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- Jakubowska, A, et al.
(författare)
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Association of PHB 1630 C andgt; T and MTHFR 677 C andgt; T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers: results from a multicenter study
- 2012
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Ingår i: British Journal of Cancer. - : Cancer Research UK / Nature Publishing Group. - 0007-0920 .- 1532-1827. ; 106:12, s. 2016-2024
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. Two genes of special interest are prohibitin (PHB) and methylene-tetrahydrofolate reductase (MTHFR), both of which are important either directly or indirectly in maintaining genomic integrity. less thanbrgreater than less thanbrgreater thanMETHODS: To evaluate the potential role of genetic variants within PHB and MTHFR in breast and ovarian cancer risk, 4102 BRCA1 and 2093 BRCA2 mutation carriers, and 6211 BRCA1 and 2902 BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) were genotyped for the PHB 1630 Candgt;T (rs6917) polymorphism and the MTHFR 677 Candgt;T (rs1801133) polymorphism, respectively. less thanbrgreater than less thanbrgreater thanRESULTS: There was no evidence of association between the PHB 1630 Candgt;T and MTHFR 677 Candgt;T polymorphisms with either disease for BRCA1 or BRCA2 mutation carriers when breast and ovarian cancer associations were evaluated separately. Analysis that evaluated associations for breast and ovarian cancer simultaneously showed some evidence that BRCA1 mutation carriers who had the rare homozygote genotype (TT) of the PHB 1630 Candgt;T polymorphism were at increased risk of both breast and ovarian cancer (HR 1.50, 95% CI 1.10-2.04 and HR 2.16, 95% CI 1.24-3.76, respectively). However, there was no evidence of association under a multiplicative model for the effect of each minor allele. less thanbrgreater than less thanbrgreater thanCONCLUSION: The PHB 1630TT genotype may modify breast and ovarian cancer risks in BRCA1 mutation carriers. This association need to be evaluated in larger series of BRCA1 mutation carriers.
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- Pansuriya, Twinkal C., et al.
(författare)
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Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome
- 2011
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 43:12, s. 1256-1261
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Tidskriftsartikel (refereegranskat)abstract
- Ollier disease and Maffucci syndrome are non-hereditary skeletal disorders characterized by multiple enchondromas (Ollier disease) combined with spindle cell hemangiomas (Maffucci syndrome). We report somatic heterozygous mutations in IDH1 (c.394C>T encoding an R132C substitution and c.395G>A encoding an R132H substitution) or IDH2 (c.516G>C encoding R172S) in 87% of enchondromas (benign cartilage tumors) and in 70% of spindle cell hemangiomas (benign vascular lesions). In total, 35 of 43 (81%) subjects with Ollier disease and 10 of 13 (77%) with Maffucci syndrome carried IDH1 (98%) or IDH2 (2%) mutations in their tumors. Fourteen of 16 subjects had identical mutations in separate lesions. Immunohistochemistry to detect mutant IDH1 R132H protein suggested intraneoplastic and somatic mosaicism. IDH1 mutations in cartilage tumors were associated with hypermethylation and downregulated expression of several genes. Mutations were also found in 40% of solitary central cartilaginous tumors and in four chondrosarcoma cell lines, which will enable functional studies to assess the role of IDH1 and IDH2 mutations in tumor formation.
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- Ding, Yuan C, et al.
(författare)
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A nonsynonymous polymorphism in IRS1 modifies risk of developing breast and ovarian cancers in BRCA1 and ovarian cancer in BRCA2 mutation carriers
- 2012
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - : American Association for Cancer Research. - 1055-9965 .- 1538-7755. ; 21:8, s. 1362-1370
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: We previously reported significant associations between genetic variants in insulin receptor substrate 1 (IRS1) and breast cancer risk in women carrying BRCA1 mutations. The objectives of this study were to investigate whether the IRS1 variants modified ovarian cancer risk and were associated with breast cancer risk in a larger cohort of BRCA1 and BRCA2 mutation carriers.METHODS: IRS1 rs1801123, rs1330645, and rs1801278 were genotyped in samples from 36 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analyzed by a retrospective cohort approach modeling the associations with breast and ovarian cancer risks simultaneously. Analyses were stratified by BRCA1 and BRCA2 status and mutation class in BRCA1 carriers.RESULTS: Rs1801278 (Gly972Arg) was associated with ovarian cancer risk for both BRCA1 (HR, 1.43; 95% confidence interval (CI), 1.06-1.92; P = 0.019) and BRCA2 mutation carriers (HR, 2.21; 95% CI, 1.39-3.52, P = 0.0008). For BRCA1 mutation carriers, the breast cancer risk was higher in carriers with class II mutations than class I mutations (class II HR, 1.86; 95% CI, 1.28-2.70; class I HR, 0.86; 95%CI, 0.69-1.09; P(difference), 0.0006). Rs13306465 was associated with ovarian cancer risk in BRCA1 class II mutation carriers (HR, 2.42; P = 0.03).CONCLUSION: The IRS1 Gly972Arg single-nucleotide polymorphism, which affects insulin-like growth factor and insulin signaling, modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers and breast cancer risk in BRCA1 class II mutation carriers.Impact: These findings may prove useful for risk prediction for breast and ovarian cancers in BRCA1 and BRCA2 mutation carriers.
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- Purdue, Mark P, et al.
(författare)
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Genome-wide association study of renal cell carcinoma identifies two susceptibility loci on 2p21 and 11q13.3
- 2011
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 43:1, s. 60-65
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Tidskriftsartikel (refereegranskat)abstract
- We conducted a two-stage genome-wide association study of renal cell carcinoma (RCC) in 3,772 affected individuals (cases) and 8,505 controls of European background from 11 studies and followed up 6 SNPs in 3 replication studies of 2,198 cases and 4,918 controls. Two loci on the regions of 2p21 and 11q13.3 were associated with RCC susceptibility below genome-wide significance. Two correlated variants (r² = 0.99 in controls), rs11894252 (P = 1.8 × 10⁻⁸) and rs7579899 (P = 2.3 × 10⁻⁹), map to EPAS1 on 2p21, which encodes hypoxia-inducible-factor-2 alpha, a transcription factor previously implicated in RCC. The second locus, rs7105934, at 11q13.3, contains no characterized genes (P = 7.8 × 10⁻¹⁴). In addition, we observed a promising association on 12q24.31 for rs4765623, which maps to SCARB1, the scavenger receptor class B, member 1 gene (P = 2.6 × 10⁻⁸). Our study reports previously unidentified genomic regions associated with RCC risk that may lead to new etiological insights.
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- Hoogenkamp, Henk R., et al.
(författare)
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Seamless Vascularized Large-Diameter Tubular Collagen Scaffolds Reinforced with Polymer Knittings for Esophageal Regenerative Medicine
- 2014
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Ingår i: Tissue Engineering. Part C, Methods. - : Mary Ann Liebert Inc. - 1937-3384 .- 1937-3392. ; 20:5, s. 423-430
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Tidskriftsartikel (refereegranskat)abstract
- A clinical demand exists for alternatives to repair the esophagus in case of congenital defects, cancer, or trauma. A seamless biocompatible off-the-shelf large-diameter tubular scaffold, which is accessible for vascularization, could set the stage for regenerative medicine of the esophagus. The use of seamless scaffolds eliminates the error-prone tubularization step, which is necessary when emanating from flat scaffolds. In this study, we developed and characterized three different types of seamless tubular scaffolds, and evaluated in vivo tissue compatibility, including vascularization by omental wrapping. Scaffolds (luminal O approximate to 1.5cm) were constructed using freezing, lyophilizing, and cross-linking techniques and included (1) single-layered porous collagen scaffold, (2) dual-layered (porous+dense) collagen scaffold, and (3) hybrid scaffold (collagen+incorporated polycaprolacton knitting). The latter had an ultimate tensile strength comparable to a porcine esophagus. To induce rapid vascularization, scaffolds were implanted in the omentum of sheep using a wrapping technique. After 6 weeks of biocompatibility, vascularization, calcification, and hypoxia were evaluated using immunohistochemistry. Scaffolds were biocompatible, and cellular influx and ingrowth of blood vessels were observed throughout the whole scaffold. No calcification was observed, and slight hypoxic conditions were detected only in the direct vicinity of the polymer knitting. It is concluded that seamless large-diameter tubular collagen-based scaffolds can be constructed and vascularized in vivo. Such scaffolds provide novel tools for esophageal reconstruction.
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- Sun, Weilun, et al.
(författare)
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Improving the Cell Distribution in Collagen-Coated Poly-Caprolactone Knittings
- 2012
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Ingår i: TISSUE ENG PART C-ME. - : Mary Ann Liebert Inc. - 1937-3384. ; 18:10, s. 731-739
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Tidskriftsartikel (refereegranskat)abstract
- Adequate cellular in-growth into biomaterials is one of the fundamental requirements of scaffolds used in regenerative medicine. Type I collagen is the most commonly used material for soft tissue engineering, because it is nonimmunogenic and a highly porous network for cellular support can be produced. However, in general, adequate cell in-growth and cell seeding has been suboptimal. In this study we prepared collagen scaffolds of different collagen densities and investigated the cellular distribution. We also prepared a hybrid polymer-collagen scaffold to achieve an optimal cellular distribution as well as sufficient mechanical strength. Collagen scaffolds [ranging from 0.3% to 0.8% (w/v)] with and without a mechanically stable polymer knitting [polycaprolactone (PCL)] were prepared. The porous structure of collagen scaffolds was characterized using scanning electron microscopy and hematoxylin-eosin staining. The mechanical strength of hybrid scaffolds (collagen with or without PCL) was determined using tensile strength analysis. Cellular in-growth and interconnectivity were evaluated using fluorescent bead distribution and human bladder smooth muscle cells and human urothelium seeding. The lower density collagen scaffolds showed remarkably deeper cellular penetration and by combining it with PCL knitting the tensile strength was enhanced. This study indicated that a hybrid scaffold prepared from 0.4% collagen strengthened with knitting achieved the best cellular distribution.
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