Genetic variations affecting serum carcinoembryonic antigen levels and status of regional lymph nodes in patients with sporadic colorectal cancer from Southern China.

BACKGROUND: Serum carcinoembryonic antigen (sCEA) level might be an indicator of disease. Indeed, an elevated sCEA level is a prognostic factor in colorectal cancer (CRC) patients. However, the genetic determinants of sCEA level in healthy and CRC population remains unclear. Thus we investigated the genetic markers associated with elevated serum sCEA level in these two populations and its clinical implications. METHODS AND FINDINGS: Genome-wide association study (GWAS) was conducted in a cohort study with 4,346 healthy male adults using the Illumina Omni 1 M chip. Candidate SNPs associated with elevated sCEA levels were validated in 194 CRC patients on ABI Taqman platform. Eight candidate SNPs were validated in CRC patients. The rs1047781 (chr19- FUT2) (A/T) was associated with elevated sCEA levels, and rs8176746 (chr9- ABO) was associated with the regional lymph metastasis in the CRC patients. The preoperative sCEA level was a risk factor for tumor recurrence in 5 years after operation (OR = 1.427, 95% CI: 1.005∼1.843, P = 0.006). It was also one of the risk factors for regional lymph node metastasis (OR = 2.266, 95% CI: 1.196∼4.293, P = 0.012). The sCEA level in rs1047781-T carriers was higher than that in the A carriers in CRC patients without lymph node metastasis (P = 0.006). The regional lymph node metastasis in patients with homozygote AA of rs8176746 was more common than that in the heterozygote AG carriers (P = 0.022). In addition, rs1047781-AT and TT CRC patients exhibited a worse disease-free survival than AA genotype carriers (P = 0.023). CONCLUSIONS: We found candidate SNPs associated with elevated sCEA levels in both healthy males and CRC population. Rs1047781 (chr19- FUT2) may be the susceptible locus for recurrence of CRC in a population from Southern China

Tumor-free survival analysis of CRC patients stratified by rs1047781+rs8176746 genotypes.

<p>Subjects were divided into 2 groups by genetic maker (rs1047781+rs8176746). Group 1 was rs1047781 (AA) +rs8176746 (AA+AG) and group 2 was rs1047781 (AT+TT) +rs8176746 (AA+AG). The disease-free time of subgroups was significantly different (<i>p</i> = 0.023).</p

Tumor-free survival analysis of CRC patients stratified by preoperative sCEA levels.

<p>The tumor-free time was different between CRC patients with preoperative CEA levels at <5 and ≥5 ng/ml (<i>p</i> = 0.001).</p

Univariate analysis of factors affecting the preoperative CEA levels in CRC patients.

1<p>The CEA level was represented by median.</p>2<p>The tumor size was represented by the max diameter of primary tumor. The patients with regional lymph nodes metastases or distant metastases were excluded in this analysis.</p

Tumor-free survival analysis of CRC patients stratified by regional lymph nodes.

<p>The tumor-free time was different between CRC patients with and without lymph node metastases (<i>p</i><0.001).</p

Tumor-free survival analysis of CRC patients stratified by rs1047781.

<p>With rs1047781 (chr-19 FUT2), the disease-free time of CRC patients grouped by allelic genotypes (AA, AT and TT) was not significantly different (<i>p</i> = 0.066).</p

Association between RLN metastasis and preoperative sCEA levels (stratified by rs1047781 genotypes).

1<p>The values of CEA levels and times were represented by median values, and the range of sCEA level is shown.</p>2<p>St. J-T statistic was represented using the standard statistic of Jonckheere-Terpstra test.</p>3<p>The distant organs included liver, lung and omentum.</p>4<p>The rate of tumor lymph node metastasis was adjusted.</p>5<p>The statistical evaluation for CEA levels was performed by Mann-Whitney U test.</p

Tumor-free survival analysis of CRC patients stratified by rs8176746 genotypes.

<p>With rs8176746 (chr-9 ABO), the disease-free time of CRC patients grouped by allelic genotypes (AA and AG) was not significantly different (<i>p</i> = 0.366). Subjects with genotype GG were excluded (n = 2).</p