The BRMS1 metastasis suppressor was recently shown to negatively regulate NF-κB signaling and down regulate NF-κB-dependent uPA expression. Here we confirm that BRMS1 expression correlates with ...reduced NF-κB DNA binding activity in independently derived human melanoma C8161.9 cells stably expressing BRMS1. We show that knockdown of BRMS1 expression in these cells using small interfering RNA (siRNA) leads to the reactivation of NF-κB DNA binding activity and re-expression of uPA. Further, we confirm that BRMS1 expression does not alter IKKβ kinase activity suggesting that BRMS1-dependent uPA regulation does not occur through inhibition of the classical upstream activators of NF-κB. BRMS1 has been implicated as a corepressor of HDAC1 and consistent with this, we show that BRMS1 promotes HDAC1 recruitment to the NF-κB binding site of the uPA promoter and is associated with reduced H3 acetylation. We also confirm that BRMS1 expression stimulates disassociation of p65 from the NF-κB binding site of the uPA promoter consistent with its reduced DNA binding activity. These data suggest that BRMS1 recruits HDAC1 to the NF-κB binding site of the uPA promoter, modulates histone acetylation of p65 on the uPA promoter, leading to reduced NF-κB binding activity on its consensus sequence, and reduced transactivation of uPA expression.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
To better understand the characteristics associated with a participant's willingness to consent to the Mayo Clinic Biobank (MCB) and examine factors associated with willingness to participate in ...follow-up studies embedded within MCB that require re-contact and participant approval.
Consent rates were compared across patient demographics to the MCB. Rates of participation to follow-up studies were also compared across demographics and request types.
Among 272,102 Mayo Clinic patients invited to the MCB, 48,314 (19%) consented across the three recruitment sites within 90 days of initial invitation. A significant age by gender interaction was identified, showing young males consent at a lower rate than young females and older males consent at a higher rate than older females. Over the recruitment time frame of 2009-2015, there was a significant decrease in consent rates (decline of 2.5%/year). Of the 57,041 consented MCB participants, 33,487 participants (59%) have been invited to participate in follow-up studies via re-contact. Follow-up studies of the MCB may require participants to provide additional samples, complete questionnaires, and/or release their identity to a research team. MCB participants have been invited to enroll in a median of two studies (IQR: 1-3). Seventy-one percent of participants consented to at least one follow-up study, with individual follow-up study consent rates ranging from 14 to 87% depending on study type, with a median consent rate of 61% (IQR: 47-70%). Studies requesting return of a questionnaire had the highest participation rates. White participants, older participants, and participants with some college or a degree were significantly more likely to participate to follow-up studies, while there was no association with gender.
Consent rates among younger and non-white patients were lower than in older, white patients. However, we also found that participation rates among those already enrolled in the biobank were much higher than those seen in new recruitment efforts, external to an existing biobank. We thus demonstrate an important way that biobanks can advance precision medicine goals: through provision of populations from which studies can draw participants for future studies.
Colorectal cancer (CRC) in densely affected families without Lynch Syndrome may be due to mutations in undiscovered genetic loci. Familial linkage analyses have yielded disparate results; the use of ...exome sequencing in coding regions may identify novel segregating variants.
We completed exome sequencing on 40 affected cases from 16 multicase pedigrees to identify novel loci. Variants shared among all sequenced cases within each family were identified and filtered to exclude common variants and single-nucleotide variants (SNV) predicted to be benign.
We identified 32 nonsense or splice-site SNVs, 375 missense SNVs, 1,394 synonymous or noncoding SNVs, and 50 indels in the 16 families. Of particular interest are two validated and replicated missense variants in CENPE and KIF23, which are both located within previously reported CRC linkage regions, on chromosomes 1 and 15, respectively.
Whole-exome sequencing identified DNA variants in multiple genes. Additional sequencing of these genes in additional samples will further elucidate the role of variants in these regions in CRC susceptibility.
Exome sequencing of familial CRC cases can identify novel rare variants that may influence disease risk.
A substantial proportion of familial colorectal cancer (CRC) is not a consequence of known susceptibility loci, such as mismatch repair (MMR) genes, supporting the existence of additional loci. To ...identify novel CRC loci, we conducted a genome-wide linkage scan in 356 white families with no evidence of defective MMR (i.e., no loss of tumor expression of MMR proteins, no microsatellite instability (MSI)-high tumors, or no evidence of linkage to MMR genes). Families were ascertained via the Colon Cancer Family Registry multi-site NCI-supported consortium (Colon CFR), the City of Hope Comprehensive Cancer Center, and Memorial University of Newfoundland. A total of 1,612 individuals (average 5.0 per family including 2.2 affected) were genotyped using genome-wide single nucleotide polymorphism linkage arrays; parametric and non-parametric linkage analysis used MERLIN in a priori-defined family groups. Five lod scores greater than 3.0 were observed assuming heterogeneity. The greatest were among families with mean age of diagnosis less than 50 years at 4q21.1 (dominant HLOD = 4.51, α = 0.84, 145.40 cM, rs10518142) and among all families at 12q24.32 (dominant HLOD = 3.60, α = 0.48, 285.15 cM, rs952093). Among families with four or more affected individuals and among clinic-based families, a common peak was observed at 15q22.31 (101.40 cM, rs1477798; dominant HLOD = 3.07, α = 0.29; dominant HLOD = 3.03, α = 0.32, respectively). Analysis of families with only two affected individuals yielded a peak at 8q13.2 (recessive HLOD = 3.02, α = 0.51, 132.52 cM, rs1319036). These previously unreported linkage peaks demonstrate the continued utility of family-based data in complex traits and suggest that new CRC risk alleles remain to be elucidated.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The importance of inflammation pathways to the development of many human cancers prompted us to examine the associations between single-nucleotide polymorphisms (SNP) in inflammation-related genes ...and risk of ovarian cancer. In a multisite case-control study, we genotyped SNPs in a large panel of inflammatory genes in 930 epithelial ovarian cancer cases and 1,037 controls using a custom array and analyzed by logistic regression. SNPs with P < 0.10 were evaluated among 3,143 cases and 2,102 controls from the Follow-up of Ovarian Cancer Genetic Association and Interaction Studies (FOCI) post-GWAS collaboration. Combined analysis revealed association with SNPs rs17561 and rs4848300 in the interleukin gene IL1A which varied by histologic subtype (P(heterogeneity) = 0.03). For example, IL1A rs17561, which correlates with numerous inflammatory phenotypes, was associated with decreased risk of clear cell, mucinous, and endometrioid subtype, but not with the most common serous subtype. Genotype at rs1864414 in the arachidonate 5-lipoxygenase ALOX5 was also associated with decreased risk. Thus, inherited variation in IL1A and ALOX5 seems to affect ovarian cancer risk which, for IL1A, is limited to rarer subtypes. Given the importance of inflammation in tumorigenesis and growing evidence of subtype-specific features in ovarian cancer, functional investigations will be important to help clarify the importance of inherited variation related to inflammation in ovarian carcinogenesis.
We previously reported linkage of a prostate cancer tumor aggressiveness locus to chromosome 7q32–q33, a region also associated with a high frequency of allelic imbalance in prostate tumors. The ...smallest region of allelic imbalance contains the podocalyxin-like (PODXL) gene, which we evaluate here as a candidate prostate cancer aggressiveness gene mapping to 7q32–q33. DNA from probands of linked families was examined for germ-line mutations in PODXL. A variable in-frame deletion, four missense variants and two nonsense variants were identified in linked men. Variants that affected amino acid sequence were further evaluated for association with risk of prostate cancer and tumor aggressiveness in a family-based case–control population (439 cases and 479 sibling controls). The presence of any single in-frame deletion was positively associated with prostate cancer odds ratio (OR)=2.14, 95% confidence interval (95%CI)=1.09–4.20, P=0.03 and the presence of two copies of any deletion further increased risk (OR=2.58, 95%CI=1.23–5.45, P=0.01). This finding was strengthened when stratifying among men with more aggressive disease (high grade or stage): OR=3.04 for one deletion (95%CI=1.01–9.15) and OR=4.42 for two deletions (95%CI=1.32–14.85, P=0.02). A weak positive association was also observed between prostate cancer risk and PODXL variant 340A (in linkage disequilibrium with another variant, 587T) (OR=1.48, 95%CI=1.02–2.14, P=0.04). These results implicate PODXL as a candidate prostate cancer tumor aggressiveness gene mapping to chromosome 7q32–q33.
Carboxypeptidase 4 (CPA4) is a zinc-dependent metallocarboxypeptidase on chromosome 7q32 in a region linked to prostate cancer aggressiveness. CPA4 is involved in the histone hyperacetylation pathway ...and may modulate the function of peptides that affect the growth and regulation of prostate epithelial cells. We examined the association between genetic variation in CPA4 and intermediate-to-high risk prostate cancer.
We studied 1012 men (506 cases and 506 controls) from Cleveland, Ohio. All cases had Gleason > or = 7, clinical stage > or = T2c, or PSA > or = 10 ng/mL at diagnosis. Six CPA4 single-nucleotide polymorphisms were genotyped, and evaluated for their relation to prostate cancer. We also evaluated whether CPA4 variants influence risk of disease among men diagnosed at an earlier age (< 66 years).
The nonsynonymous coding SNP (rs2171492, Cys303Gly) in CPA4 was associated with an increased risk of aggressive prostate cancer among younger patients (< 66 years). Specifically, men carrying the TT genotype had an approximately two-fold increased risk for being diagnosed with intermediate-to-high risk disease (Odds Ratio = 1.83, p = 0.04). In the overall population (all ages) none of the CPA4 SNPs demonstrated a statistically significant association with prostate cancer.
Coding variation in CPA4 may confer increased risk of intermediate-to-high risk prostate cancer among younger patients. Further work is needed to identify the functional aspects of this variation and understand its biological effects on prostate cancer. Such work may translate into more precise screening of higher risk individuals as well as guiding clinicians and patients toward earlier and more definitive treatment modalities in patients genetically identified as higher risk.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Candidate genes involved with androgen metabolism have been hypothesized to affect the risk of prostate cancer. To further
investigate this, we evaluated the relationship between prostate cancer and ...multiple potentially functional polymorphisms
in three genes involved in androgen metabolism: CYP1B1 (two single nucleotide polymorphisms: 355G/T and 4326C/G ), prostate-specific antigen ( PSA/KLK3 (three single nucleotide polymorphisms: −158A/G, −4643G/A , and −5412C/T ), and CYP11α (tttta) n repeat, using a moderately large ( n = 918) sibling-based case-control population. When looking at all subjects combined, no association was observed between
any polymorphism—or their haplotypes—and prostate cancer risk. However, among men with more aggressive prostate cancer, the
CYP1B1 355G/T variant was positively associated with disease: carrying one or two T alleles gave odds ratios (OR) of 1.90 95% confidence interval (95% CI), 1.09-3.31; P = 0.02 and 3.73 (95% CI, 1.39-10.0; P = 0.009), respectively. Similarly, carrying the CYP1B1 355T-4326C haplotype was positively associated with prostate cancer among men with high aggressive disease ( P = 0.01). In addition, the PSA −158G/−158G genotype was positively associated with prostate cancer among men with less aggressive disease (OR, 2.71; 95% CI, 1.06-6.94;
P = 0.04). Our findings suggest that CYP1B1 and PSA variants may affect the risk of prostate cancer and tumor aggressiveness.
ABSTRACT
Due to its potential as a biomarker for early cancer detection, blood‐based DNA methylation (DNAm) is of interest in cancer research. Specifically, highly predictive mechanisms for early ...detection of epithelial ovarian cancer (EOC) are desired, so previous studies have compared DNAm between EOC cases and controls. However, case‐control studies are confounded by the distribution of white blood cell types through an immune response induced by the cancer. Rather than determining the distribution of the cell types manually or investigating isolated cell types, an alternative approach involves the use of complete blood count (CBC), which is routinely collected. In the analysis of an EOC case‐control study of DNAm, we incorporate CBC measures to adjust for this confounding and compare DNAm between 242 EOC cases and 181 age‐matched controls (assayed on the Illumina Infinium HumanMethylation27 or HumanMethylation450 Beadchips), at both the individual CpG and CpG island levels. We found that adjustment for leukocyte distribution using CBC measurements dramatically reduced confounding, with 62 single CpG sites found to be associated with EOC status after adjustment (P < 5E‐8). Additionally, regional DNAm was assessed by applying principal components analysis to CpG islands. The top associated CpG island (P = 7E‐6) was located in the promoter/transcription start site of the human basonuclin 2 gene (BNC2), a known susceptibility gene for EOC risk identified through GWAS. Follow‐up studies are necessary to establish the role of BNC2 in blood‐based DNA and EOC, including prospective studies to validate this region as a potential biomarker and predictor of EOC susceptibility.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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