SWI/SNF (SWItch/sucrose non-fermentable) complexes are ATP-dependent chromatin remodeling enzymes critically involved in the regulation of multiple functions, including gene expression, differentiation, development, DNA repair, cell adhesion and cell cycle control. BRM, a key SWI/SNF complex subunit, is silenced in 15–20% of many solid tumors. As BRM-deficient mice develop 10-fold more tumors when exposed to carcinogens, BRM is a strong candidate for a cancer susceptibility gene. In this paper, we show that BRM is regulated by transcription, thus demonstrating that the promoter region is important for BRM expression. We sequenced the BRM promoter region, finding two novel promoter indel polymorphisms, BRM −741 and BRM −1321, that are in linkage disequilibrium (D′ ≥0.83). The variant insertion alleles of both polymorphisms produce sequence variants that are highly homologous to myocyte enhancer factor-2 (MEF2) transcription factor-binding sites; MEF2 is known to recruit histone deacetylases that silence BRM expression. Each polymorphic BRM insertion variant is found in ~20% of Caucasians, and each correlates strongly with the loss of protein expression of BRM, both in cancer cell lines (P=0.009) and in primary human lung tumor specimens (P=0.015). With such strong functional evidence, we conducted a case–control study of 1199 smokers. We found an increased risk of lung cancer when both BRM homozygous promoter insertion variants were present: adjusted odds ratio of 2.19 (95% confidence interval, 1.40–3.43). Thus, we here demonstrate a strong functional association between these polymorphisms and loss of BRM expression. These polymorphisms thus have the potential to identify a sub-population of smokers at greater lung cancer risk, wherein this risk could be driven by an aberrant SWI/SNF chromatin-remodeling pathway.

A meta-analysis in Caucasians was conducted to investigate the possible association of uridine diphosphate glucuronosyltransferase (UGT) 1A1 gene polymorphisms with irinotecan (IRI)-induced neutropenia and diarrhoea in colorectal cancer (CRC). We searched PubMed and Embase until May 2012 to identify eligible studies, extracted data, assessed methodological quality, and performed statistical analysis using REVMAN 5.1 and R software. Subgroups meta-analyses were performed in groups representing different IRI combination regimens and IRI doses. Sixteen trials were included. UGT1A1*28/*28 genotype was associated with more than fourfold (odds ratio (OR)=4.79, 95% confidence intervals (CI): 3.28–7.01; P<0.00001) and threefold (OR=3.44, 95% CI: 2.45–4.82; P<0.00001) increases in the risk of neutropenia when compared with wild type and with at least one UGT1A1*1 allele, respectively. UGT1A1*1/*28 genotype had an OR of 1.90 (95% CI: 1.44–2.51; P<0.00001) for an increased risk of neutropenia. A twofold increase in risk of diarrhoea was associated with UGT1A1*28/*28 genotype (OR=1.84, 95% CI: 1.24–2.72; P=0.002). In subgroup meta-analysis, the higher incidence of diarrhoea in UGT1A1*28/*28 patients was limited to studies where when IRI was given at higher doses (OR=2.37, 95% CI: 1.39–4.04; P=0.002) or combined with 5-fluorouracil (FU or analogue) (OR=1.78, 95% CI: 1.16–2.75; P=0.009). Genotyping of UGT1A1*28 polymorphism before treatment for CRC can tailor IRI therapy and reduce the IRI-related toxicities. IRI-combined 5-FU (or analogue) and a high-dose IRI therapy enhance IRI-induced diarrhoea among patients bearing the UGT1A1*28 allele. Although the toxicity relationships were much stronger with the UGT1A1*28 homozygous variant, associations were also found with the UGT1A1*28 heterozygous variant.

Purpose: From the published literature, we identified 23 germ line sequence variants in 17 genes from hypothesis-generating studies that were associated with prognosis of head and neck cancer, including sequence variants of DNA repair (ERCC1, ERCC4, ERCC5, MSH2, XPA, ERCC2, XRCC1, XRCC3), DNA methylation (DNMT3B), cell cycle and proliferation (CCND1, TP53), xenobiotic metabolism (GSTM1, GSTT1, CYP2D6), metastatic -potential (MMP3), immunologic (CTLA4), and growth factor pathways (FGFR4). The purpose of this study was to validate the role of these 23 sequence variants for overall (OS) and disease-free survival (DFS) in a large, comprehensive, well-annotated data set of patients with head and neck cancer.Experimental Design: We genotyped these sequence variants in 531 patients with stage I and II radiation-treated head and neck cancer (originally recruited for an alpha-tocopherol/beta-carotene placebo-controlled secondary prevention study), and analyzed using Cox proportional hazards models, stratified by treatment arm, adjusting for clinical prognostic factors.Results: Two OS associations were statistically significant for each variant allele when compared with the wild-type: CTLA4:A49G [rs231775; adjusted HR (aHR), 1.32 (1.1-1.6); P ¼ 0.01] and XRCC1:Arg339Gln [rs25487; aHR, 1.28 (1.05-1.57); P ¼ 0.02]. Both of these sequence variants had significant results in the opposite direction as prior published literature. Two DFS associations were of borderline significance in the same direction as prior literature: ERCC2:Lys751Gln [rs13181; aHR, 0.80 (0.6-1.0); P ¼ 0.05] and TP53: Arg72Pro [rs1042522; aHR, 1.28 (1.0-1.6); P ¼ 0.03], comparing number of variant alleles with reference of zero variants.Conclusions: None of the prognostic sequence variants previously published was validated for OS in our patients with early-stage radiation-treated head and neck cancer, though rs1381and rs1042522 had borderline significant association with DFS.

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The SWI/SNF chromatin remodeling complex is an important regulator of gene expression that has been linked to cancer development. Expression of Brahma (BRM), a critical catalytic subunit of SWI/SNF, is lost in a variety of solid tumors. Two novel BRM promoter polymorphisms (BRM-741 and BRM-1321) have been correlated with BRM loss and elevated cancer risk. The aim(s) of this study were to examine BRM expression in head and neck squamous cell carcinoma (HNSCC) and to correlate BRM polymorphisms with HNSCC risk. BRM expression studies were performed on eight HNSCC cell lines and 76 surgically resected tumor samples. A case-control study was conducted on 668 HNSCC patients (oral cavity, oropharynx, larynx and hypopharynx) and 700 healthy matched controls. BRM expression was lost in 25% of cell lines and 16% of tumors. The homozygous genotype of each polymorphism was significantly associated with increased HNSCC risk [BRM-741: adjusted odds ratio (aOR) 1.75, 95% CI 1.2-2.3, P < 0.001; BRM-1321: aOR 1.65, 95% CI 1.2-2.2, P < 0.001]. Individuals that were homozygous for both BRM polymorphisms had a more than 2-fold increase in the risk of HNSCC (aOR 2.23, 95% CI 1.5-3.4, P < 0.001). A particularly elevated risk was seen within the oropharynx, human papillomavirus-positive subgroup for carriers of both homozygous variants (aOR 3.09, 95% CI 1.5-6.8, P = 0.004). BRM promoter polymorphisms appear to act as susceptibility markers of HNSCC with potential utility in screening, prevention and treatment.

Purpose: Two germline Fc-g receptor (FCGR) polymorphisms, rs1801274 [FCGR2A;His(H)131Arg(R)] and rs396991 [FCGR3A; Phe(F)158Val(V)] produce altered proteins through amino acid substitutions; both are reported to be associated with cetuximabrelated outcomes. We performed a validation of these polymorphisms in NCIC CTG CO.17, a randomized trial of cetuximab monotherapy in refractory, metastatic colorectal cancer expressing EGFR.Experimental Design: DNA extracted from formalin-fixed paraffin-embedded tissue was genotyped. In addition to log-rank tests, Cox proportional hazard models assessed their relationships with overall (OS) and progression-free survival (PFS), adjusting for clinically important prognostic factors, along with a polymorphism-treatment arm interaction term.

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BackgroundWhether 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.Methodology/Principal FindingsLiterature 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).Conclusions/SignificanceUGT1A1*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.