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Obesity affects more than 600 million people worldwide and causes 4 million excess deaths every year through its related co-morbidities, such as type 2 diabetes and heart disease. Detrimental anatomical distribution of body fat, specifically visceral fat accumulation, is a major driver of this mortality risk. There is clear evidence that underlying genetic predisposition plays a major role in determining body fat mass and distribution. Most genome-wide association studies to date have focused on anthropometric, rather than direct, measures of adiposity, such as BMI and WHR, and have successfully identified over a thousand candidate loci. However, the mechanisms via which these loci exert their effect is most often unknown. Thus, our understanding of the full impact and mechanisms underpinning the genetic contribution to human adiposity is incomplete. Here, we aim to further understand how human genomic variation contributes to body composition by using refined measures of adiposity and by gaining functional insight into the role of the resulting candidate loci.We worked with non-invasive imaging phenotypes in UKBiobank, a population cohort that includes 500,000 participants from across the UK. Of these, 5,000 have undergone DXA scans that allow for the direct measurement of fat and lean mass throughout the body. We first established a way to impute the DXA adiposity patterns in the rest of the UKBiobank cohort, using anthropometric measures of body size. These imputed phenotypes provided accurate predictions of the underlying adiposity traits (R~0.8) and were used to increase our novel discovery power in a genome-wide association framework. Out of the hundreds of associated loci, we sought to replicate the 27 strongest associations (P-value

To investigate the association between single nucleotide polymorphisms (SNPs) of A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) 14 (ADAMTS14) gene and susceptibility to knee osteoarthritis (KOA) in Chinese Han population. Using a case–control design, we enrolled 346 KOA patients and 480 healthy controls. Peripheral blood samples were extracted from each subject. Genotype was determined by sequencing PCR products. The genotype frequencies between cases and controls were compared. The genotype distribution was in accordance with Hardy–Weinberg equilibrium. The minor G allele in case group was significantly higher than in the control group (21.4 compared with 8.8%, P=0.000, odds ratio (OR) = 1.71 (95% confidence interval (CI): 1.39–2.11). The GG genotype and the GG/AG combination were more common in the osteoarthritis (OA) group than in the control group. Compared with AA genotype, the GG (OR = 3.09, 95%CI: 2.01–4.75), AG (OR = 2.55, 95%CI: 1.64–3.96), and GG/AG (OR = 1.57, 95%CI: 1.19–2.07) increased the risk of OA. Multiple logistic confirmed the findings by adjusting some potential factors. Subgroup analysis indicated that the ras4747096 was still significantly associated with KOA. There were no significant differences in allele frequency or genotypes frequency for erythrocyte sedimentation rate and C-reaction protein in OA patients (P>0.05). ADAMTS14 gene polymorphism was associated with KOA, and the GG genotype increased the risk of KOA in Chinese Han population. The ADAMTS14 may be a diagnostic marker and therapeutic target for KOA treatment. The future study should explore the specific molecular mechanism.

Chondrosarcoma is one of the most common bone tumors, and at present, there is no non-invasive treatment option for this cancer. The chondrosarcoma OUMS-27 cell line produces proteoglycan and type II, IX, and XI collagens, which constitutes cartilage tissue. A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) proteases are a group of secreted proteases, which include the procollagen N-proteinases ADAMTS-2, -3 and -14. These procollagen N-proteinases perform a role in the processing of procollagens to collagen and the maturation of type I collagen. The present study aimed to improve the understanding of the causes of metastasis, local invasion and resistance to chemo- and radiotherapy in chondrosarcoma, as well as the effect of insulin on cancer cells. The present study was designed to reveal the effects of insulin on procollagen N-proteinases in chondrosarcoma OUMS-27 cells. The cells were cultured in Dulbecco’s modified Eagle’s medium (DMEM) alone or in DMEM containing 10 µg/ml insulin. The medium was changed every other day for 11 days. The cells were harvested on days 1, 3, 7 and 11, and total RNA isolation was performed immediately following harvesting. The expression levels of ADAMTS2, ADAMTS3 and ADAMTS14 mRNA were estimated by reverse transcription-quantitative polymerase chain reaction using appropriate primers. ADAMTS2 mRNA expression was found to be decreased on day 7 (P=0.028) and increased at day 11 compared with the control group (P=0.016). The increase in mRNA concentration at day 11 was significantly different compared to the concentrations on days 3 (P=0.047) and 7 (P=0.008). The expression of ADAMTS3 mRNA decreased immediately subsequent to insulin induction on day 1 compared with the control group (P=0.008). The most evident decrease in mRNA concentration was seen at day 7 subsequent to insulin induction (P=0.008). The present results demonstrated that ADAMTS2 and ADAMTS3 may perform a role in the invasion and metastasis of tumors, and may also possess proteolytic activity that results in the breakdown of the extracellular matrix (ECM). Insulin itself can modulate the biosynthesis of ECM macromolecules that are altered in diabetes through various pathways. © 2015, Spandidos Publications. All rights reserved.

A disintegrin and metalloproteinase with thrombospondin motif 14 (ADAMTS14) is a member of the zinc-dependent protease family that is implicated in the occurrence and progression of tumors. Oral cancer (OC) is a common cancer worldwide, but it is particularly prevalent in Taiwan. However, whether the expression of ADAMTS14 is correlated with the carcinogenesis and progression of oral squamous cell carcinoma (OSCC) has not yet been investigated. In this study, we used immunohistochemistry (IHC) to examine 250 OSCC specimens in order to identify correlations between the cytoplasmic expression of ADAMTS14 and (1) clinicopathological features of OSCC as well as (2) clinical outcomes of OSCC. Our results indicate that cytoplasmic expression of ADAMTS14 was lower in OSCC tissues than in normal tissues. In analyzing correlations between ADAMTS14 expression and clinicopathological features, we found that negative cytoplasmic expression of ADAMTS14 was significantly associated with higher frequencies of lymph node metastasis and more advanced AJCC stages (III/IV). Kaplan&ndash, Meier survival analysis revealed that negative cytoplasmic expression of ADAMTS14 was also associated with significantly worse OSCC survival. Univariate and multivariate analyses confirmed that cytoplasmic expression of ADAMTS14 was associated with lymph node metastasis, tumor stage, and tumor grade and also indicated that cytoplasmic ADAMTS14 expression may be an independent prognostic factor for OSCC. This is the first study to report that the cytoplasmic expression level of ADAMTS14 is associated with OSCC prognosis and tumor progression. Our data indicate that ADAMTS14 can serve as a prognostic marker and a potential therapeutic target for OSCC.

// Sergio Alonso 1, 2 , Yuichi Dai 1, 3, 4 , Kentaro Yamashita 1 , Shina Horiuchi 1 , Tomoko Dai 1, 3 , Akihiro Matsunaga 1 , Rosa Sanchez-Munoz 1 , Cristina Bilbao-Sieyro 5 , Juan Carlos Diaz-Chico 5 , Andrei V. Chernov 6 , Alex Y. Strongin 6 , Manuel Perucho 1, 2, 7 1 Tumor Initiation and Maintenance Program, Sanford-Burnham Medical Research Institute (SBMRI), La Jolla, California, USA 2 Institute of Predictive and Personalized Medicine of Cancer (IMPPC), IGTP, Badalona, Barcelona, Spain 3 Dept. of Pathology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan 4 Dept. of Diagnostic Pathology, Tsukuba Memorial Hospital, Tsukuba, Ibaraki, Japan 5 Dept. of Biochemistry and Molecular Biology, Cancer Research Institute of The Canary Islands, University of Las Palmas de Gran Canaria, Spain 6 Cancer Research Center, Sanford-Burnham Medical Research Institute (SBMRI), La Jolla, California, USA 7 Institucio Catalana de Recerca i Estudis Avancats (ICREA), Barcelona, Spain Correspondence to: Manuel Perucho, e-mail: mperucho@imppc.org Keywords: KRAS mutations, TP53 mutations, MGMT , O 6 -methylguanine-DNA methyltransferase, ADAMTS14 , CRC, colorectal cancer Received: November 28, 2014 Accepted: December 04, 2014 Published: February 02, 2015 ABSTRACT Somatic hypermethylation of the O 6 -methylguanine-DNA methyltransferase gene ( MGMT ) was previously associated with G > A transition mutations in KRAS and TP53 in colorectal cancer (CRC). We tested the association of MGMT methylation with G > A mutations in KRAS and TP53 in 261 CRCs. Sixteen cases, with and without MGMT hypermethylation, were further analyzed by exome sequencing. No significant association of MGMT methylation with G > A mutations in KRAS, TP53 or in the whole exome was found ( p > 0.5 in all comparisons). The result was validated by in silico comparison with 302 CRCs from The Cancer Genome Atlas (TCGA) consortium dataset. Transcriptional silencing associated with hypermethylation and stratified into monoallelic and biallelic. We also found a significant clustering ( p = 0.001) of aberrant hypermethylation of MGMT and the matrix metalloproteinase gene ADAMTS14 in normal colonic mucosa of CRC patients. This suggested the existence of an epigenetic field defect for cancerization disrupting the methylation patterns of several loci , including MGMT or ADAMTS14 , that may lead to predictive biomarkers for CRC. Methylation of these loci in normal mucosa was more frequent in elder ( p = 0.001) patients, and particularly in African Americans ( p = 1 × 10 −5 ), thus providing a possible mechanistic link between somatic epigenetic alterations and CRC racial disparities in North America.