Two functional indel polymorphisms in the promoter region of the Brahma gene (BRM) and disease risk and progression-free survival in colorectal cancer

Background and objective The Brahma gene (BRM) encodes a catalytic ATPase subunit of the Switch/Sucrose non-fermentable (SWI/SNF) complex, which modulates gene expression and many important cellular processes. Two indel polymorphisms in the promoter region of BRM (BRM-741 and BRM-1321) are associated with its reduced expression and the risk of susceptibility or survival outcomes in multiple solid cancers. In this study, we have examined these variants in relation to susceptibility and survival outcomes in colorectal cancer. Methods Genotypes were obtained using TaqMan assays in 427 cases and 408 controls. Multivariate logistic and Cox regression models were fitted to examine the associations of the BRM-741 and BRM-1321 genotypes adjusting for relevant covariates. Sub-group analyses based on tumor location and patient sex were also performed. In all analyses, indels were examined individually as well as in combination. Results Our results showed that there was no association between the BRM polymorphisms and the risk of colorectal cancer. However, genotype combinations of the BRM-741 and BRM-1321 variants were associated with the risk of colon cancer. Particularly, patients having at least one variant allele had increased risk of colon cancer when compared to patients with the double wild-type genotype. In the survival analyses, BRM-741 heterozygosity was associated with longer progression-free survival time in the colorectal cancer patients. A stronger association was detected in the male patients under the recessive genetic model where the homozygosity for the variant allele of BRM-741 was associated with shorter progression-free survival time. Conclusions Our analyses suggest that BRM-741 and BRM-1321 indels are associated with the risk of developing colon cancer and the BRM-741 indel is associated with the disease progression in colorectal cancer patients, especially in the male patients. Although our results show a different relationship between these indels and colorectal cancer compared to other cancer sites, they also suggest that BRM and its promoter variants may have biological roles in susceptibility and survival outcomes in colorectal cancers. Performing further analyses in additional and larger cohorts are needed to confirm our conclusions

Distribution of HLA-A, -B and -DRB1 Genes and Haplotypes in the Tujia Population Living in the Wufeng Region of Hubei Province, China

BACKGROUND: The distribution of HLA alleles and haplotypes varies widely between different ethnic populations and geographic areas. Before any genetic marker can be used in a disease-associated study it is therefore essential to investigate allelic frequencies and establish a genetic database. METHODOLOGY/PRINCIPAL FINDINGS: This is the first report of HLA typing in the Tujia group using the Luminex HLA-SSO method HLA-A, -B and -DRB1 allelic distributions were determined in 124 unrelated healthy Tujia individuals, and haplotypic frequencies and linkage disequilibrium parameters were estimated using the maximum-likelihood method. In total 10 alleles were detected at the HLA-A locus, 21 alleles at the HLA-B locus and 14 alleles at the HLA-DRB1 locus. The most frequently observed alleles in the HLA-I group were HLA-A*02 (35.48%), A*11 (28.23%), A*24 (15.73%); HLA-B*40 (25.00%), B*46 (16.13%), and B*15 (15.73%). Among HLA-DRB1 alleles, high frequencies of HLA-DRB1*09 (25.81%) were observed, followed by HLA-DRB1*15 (12.9%), and DRB1*12 (10.89%). The two-locus haplotypes at the highest frequency were A*02-B*46A (8.47%), followed by A*11-B*40 (7.66%), A*02-B*40 (8.87%), A*11-B*15 (6.45%), A*02-B*15 (6.05%), B*40-DRB1*09 (9.27%) and B*46-DRB1*09 (6.45%). The most common three-locus haplotypes found in the Tujia population were A*02-B*46-DRB1*09 (4.84%) and A*02-B*40-DRB1*09 (4.03%). Fourteen two-loci haplotypes had significant linkage disequilibrium. Construction of a neighbor-joining phylogenetic tree and principal component analysis using the allelic frequencies at HLA-A was performed to compare the Tujia group and twelve other previously reported populations. The Tujia population in the Wufeng of Hubei Province had the closest genetic relationship with the central Han population, and then to the Shui, the Miao, the southern Han and the northern Han ethnic groups. CONCLUSIONS/SIGNIFICANCE: These results will become a valuable source of data for tracing population migration, planning clinical organ transplantation, carrying out HLA-linked disease-associated studies and forensic identification

Characteristics and methodological quality of studies included in meta analysis.

a<p>C, Caucasian; U, Unknown.</p>b<p>median or mean age.</p>c<p>S, Single centre; M, Multicentre.</p>d<p>SPR, Sizing of PCR products; PYRS, Pyrosequencing; Sequencing, other DNA sequencing methods.</p>e<p>IR(I), irinotecan; 5FU, 5-fluorouracil; CAPe, capecitabine; OX(A), oxaliplatin; LV, leucovorin; XEL, xeloda; TEGAF, uracil/tegafur/LV.</p>f<p>RECIST, Response Evaluation Criteria in Solid Tumors.</p>g<p>R, analysis was planned retrospectively; P, analysis was planned prospectively.</p>h<p>TR, therapeutic response; PFS, progression-free survival; OS, overall survival.</p>i<p>These data were not available.</p

Association between UGT1A1*28 Polymorphisms and Clinical Outcomes of Irinotecan-Based Chemotherapies in Colorectal Cancer: A Meta-Analysis in Caucasians

<div><p>Background</p><p>Whether UGT1A1*28 genotype is associated with clinical outcomes of irinotecan (IRI)-based chemotherapy in Colorectal cancer (CRC) is an important gap in existing knowledge to inform clinical utility. Published data on the association between UGT1A1*28 gene polymorphisms and clinical outcomes of IRI-based chemotherapy in CRC were inconsistent.</p> <p>Methodology/Principal Findings</p><p>Literature retrieval, trials selection and assessment, data collection, and statistical analysis were performed according to the PRISMA guidelines. Primary outcomes included therapeutic response (TR), progression-free survival (PFS) and overall survival (OS). We calculated odds ratios (OR) and hazard ratios (HR) with 95% confidence intervals (CI). Twelve clinical trials were included. No statistical heterogeneity was detected in analyses of all studies and for each subgroup. Differences in TR, PFS and OS for any genotype comparison, UGT1A1*28/*28 versus (vs) UGT1A1*1/*1 (homozygous model), UGT1A1*1/*28 vs UGT1A1*1/*1 (heterozygous model), and UGT1A1*28/*28 vs all others (recessive model, only for TR) were not statistically significant. IRI dose also did not impact upon TR and PFS differences between UGT1A1 genotype groups. A statistically significant increase in the hazard of death was found in Low IRI subgroup of the homozygous model (HR = 1.48, 95% CI = 1.06–2.07; P = 0.02). The UGT1A1*28 allele was associated with a trend of increase in the hazard of death in two models (homozygous model: HR = 1.22, 95% CI = 0.99–1.51; heterozygous model: HR = 1.13, 95% CI = 0.96–1.32). These latter findings were driven primarily by one single large study (Shulman et al. 2011).</p> <p>Conclusions/Significance</p><p>UGT1A1*28 polymorphism cannot be considered as a reliable predictor of TR and PFS in CRC patients treated with IRI-based chemotherapy. The OS relationship with UGT1A1*28 in the patients with lower-dose IRI chemotherapy requires further validation.</p> </div

The association between UGT1A1*/28 polymorphisms and therapeutic response, progression-free survival and overall survival.

<p>P_het^a : P values for the between-study heterogeneity.</p

Distribution of baseline characteristics of the study cohorts.

<p>Distribution of baseline characteristics of the study cohorts.</p

Forest plots of three comparisons; outcome: therapeutic response.

<p>2A: *28/*28 versus *1/*1; 2B: *1/*28 versus *1/*1; 2C: *28/*28 versus *1/*28 or *1/*1.</p

<i>BRM</i> promoter indels and progression-free survival in colorectal cancer.

<p><i>BRM</i> promoter indels and progression-free survival in colorectal cancer.</p

Forest plots of two comparisons, outcome: progression-free survival.

<p>3A: *28/*28 versus *1/*1; 3B: *1/*28 versus *1/*1.</p

Kaplan-Meier curves for the <i>BRM</i>-741 indel under the co-dominant genetic model in the colorectal cancer cases.

<p>P value of the log-rank test is 0.017.</p