</i>. <i>PIM2</i> and <i>TAOK1</i> are two other target oncogenes of miR-24.</p

Pedigree of <i>APC</i> mutation-negative familial CRC family 1.

<p>Arrow indicates the proband.</p

Association of CEU-identified iSNP/sSNPs with CRC risk in SCH.

<p>CEPH Europeans (CEU)-identified index and surrogate SNPs in bold and italics font respectively.</p><p>Singapore Chinese (SCH) surrogate SNPs that are different from the CEU i/sSNPs in normal font.</p><p>¹Minor allele frequencies (Caucasian/Chinese Han Beijing) from HapMap Release 28.</p><p>²Note: Minor allele in CEU maybe major allele in SCH/CHB.</p><p>^aSignificant after Bonferroni correction (P<0.0031).</p><p>SNP locations based on Human Genome build 36.</p

Local pairwise LD plots.

<p>The plots for SNPs at chromosomes 19q13.11 (A), 11q23.1 (B), 20p12.3 (C) and 20p12.3 (D) were derived from SCH controls and HapMap CHB individuals respectively. Arrow and arrowhead indicate positions of iSNP and sSNPs interrogated. The sSNPs interrogated at chromosomes 11q23.1 (B) and 20p12.3 (D) were rs3087967 and rs5005940 respectively. LD was measured as R².</p

Distribution of clinicopathological features among cases and controls.

<p>Distribution of clinicopathological features among cases and controls.</p

Comparison of effect sizes of CEU-identified variants for CRC across CEU and three different Chinese populations.

#<p>CEU SNP reference sources: as reported in the GWAS catalogue for CRC: <a href="http://www.genome.gov/gwastudies/index.cfm?pageid=26525384#searchForm" target="_blank">http://www.genome.gov/gwastudies/index.cfm?pageid=26525384#searchForm</a>.</p><p>?Northern Chinese (reference 5); ^&Hong Kong Chinese (reference 6); NP =  non-polymorphic; NS =  no surrogate SNP at high LD within 100 kb of iSNP; empty cell  =  SNP not interrogated; *show evidence of being associated with CRC risk; **show evidence of being associated with rectal cancer risk.</p