Elinor Sawyer

Polymorphisms near TBX5 and GDF7 are associated with increased risk for Barrett's esophagus.

Background & Aims Barretts 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 Barretts 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.

Evaluation of variants in the CHEK2, BRIP1 and PALB2 genes in an Irish breast cancer cohort

It has been proposed that rare variants within the double strand break repair genes CHEK2, BRIP1 and PALB2 predispose to breast cancer. The aim of this study was to evaluate the prevalence of these variants in an Irish breast cancer cohort and determine their contribution to the development of breast cancer in the west of Ireland. We evaluated the presence of CHEK2_1100delC variant in 903 breast cancer cases and 1,016 controls. Six previously described variants within BRIP1 and five within PALB2 were screened in 192 patients with early-onset or familial breast cancer. Where a variant was evident, it was then examined in the remainder of our 711 unselected breast cancer cases. CHEK2_1100delC was found in 5/903 (0.5%) breast cancer cases compared to 1/1016 (0.1%) controls. One mutation at BRIP1 (2392 C>T) was identified in the early-onset/familial cohort. Examination of this variant in the remainder of our cohort (711 cases) failed to identify any additional cases. None of the previously described PALB2 variants were demonstrated in the early-onset/familial cohort. We show evidence of CHEK2_1100delC and BRIP1 2392 C>T within the Irish population. CHEK2_1100delC and BRIP1 mutations incidence in Ireland is similar to that found in other unselected breast cancer cohorts from northern European countries. We found no evidence to suggest that PALB2 mutation is an important breast cancer predisposition gene in this population.

The TGFBR1*6A/9A polymorphism is not associated with differential risk of breast cancer

A polymorphic 9-bp deletion in exon 1 of TGFBR1 (TGFBR1*6A) has been identified as a low-penetrance cancer susceptibility allele. The strongest association in the initial studies was with breast cancer; however, these studies included patients with different types of cancer, including colon, cervical and breast carcinomas, with only a small proportion being breast cancer patients. In subsequent case–control studies focussing on breast cancer alone, the results have been equivocal. In order to clarify whether TGFBR1*6A is associated with breast cancer risk, we have genotyped this polymorphism in 988 breast cancer cases and 1,016 controls from the West of Ireland and also performed a meta-analysis of previously published data (5,150 cases and 6,344 controls). In our series from the West of Ireland, we found no association (genotypic odds ratio (OR) under a dominant modelxa0=xa00.93, 95% confidence interval (CI) 0.73–1.19, Pxa0=xa00.57; allelic ORxa0=xa00.93, 95% CI 0.74–1.15, Pxa0=xa00.49). Meta-analysis showed evidence of heterogeneity among studies. Using the random effects model, it was found that there was no evidence of an association of the *6A allele with breast cancer (genotypic OR under a dominant modelxa0=xa01.10, 95% CIxa0=xa00.94–1.28, Pxa0=xa00.24, allelic ORxa0=xa01.12, 95% CI 0.97–1.31, Pxa0=xa00.13). In conclusion, our study shows that there is no association between TGFBR1*6A and breast cancer risk.