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Jfri A, Litvinov IV, Netchiporouk E, O'Brien E. Novel variants of MEFV and NOD2 genes in familial hidradenitis suppurativa: A case report. SAGE Open Med Case Rep 2020; 8:2050313X20953113. [PMID: 33029352 PMCID: PMC7522817 DOI: 10.1177/2050313x20953113] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
We report a two-generation Canadian family of Armenian ancestry with hidradenitis suppurativa where novel mutations in MEVF and NOD2 genes were identified. The father and both children shared a mild-to-moderate hidradenitis suppurativa phenotype together with the features of follicular occlusion (e.g. acne and scalp folliculitis). Based on our findings and previous literature, we recommend considering genetic testing with a periodic fever/autoinflammatory disorder panel in patients with a strong family history of hidradenitis suppurativa and lack of common triggers such as smoking and being overweight.
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Affiliation(s)
- Abdulhadi Jfri
- Division of Dermatology, McGill University Health Centre, Montreal General Hospital, Montreal, QC, Canada
| | - Ivan V Litvinov
- Division of Dermatology, McGill University Health Centre, Montreal General Hospital, Montreal, QC, Canada
| | - Elena Netchiporouk
- Division of Dermatology, McGill University Health Centre, Montreal General Hospital, Montreal, QC, Canada
| | - Elizabeth O'Brien
- Division of Dermatology, McGill University Health Centre, Montreal General Hospital, Montreal, QC, Canada
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Hsieh SM, Look MP, Sieuwerts AM, Foekens JA, Hunter KW. Distinct inherited metastasis susceptibility exists for different breast cancer subtypes: a prognosis study. Breast Cancer Res 2010; 11:R75. [PMID: 19825179 PMCID: PMC2790856 DOI: 10.1186/bcr2412] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2009] [Revised: 09/17/2009] [Accepted: 10/13/2009] [Indexed: 12/12/2022] Open
Abstract
Introduction Previous studies in mouse models and pilot epidemiology studies have demonstrated that inherited polymorphisms are associated with inherited risk of tumor progression and poor outcome in human breast cancer. To extend these studies and gain better understanding of the function of inherited polymorphism in breast cancer progression, a validation prognosis study was performed in a large independent breast cancer patient population. Methods The study population consisted of 1863 Dutch patients with operable primary breast cancer from Rotterdam, The Netherlands. Genomic DNA was genotyped for the missense Pro436Leu RRP1B single nucleotide polymorphism (SNP) rs9306160 and the intronic SIPA1 SNP rs2448490 by SNP-specific PCR. Results A significant association of variants in RRP1B with metastasis-free survival was observed (P = 0.012), validating the role of RRP1B with inherited metastatic susceptibility. Stratification of patients revealed that association with patients' survival was found to be specifically restricted to estrogen receptor positive, lymph node-negative (ER+/LN-) patients (P = 0.011). The specific association with metastasis-free survival only in ER+/LN- patients was replicated for SIPA1, a second metastasis susceptibility gene known to physically interact with RRP1B (P = 0.006). Combining the genotypes of these two genes resulted in the significant ability to discriminate patients with poor metastasis-free survival (HR: 0.40, 95% CI: 0.24 to 0.68, P = 0.001). Conclusions These results validate SIPA1 and RRP1B as metastasis susceptibility genes and suggest that genotyping assays may be a useful supplement to other clinical and molecular indicators of prognosis. The results also suggest that lymphatic and hematogeneous metastases are genetically distinct that may involve different mechanisms. If true, these results suggest that metastatic disease, like primary breast cancer, may be multiple diseases and that stratification of late stage patients may therefore be required to fully understand breast cancer progression and metastasis.
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Affiliation(s)
- Szu-Min Hsieh
- Laboratory of Cancer Biology and Genetics, NCI, NIH, Room 5046, 37 Convent Drive, Bethesda, Maryland 20892-4264, USA.
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Lakner L, Csöngei V, Magyari L, Varga M, Miheller P, Sarlós P, Orosz P, Bári Z, Takács I, Járomi L, Sáfrány E, Sipeky C, Bene J, Tulassay Z, Döbrönte Z, Melegh B. [Possible role of selected IGR and SLC22A4/SLC22A5 loci in development of inflammatory bowel diseases]. Orv Hetil 2009; 150:1375-1380. [PMID: 19581171 DOI: 10.1556/oh.2009.28677] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
UNLABELLED The IBD5 locus (MIM#606348) on chromosome 5q31 has been demonstrated to confer increased risk for inflammatory bowel disease. Controversial reports have been published about the significance of individual loci located in this region. Here we investigated the possible genetic association of inflammatory bowel diseases with C1672T of SLC22A4 and G-207C SLC22A5 alleles, and with IGR2096a_1 (rs12521868) and IGR2198a_1 (rs11739135) susceptibility variants of the IBD5 region located on chromosome 5q31. PATIENTS AND METHODS Total of 440 patients, 206 with Crohn's disease, 234 with ulcerative colitis, and 279 controls were studied by PCR-RFLP methods. RESULTS Neither the C1672T, and G-207C alleles, nor the TC haplotype were found to confer risk for Crohn's disease or ulcerative colitis. By contrast, both of the minor allele frequencies of IGR2096a_1 T (48.1%) and IGR2198a_1 C (46.1%) were increased in Crohn's disease subjects as compared with the controls (38.5% and 38.4%, respectively; p<0.05). Using regression analysis adjusted to age and gender these alleles were found to confer risk for Crohn's disease (OR=1.694, 95% CI: 1.137-2.522; p=0.010 for T allele, OR=1.644, 95% CI=1.103-2.449; p=0.015 for C allele of IGRs). In UC no such associations were found. CONCLUSIONS Our results revealed the susceptibility nature of the examined IGR minor alleles in Hungarians, which nation differs historically from the surrounding Caucasian populations in origin of the founders of the state.
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Affiliation(s)
- Lilla Lakner
- Vas Megyei Markusovszky Kórház Nonprofit Zrt. Gasztroenterológiai és Belgyógyászati Osztály Szombathely
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Lakner L, Csöngei V, Sarlós P, Járomi L, Sáfrány E, Varga M, Orosz P, Magyari L, Bene J, Miheller P, Tulassay Z, Melegh B. IGR2096a_1 T and IGR2198a_1 C alleles on IBD5 locus of chromosome 5q31 region confer risk for Crohn's disease in Hungarian patients. Int J Colorectal Dis 2009; 24:503-507. [PMID: 19214536 DOI: 10.1007/s00384-009-0670-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/21/2009] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS We investigated the possible association of IBD with C1672T of SLC22A4 and G-207C of SLC22A5 alleles, and with the novel IGR2096a_1 (rs12521868) and IGR2198a_1 (rs11739135) susceptibility loci, all located on IBD5 locus of chromosome 5q31. MATERIALS AND METHODS DNA of 217 Crohn's disease, 252 ulcerative colitis, and 290 control patients were analyzed by polymerase chain reaction/restriction fragment length polymorphism methods. RESULTS Neither the C1672T and G-207C alleles, nor the TC haplotype were found to be risk factors. By contrast, the minor allele frequencies of IGR2096a_1 T (47.2%) and IGR2198a_1 C (45.9%) were increased in Crohn's disease compared with the controls (38.2% and 37.7%, respectively; p < 0.05); multivariate regression analysis revealed a risk nature for Crohn's disease (OR = 1.748, 95% CI 1.186-2.574; p = 0.007 for T allele, OR = 1.646, 95% CI 1.119-2.423, p = 0.011 for C allele of IGRs). CONCLUSION The data suggest a special haplotype arrangement of susceptibility genes at the IBD5 locus in Hungarians, which nation differs historically from the surrounding Caucasian ethnicities in its origin.
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Affiliation(s)
- Lilla Lakner
- Department of Medicine and Gastroenterology, Markusovszky Hospital, Szombathely, Hungary
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Crawford NPS, Qian X, Ziogas A, Papageorge AG, Boersma BJ, Walker RC, Lukes L, Rowe WL, Zhang J, Ambs S, Lowy DR, Anton-Culver H, Hunter KW. Rrp1b, a new candidate susceptibility gene for breast cancer progression and metastasis. PLoS Genet 2007; 3:e214. [PMID: 18081427 PMCID: PMC2098807 DOI: 10.1371/journal.pgen.0030214] [Citation(s) in RCA: 75] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2007] [Accepted: 10/12/2007] [Indexed: 12/20/2022] Open
Abstract
A novel candidate metastasis modifier, ribosomal RNA processing 1 homolog B (Rrp1b), was identified through two independent approaches. First, yeast two-hybrid, immunoprecipitation, and functional assays demonstrated a physical and functional interaction between Rrp1b and the previous identified metastasis modifier Sipa1. In parallel, using mouse and human metastasis gene expression data it was observed that extracellular matrix (ECM) genes are common components of metastasis predictive signatures, suggesting that ECM genes are either important markers or causal factors in metastasis. To investigate the relationship between ECM genes and poor prognosis in breast cancer, expression quantitative trait locus analysis of polyoma middle-T transgene-induced mammary tumor was performed. ECM gene expression was found to be consistently associated with Rrp1b expression. In vitro expression of Rrp1b significantly altered ECM gene expression, tumor growth, and dissemination in metastasis assays. Furthermore, a gene signature induced by ectopic expression of Rrp1b in tumor cells predicted survival in a human breast cancer gene expression dataset. Finally, constitutional polymorphism within RRP1B was found to be significantly associated with tumor progression in two independent breast cancer cohorts. These data suggest that RRP1B may be a novel susceptibility gene for breast cancer progression and metastasis. Metastasis, which is defined as the spread of malignant tumor cells from their original site to other parts of the body, accounts for the vast majority of solid cancer-related mortality. Our laboratory has previously shown that host germline-encoded variation modifies primary tumor metastatic capacity. Here, we detail how germline-encoded Rrp1b variation likely modulates metastasis. In mice, constitutional Rrp1b variation correlates with ECM gene expression, which are genes commonly differentially regulated in metastasis prone tumors. Furthermore, we demonstrate that Rrp1b expression levels are modulated by germline variation in mice with differing metastatic propensities, and that variation of Rrp1b expression in a highly metastatic mouse mammary tumor cell line modifies progression. Differential RRP1B functionality also appears to play an important role in human breast cancer progression. Specifically, we demonstrate that a microarray gene expression signature indicative of differential RRP1B expression predicts breast cancer-specific survival. Furthermore, we show that germline-encoded RRP1B variation is associated with markers of outcome in two breast cancer populations. In summary, these data suggest that Rrp1b may be a germline-encoded metastasis modifier in both mice and humans, which leads to the possibility that knowledge of RRP1B functionality and variation in breast cancer might facilitate improved assessment of prognosis.
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Affiliation(s)
- Nigel P. S Crawford
- Laboratory of Population Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Xiaolan Qian
- Laboratory of Cellular Oncology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Argyrios Ziogas
- Epidemiology Division, Department of Medicine, University of California Irvine, Irvine, California, United States of America
| | - Alex G Papageorge
- Laboratory of Cellular Oncology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Brenda J Boersma
- Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Renard C Walker
- Laboratory of Population Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Luanne Lukes
- Laboratory of Population Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
| | - William L Rowe
- Laboratory of Population Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Jinghui Zhang
- Laboratory of Population Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Stefan Ambs
- Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Douglas R Lowy
- Laboratory of Cellular Oncology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Hoda Anton-Culver
- Epidemiology Division, Department of Medicine, University of California Irvine, Irvine, California, United States of America
| | - Kent W Hunter
- Laboratory of Population Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
- * To whom correspondence should be addressed. E-mail:
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Crawford NPS, Colliver DW, Eichenberger MR, Funke AA, Kolodko V, Cobbs GA, Petras RE, Galandiuk S. CARD15 genotype-phenotype relationships in a small inflammatory bowel disease population with severe disease affection status. Dig Dis Sci 2007; 52:2716-24. [PMID: 17404888 DOI: 10.1007/s10620-006-9208-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2005] [Accepted: 12/30/2005] [Indexed: 01/29/2023]
Abstract
Inflammatory bowel disease (IBD; MIM# 266600) is subdivided on the basis of clinical findings as either Crohn's disease (CD), ulcerative colitis (UC), or indeterminate colitis (IC). Three previously described mutations within the IBD susceptibility gene CARD15 (R702W, G908R, 1007fs) increase susceptibility to CD with a terminal ileal and/or ileocolonic location and fibrostenosing behavior. We undertook an association study using 477 unrelated IBD patients (248 CD, 172 UC, 57 IC) and 104 population controls to determine whether these previously described associations could be replicated in a small, accurately phenotyped cohort. Case-control and family-based approaches were employed to analyze CARD15 mutant allele and haplotype data. Analyses were initially performed in unstratified IBD cohorts. The R702W mutant allele was associated with CD on case-control analysis (q=0.036, P=.004), and 1007fs with CD on pedigree disequilibrium testing (P=.020). All 3 CARD15 mutations increased susceptibility to a variety of CD subphenotypic manifestations, including early-onset CD in individuals with a family history of IBD, and CD complicated by extraintestinal disease. We also present evidence to suggest that R702W may predispose to a more generalized form of CD. Additionally, we confirm that CARD15 mutations are associated with terminal ileal/ileocolonic, and to a lesser extent, fibrostenosing CD.
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Affiliation(s)
- Nigel P S Crawford
- Price Institute for Surgical Research, Department of Surgery, University of Louisville School of Medicine, Louisville, Kentucky, USA
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Crawford NPS, Ziogas A, Peel DJ, Hess J, Anton-Culver H, Hunter KW. Germline polymorphisms in SIPA1 are associated with metastasis and other indicators of poor prognosis in breast cancer. Breast Cancer Res 2006; 8:R16. [PMID: 16563182 PMCID: PMC1483843 DOI: 10.1186/bcr1389] [Citation(s) in RCA: 82] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2005] [Revised: 02/15/2006] [Accepted: 02/20/2006] [Indexed: 12/30/2022] Open
Abstract
Introduction There is growing evidence that heritable genetic variation modulates metastatic efficiency. Our previous work using a mouse mammary tumor model has shown that metastatic efficiency is modulated by the GTPase-activating protein encoded by Sipa1 ('signal-induced proliferation-associated gene 1'). The aim of this study was to determine whether single nucleotide polymorphisms (SNPs) within the human SIPA1 gene are associated with metastasis and other disease characteristics in breast cancer. Method The study population (n = 300) consisted of randomly selected non-Hispanic Caucasian breast cancer patients identified from a larger population-based series. Genomic DNA was extracted from peripheral leukocytes. Three previously described SNPs within SIPA1 (one within the promoter [-313G>A] and two exonic [545C>T and 2760G>A]) were characterized using SNP-specific PCR. Results The variant 2760G>A and the -313G>A allele were associated with lymph node involvement (P = 0.0062 and P = 0.0083, respectively), and the variant 545C>T was associated with estrogen receptor negative tumors (P = 0.0012) and with progesterone negative tumors (P = 0.0339). Associations were identified between haplotypes defined by the three SNPs and disease progression. Haplotype 3 defined by variants -313G>A and 2760G>A was associated with positive lymph node involvement (P = 0.0051), and haplotype 4 defined by variant 545C>T was associated with estrogen receptor and progesterone receptor negative status (P = 0.0053 and P = 0.0199, respectively). Conclusion Our findings imply that SIPA1 germline polymorphisms are associated with aggressive disease behavior in the cohort examined. If these results hold true in other populations, then knowledge of SIPA1 SNP genotypes could potentially enhance current staging protocols.
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Affiliation(s)
- Nigel PS Crawford
- Laboratory of Population Genetics, National Cancer Institute/National Institutes of Health, Bethesda, Maryland, USA
| | - Argyrios Ziogas
- Epidemiology Division, Department of Medicine, University of California, Irvine, California, USA
| | - David J Peel
- Epidemiology Division, Department of Medicine, University of California, Irvine, California, USA
| | - James Hess
- Epidemiology Division, Department of Medicine, University of California, Irvine, California, USA
| | - Hoda Anton-Culver
- Epidemiology Division, Department of Medicine, University of California, Irvine, California, USA
| | - Kent W Hunter
- Laboratory of Population Genetics, National Cancer Institute/National Institutes of Health, Bethesda, Maryland, USA
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Gazouli M, Mantzaris G, Archimandritis AJ, Nasioulas G, Anagnou NP. Single nucleotide polymorphisms of OCTN1, OCTN2, and DLG5 genes in Greek patients with Crohn's disease. World J Gastroenterol 2005; 11:7525-7530. [PMID: 16437728 PMCID: PMC4725165 DOI: 10.3748/wjg.v11.i47.7525] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2005] [Revised: 06/20/2005] [Accepted: 06/24/2005] [Indexed: 02/06/2023] Open
Abstract
AIM To validate novel single nucleotide polymorphisms (SNPs) in Greek patients with Crohn's disease (CD). METHODS A total of 120 patients with CD, 85 patients with UC, and 100 unrelated healthy controls were genotyped. Genotyping was performed by allele-specific PCR or by PCR-RFLP analysis. RESULTS Our results showed that the 1672T and -207C alleles were obviously over-represented in CD patients only (P<0.01 and P<0.05, respectively) compared to the control population. The G113A polymorphism was completely absent in our studied population. The odds ratio for the carriage of the TC haplotype was 2.21 for CD patients as compared with controls. Additionally, the frequency of the TC haplotype was increased in patients with ileocolitis or colitis, and was mainly associated with the fibrostenotic phenotype of the disease. Furthermore, when the TC haplotype was compared jointly with the carriage of at least one mutation of the NOD2/CARD15 gene, there was an increased risk for CD, but not for UC, compared to controls. Regarding the location of the disease, the concomitant presence of the TC haplotype and NOD2/CARD15 mutations was mainly associated with ileocolitis or ileitis. CONCLUSION Collectively, our results suggest that the 1672T variant of the OCTN1 gene and the -207C variant of the OCTN2 gene represent risk factors for CD in the Greek population.
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Affiliation(s)
- Maria Gazouli
- Department of Biology, School of Medicine, University of Athens, Athens 11527, Greece
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