RESUMO
BACKGROUND & AIMS: Barrett's esophagus (BE) increases the risk of esophageal adenocarcinoma (EAC). We found the risk to be BE has been associated with single nucleotide polymorphisms (SNPs) on chromosome 6p21 (within the HLA region) and on 16q23, where the closest protein-coding gene is FOXF1. Subsequently, the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) identified risk loci for BE and esophageal adenocarcinoma near CRTC1 and BARX1, and within 100 kb of FOXP1. We aimed to identify further SNPs that increased BE risk and to validate previously reported associations. METHODS: We performed a genome-wide association study (GWAS) to identify variants associated with BE and further analyzed promising variants identified by BEACON by genotyping 10,158 patients with BE and 21,062 controls. RESULTS: We identified 2 SNPs not previously associated with BE: rs3072 (2p24.1; odds ratio [OR] = 1.14; 95% CI: 1.09-1.18; P = 1.8 × 10(-11)) and rs2701108 (12q24.21; OR = 0.90; 95% CI: 0.86-0.93; P = 7.5 × 10(-9)). The closest protein-coding genes were respectively GDF7 (rs3072), which encodes a ligand in the bone morphogenetic protein pathway, and TBX5 (rs2701108), which encodes a transcription factor that regulates esophageal and cardiac development. Our data also supported in BE cases 3 risk SNPs identified by BEACON (rs2687201, rs11789015, and rs10423674). Meta-analysis of all data identified another SNP associated with BE and esophageal adenocarcinoma: rs3784262, within ALDH1A2 (OR = 0.90; 95% CI: 0.87-0.93; P = 3.72 × 10(-9)). CONCLUSIONS: We identified 2 loci associated with risk of BE and provided data to support a further locus. The genes we found to be associated with risk for BE encode transcription factors involved in thoracic, diaphragmatic, and esophageal development or proteins involved in the inflammatory response.
Assuntos
Esôfago de Barrett/genética , Proteínas Morfogenéticas Ósseas/genética , Predisposição Genética para Doença , Fatores de Diferenciação de Crescimento/genética , Polimorfismo de Nucleotídeo Único , Proteínas com Domínio T/genética , Esôfago de Barrett/etiologia , Neoplasias Esofágicas/genética , Estudo de Associação Genômica Ampla , Humanos , RiscoRESUMO
Human mammaglobin (hMAM) mRNA is considered to be a promising candidate for a sensitive molecular marker for breast cancer. In this study, we attempted to relate the presence of hMAM mRNA in the peripheral blood with certain established clinicopathological features of breast cancer in order to validate its clinical utility. A total of 139 subjects including 79 with localized cancer, 33 with metastatic disease, and a control group of 27 individuals were studied. hMAM mRNA expression was assessed by reverse transcriptase polymerase chain reaction on cells from peripheral blood. The expression of hMAM mRNA was found in 0 of the 27 control subjects, 1 of the 8 stage 0 (12.5%) patients, 4 of the 16 stage I (25%) patients, 13 of the 40 stage II (32.5%) patients, 5 of the 15 stage III (33.3%) patients, and 18 of the 33 (54%) cases of metastatic disease. There was a statistically significant (P=0.045) difference in frequency between patients with localized disease (29%) and those with metastatic disease. Although trends of increasing frequency of hMAM mRNA expression existed in patients with unfavorable prognostic factors, including primary tumor size, T stage, N stage, overall stage, presence of angiolymphatic permeation, negative estrogen receptor, high 5-phase fraction (>7%), and aneuploid DNA index, none of the differences was significant. In conclusion, the clinical utility of hMAM mRNA may not be in screening or staging of breast cancer, but in following patients after surgery to detect recurrence. Further evaluation of hMAM mRNA in combination with other molecular markers to follow post-operative breast cancer patient is warranted.
