Epithelial-Myoepithelial Carcinoma of the Breast with Rhabdoid Features.

Epithelial-myoepithelial carcinoma of the breast is a rare biphasic tumor composed of intermixed malignant epithelial and myoepithelial components. Myoepithelial cells are known to adopt varied morphologies, including spindle, chondroid, clear cell, and rhabdoid morphologies, and can represent a diagnostic challenge when isolated on biopsy. Rhabdomyosarcoma, phyllodes tumor, metaplastic carcinoma, and myoepithelial carcinoma are primary breast tumors that all have been shown to exhibit rhabdoid features, whether representing true differentiation or morphological mimic. We here report an epithelial-myoepithelial carcinoma of the breast with rhabdoid features in a 76-year-old woman. The rhabdoid-appearing myoepithelial cells are negative for myogenin, consistent with a rhabdoid-like morphology rather than a true rhabdoid differentiation, comparably to previously described myoepithelial carcinoma with rhabdoid features. To our knowledge, this is the first reported case of epithelial-myoepithelial carcinoma of the breast with rhabdoid features and thus adds another entity to the differential diagnosis of breast lesions with rhabdoid features.

An assessment of the shared allelic architecture between type II diabetes and prostate cancer.

BACKGROUND: To determine whether the alleles that influence type II diabetes risk and glycemic traits also influence prostate cancer risk. METHODS: We used a multiple single-nucleotide polymorphisms (SNP) genotypic risk score to assess the average effect of alleles that increase type II diabetes risk or worsen glycemic traits on risk of prostate cancer in 19,662 prostate cancer cases and 19,715 controls from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium and 5,504 prostate cancer cases and 5,834 controls from the Cancer Research UK (CRUK) prostate cancer study. RESULTS: Calculating the average additive effect of type II diabetes or glycemic trait risk alleles on prostate cancer risk using a logistic model revealed no evidence of a shared allelic architecture between type II diabetes, or worsened glycemic status, with prostate cancer risk [OR for type II diabetes alleles: 1.00 (P = 0.58), fasting glycemia alleles: 1.00 (P = 0.67), HbA1c alleles: 1.00 (P = 0.93), 2-hour OGTT alleles: 1.01 (P = 0.14), and HOMA-B alleles: 0.99 (P = 0.57)]. CONCLUSIONS: Using genetic data from large consortia, we found no evidence for a shared genetic etiology of type II diabetes or glycemic risk with prostate cancer. IMPACT: Our results showed that alleles influencing type II diabetes and related glycemic traits were not found to be associated with the risk of prostate cancer.

Genetic regulation of vitamin D levels.

Vitamin D plays several roles in the body, influencing bone health as well as serum calcium and phosphate levels. Further, vitamin D may modify immune function, cell proliferation, differentiation, and apoptosis. Vitamin D deficiency has been associated with numerous health outcomes, including bone disease, cancer, autoimmune disease, infectious disease, type 1 and type 2 diabetes, hypertension, and heart disease, although it is unclear whether or not these associations are causal. Various twin and family studies have demonstrated moderate to high heritability for circulating vitamin D levels. Accordingly, many studies have investigated the genetic determinants of this hormone. Recent advances in the methodology of large-scale genetic association studies, including coordinated international collaboration, have identified associations of CG, DHCR1, CYP2R1, VDR, and CYP24A1 with serum levels of vitamin D. Here, we review the genetic determinants of vitamin D levels by focusing on new findings arising from candidate gene and genomewide association studies.

Copy number variation of the APC gene is associated with regulation of bone mineral density.

INTRODUCTION: Genetic studies of osteoporosis have commonly examined SNPs in candidate genes or whole genome analyses, but insertions and deletions of DNA, collectively called copy number variations (CNVs), also comprise a large amount of the genetic variability between individuals. Previously, SNPs in the APC gene have been strongly associated with femoral neck and lumbar spine volumetric bone mineral density in older men. In addition, familial adenomatous polyposis patients carrying heterozygous mutations in the APC gene have been shown to have significantly higher mean bone mineral density than age- and sex-matched controls suggesting the importance of this gene in regulating bone mineral density. We examined CNV within the APC gene region to test for association with bone mineral density. METHODS: DNA was extracted from venous blood, genotyped using the Human Hap610 arrays and CNV determined from the fluorescence intensity data in 2070 Caucasian men and women aged 47.0 ± 13.0 (mean ± SD) years, to assess the effects of the CNV on bone mineral density at the forearm, spine and total hip sites. RESULTS: Data for covariate adjusted bone mineral density from subjects grouped by APC CNV genotype showed significant difference (P=0.02-0.002). Subjects with a single copy loss of APC had a 7.95%, 13.10% and 13.36% increase in bone mineral density at the forearm, spine and total hip sites respectively, compared to subjects with two copies of the APC gene. CONCLUSIONS: These data support previous findings of APC regulating bone mineral density and demonstrate that a novel CNV of the APC gene is significantly associated with bone mineral density in Caucasian men and women.

Genetic polymorphisms of innate immunity-related inflammatory pathways and their association with factors related to type 2 diabetes.

BACKGROUND: Type 2 diabetes mellitus (T2DM) has been linked to a state of pre-clinical chronic inflammation resulting from abnormalities in the innate immune pathway. Serum levels of pro-inflammatory cytokines and acute-phase proteins, collectively known as 'inflammatory network', are elevated in the pre-, or early, stages of T2DM and increase with disease progression. Genetic variation can affect the innate immune response to certain environmental factors, and may, therefore, determine an individual's lifetime risk of disease. METHODS: We conducted a cross-sectional study in 6,720 subjects from the Twins UK Registry to evaluate the association between 18 single nucleotide polymorphisms (SNPs) in five genes (TLR4, IL1A, IL6, TNFA, and CRP) along the innate immunity-related inflammatory pathway and biomarkers of predisposition to T2DM [fasting insulin and glucose, HDL- and LDL- cholesterols, triglycerides (TGs), amyloid-A, sensitive C-reactive protein (sCRP) and vitamin D binding protein (VDBP) and body mass index (BMI)]. RESULTS: Of 18 the SNPs examined for their association with nine metabolic phenotypes of interest, six were significantly associated with five metabolic phenotypes (Bonferroni correction, P ≤ 0.0027). Fasting insulin was associated with SNPs in IL6 and TNFA, serum HDL-C with variants of TNFA and CRP and serum sCRP level with SNPs in CRP. Cross-correlation analysis among the different metabolic factors related to risk of T2DM showed several significant associations. For example, BMI was directly correlated with glucose (r = 0.11), insulin (r = 0.15), sCRP (r = 0.23), LDL-C (r = 0.067) and TGs (r = 0.18) but inversely with HDL-C (r = -0.14). sCRP was also positively correlated (P < 0.0001) with insulin (r = 0.17), amyloid-A (r = 0.39), TGs (r = 0.26), and VDBP (r = 0.36) but inversely with HDL-C (r = -0.12). CONCLUSION: Genetic variants in the innate immunity pathway and its related inflammatory cascade is associated with some metabolic risk factors for T2DM; an observation that may provide a rationale for further studying their role as biomarkers for disease early risk prediction.

WW-domain-containing oxidoreductase is associated with low plasma HDL-C levels.

Low serum HDL-cholesterol (HDL-C) is a major risk factor for coronary artery disease. We performed targeted genotyping of a 12.4 Mb linked region on 16q to test for association with low HDL-C by using a regional-tag SNP strategy. We identified one SNP, rs2548861, in the WW-domain-containing oxidoreductase (WWOX) gene with region-wide significance for low HDL-C in dyslipidemic families of Mexican and European descent and in low-HDL-C cases and controls of European descent (p = 6.9 x 10(-7)). We extended our investigation to the population level by using two independent unascertained population-based Finnish cohorts, the cross-sectional METSIM cohort of 4,463 males and the prospective Young Finns cohort of 2,265 subjects. The combined analysis provided p = 4 x 10(-4) to 2 x 10(-5). Importantly, in the prospective cohort, we observed a significant longitudinal association of rs2548861 with HDL-C levels obtained at four different time points over 21 years (p = 0.003), and the T risk allele explained 1.5% of the variance in HDL-C levels. The rs2548861 resides in a highly conserved region in intron 8 of WWOX. Results from our in vitro reporter assay and electrophoretic mobility-shift assay demonstrate that this region functions as a cis-regulatory element whose associated rs2548861 SNP has a specific allelic effect and that the region forms an allele-specific DNA-nuclear-factor complex. In conclusion, analyses of 9,798 subjects show significant association between HDL-C and a WWOX variant with an allele-specific cis-regulatory function.