Single-nucleotide polymorphisms in the lysyl oxidase-like protein 4 and complement component 3 genes are associated with increased risk for endometriosis and endometriosis-associated infertility

Department of Microbiology, Ponce School of Medicine and Health Sciences, Ponce, Puerto Rico 00716-2348, USA.
Fertility and sterility (Impact Factor: 4.59). 08/2011; 96(2):512-5. DOI: 10.1016/j.fertnstert.2011.06.001
Source: PubMed

ABSTRACT This study was conducted to assess genetic associations with endometriosis in a Puerto Rican population. Statistically significant differences in the allelic frequencies and genotype distribution of genetic variants in lysyl oxidase-like protein 4 (LOXL4) and complement component 3 (C3) were documented in patients with endometriosis-associated infertility versus controls, and in patients with endometriosis versus controls, respectively. In women who have the risk genotype at both single-nucleotide polymorphisms, the estimated risk for endometriosis nearly doubled.

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Available from: Idhaliz Flores, Sep 28, 2015
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    • "That LOX was expressed in 79% of human breast cancers revealed the attenuated metastasis of human breast cancer cells by a downregulation of adhesion kinase and the paxillin-signaling pathway [128,136]. SNPs in the LOX-like protein 4 were reported in patients with endometriosis, a semi-malignant tumor [137]. LOX overexpression can be found in myofibroblasts and myoepithelial cells around in situ tumors and at the invasion front of infiltrating breast cancers [129]. "
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    ABSTRACT: Background Carcinogenesis is widely thought to originate from somatic mutations and an inhibition of growth suppressors, followed by cell proliferation, tissue invasion, and risk of metastasis. Fewer than 10% of all cancers are hereditary; the ratio in gastric (1%), colorectal (3-5%) and breast (8%) cancers is even less. Cancers caused by infection are thought to constitute some 15% of the non-hereditary cancers. Those remaining, 70 to 80%, are called "sporadic," because they are essentially of unknown etiology. We propose a new paradigm for the origin of the majority of cancers. Presentation of hypothesis: Our paradigm postulates that cancer originates following a sequence of events that include (1) a pathogenic stimulus (biological or chemical) followed by (2) chronic inflammation, from which develops (3) fibrosis with associated changes in the cellular microenvironment. From these changes a (4) pre-cancerous niche develops, which triggers the deployment of (5) a chronic stress escape strategy, and when this fails to resolve, (6) a transition of a normal cell to a cancer cell occurs. If we are correct, this paradigm would suggest that the majority of the findings in cancer genetics so far reported are either late events or are epiphenomena that occur after the appearance of the pre-cancerous niche. Testing the hypothesis If, based on experimental and clinical findings presented here, this hypothesis is plausible, then the majority of findings in the genetics of cancer so far reported in the literature are late events or epiphenomena that could have occurred after the development of a PCN. Our model would make clear the need to establish preventive measures long before a cancer becomes clinically apparent. Future research should focus on the intermediate steps of our proposed sequence of events, which will enhance our understanding of the nature of carcinogenesis. Findings on inflammation and fibrosis would be given their warranted importance, with research in anticancer therapies focusing on suppressing the PCN state with very early intervention to detect and quantify any subclinical inflammatory change and to treat all levels of chronic inflammation and prevent fibrotic changes, and so avoid the transition from a normal cell to a cancer cell. Implication of the hypothesis: The paradigm proposed here, if proven, spells out a sequence of steps, one or more of which could be interdicted or modulated early in carcinogenesis to prevent or, at a minimum, slow down the progression of many cancers.
    BMC Cancer 05/2014; BMC Cancer(14):331. DOI:10.1186/1471-2407-14-331 · 3.36 Impact Factor
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    • "To date, the genetic risk factors for endometriosis-related infertility have included the 17β-hydroxysteroid dehydrogenase type 1, ESR1, ESR2, and luteinizing hormone beta-subunit genes [30–33]. Furthermore, polymorphisms situated in FOXP, complement component 3, and lysyl oxidase-like protein 4 genes have also been reported as genetic factors which affect fertility in women with endometriosis [27, 34]. "
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    ABSTRACT: Objective Recently, the FCRL3 −169T>C (rs7528684) single-nucleotide polymorphism (SNP) has been demonstrated to be a risk factor of endometriosis related infertility. We studied whether the FCRL −169T>C SNP can be associated with endometriosis-related infertility in a sample of the Polish population Methods Using PCR–RFLP analysis we genotyped 141 infertile women with endometriosis and 519 fertile women. FCRL3 transcript levels were determined by reverse transcription and real-time quantitative PCR analysis in CD19+ B cells from women with endometriosis-associated infertility and fertile women Results We found a significantly increased frequency of the FCRL3 C/C genotype in women with endometriosis-associated infertility than controls [OR = 1.681 (95 % CI = 1.120–2.522, p = 0.0116, pcorr = 0.0348)]. There was also a statistically increased frequency of the C/C and C/T genotypes in patients compared with controls [OR = 2.009 (95 % CI = 1.214–3.324, p = 0.0059, pcorr = 0.0177)]. The p value of the χ2 test for the trend observed for the FCRL3 −169T>C polymorphism was also statistically significant (ptrend = 0.0012, pcorr = 0.0036). We also found significantly increased FCRL3 transcript levels in carriers of the FCRL3 −169 CC vs TT and CT vs TT genotype both in women with endometriosis-related infertility (p = 0.012; p = 0.015) and fertile women (p = 0.017; p = 0.032) Conclusions FCRL3 −169T>C polymorphism alters the expression of FCRL3 and can be a risk factor of endometriosis-related infertility.
    Archives of Gynecology 04/2013; 288(4). DOI:10.1007/s00404-013-2829-5 · 1.36 Impact Factor
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    ABSTRACT: The therapeutic targeting of extracellular proteins is becoming hugely attractive in light of evidence implicating the tumour microenvironment as pivotal in all aspects of tumour initiation and progression. Members of the lysyl oxidase (LOX) family of proteins are secreted by tumours and are the subject of much effort to understand their roles in cancer. In this Review we discuss the roles of members of this family in the remodelling of the tumour microenvironment and their paradoxical roles in tumorigenesis and metastasis. We also discuss how targeting this family of proteins might lead to a new avenue of cancer therapeutics.
    Nature Reviews Cancer 07/2012; 12(8):540-52. DOI:10.1038/nrc3319 · 37.40 Impact Factor
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