Vitiligo is an acquired disease characterized principally by patchy depigmentation of skin and overlying hair. Generalized vitiligo （GV）, the predominant form of the disorder, results from autoimmune loss of melanoc...Vitiligo is an acquired disease characterized principally by patchy depigmentation of skin and overlying hair. Generalized vitiligo （GV）, the predominant form of the disorder, results from autoimmune loss of melanocytes from affected regions. GV is a ＂complex trait＂, inherited in a non-Mendelian polygenic, multifactorial manner. GV is epidemiologically associated with other autoimmune diseases, both in GV patients and in their close relatives, suggesting that shared genes underlie susceptibility to this group of diseases. Early candidate gene association studies yielded a few successes, such as PTPN22, but most such reports now appear to be false-positives. Subsequent genomewide linkage studies identified NLRP1 and XBP1, apparent true GV susceptibility genes involved in immune regulation, and recent genome-wide association studies （GWAS） of GV in Caucasian and Chinese populations have yielded a large number of additional validated GV susceptibility genes. Together, these genes highlight biological systems and pathways that reach from the immune cells to the melanocyte, and provide insights into both disease pathogenesis and potential new targets for both treatment and even prevention of GV and other autoimmune diseases in genetically susceptible individuals.展开更多
Epigenetic mechanisms, including DNA methylation, are responsible for determining and maintaining cell fate, stably differentiating the various tissues in our bodies. Increasing evidence shows that DNA methylation pla...Epigenetic mechanisms, including DNA methylation, are responsible for determining and maintaining cell fate, stably differentiating the various tissues in our bodies. Increasing evidence shows that DNA methylation plays a significant role in cancer, from the silencing of tumor suppressors to the activation of oncogenes and the promotion of metastasis. Recent studies also suggest a role for DNA methylation in drug resistance. This perspective article discusses how DNA methylation may contribute to the development of acquired endocrine resistance, with a focus on breast cancer. In addition, we discuss DNA methylome profiling and how recent developments in this field are shedding new light on the role of epigenetics in endocrine resistance. Hormone ablation is the therapy of choice for hormone-sensitive breast tumors, yet as many as 40% of patients inevitably relapse, and these hormone refractory tumors often have a poor prognosis. Epigenetic studies could provide DNA methylation biomarkers to predict and diagnose acquired resistance in response to treatment. Elucidation of epigenetic mechanisms may also lead to the development of new treatments that specifically target epigenetic abnormalities or vulnerabilities in cancer cells. Expectations must be tempered by the fact that epigenetic mechanisms of endocrine resistance remain poorly understood, and further study is required to better understand how altering epigenetic pathways with therapeutics can promote or inhibit endocrine resistance in different contexts. Going forward, DNA methylome profiling will become increasingly central to epigenetic research, heralding a network-based approach to epigenetics that promises to advance our understanding of the etiology of cancer in ways not previously possible.展开更多
The epithelium of the human epididymis maintains an appropriate luminal environment for sperm maturation that is essential for male fertility. Regional expression of small noncoding RNAs such as microRNAs contributes ...The epithelium of the human epididymis maintains an appropriate luminal environment for sperm maturation that is essential for male fertility. Regional expression of small noncoding RNAs such as microRNAs contributes to segment-specific gene expression and differentiated functions. MicroRNA profiles were reported in human epididymal tissues but not specifically in the epithelial cells derived from those regions. Here, we reveal miRNA signatures of primary cultures of caput, corpus, and cauda epididymis epithelial cells and of the tissues from which they were derived. We identify 324 epithelial cell-derived microRNAs and 259 tissue-derived microRNAs in the epididymis, some of which displayed regionalized expression patterns in cells and/or tissues. Caput cell-enriched miRNAs included miR-573 and miR-155. Cauda cell-enriched miRNAs included miR-1204 and miR-770. Next, we determined the gene ontology pathways associated with in silico predicted target genes of the differentially expressed miRNAs. The effect of androgen receptor stimulation on miRNA expression was also investigated. These data show novel epithelial cell-derived miRNAs that may regulate the expression of important gene networks that are responsible for the regionalized gene expression and function of the epididymis.展开更多
Non-syndromic cleft lip with or without cleft palate （nsCL/P） is among the most common major birth defects, with complex inheritance involving multiple genes and environmental factors. Numerous studies of MTHFR, enc...Non-syndromic cleft lip with or without cleft palate （nsCL/P） is among the most common major birth defects, with complex inheritance involving multiple genes and environmental factors. Numerous studies of MTHFR, encoding methylenetetrahydrofolate reductase, which catalyzes the rate-limiting step of folic acid biosynthesis, have shown inconsistent association of two common hypomorphic allelic variants, C677T and A1298C, in nsCL/P patients and, in some cases, their mothers. We have studied the MTHFR C677T and A1298C polymorphisms in nsCL/P patients, their mothers, and population-matched controls from northern Venezuela. We found no evidence for contribution of the MTHFR C677T and A1298C variants to the risk of nsCL/P in northern Venezuela. Overall, our findings fail to support a causal role of either the MTHFR C677T or A 1298C variants in the pathogenesis of nsCL/P in northern Venezuela.展开更多
AIM:To characterize clinicopathological and familial features of early-onset colorectal cancer(CRC) and compare features of tumors with and without microsatellite instability(MSI).METHODS:Forty-five patients with CRC ...AIM:To characterize clinicopathological and familial features of early-onset colorectal cancer(CRC) and compare features of tumors with and without microsatellite instability(MSI).METHODS:Forty-five patients with CRC aged 45 or younger were included in the study.Clinical information,a three-generation family history,and tumor samples were obtained.MSI status was analyzed and mismatch repair genes were examined in the MSI families.Tumors were included in a tissue microarray and an immunohistochemical study was carried out with a panel of selected antibodies.RESULTS:Early onset CRC is characterized by advanced stage at diagnosis,right colon location,low-grade of differentiation,mucin production,and presence of polyps.Hereditary forms represent at least 21% of cases.Eighty-one percent of patients who died during followup showed a lack of expression of cyclin E,which could be a marker of poor prognosis.β-catenin expression was normal in a high percentage of tumors.CONCLUSION:Early-onset CRC has an important familial component,with a high proportion of tumors showing microsatellite stable.Cyclin E might be a poor prognosis factor.展开更多
Background & Aims: Mutations in the mismatch repair genes cause hereditary nonpolyposis colorectal cancer (HNPCC) syndrome and convey high lifetime cancer risks for colorectal (CRC) and endometrial cancer. Current...Background & Aims: Mutations in the mismatch repair genes cause hereditary nonpolyposis colorectal cancer (HNPCC) syndrome and convey high lifetime cancer risks for colorectal (CRC) and endometrial cancer. Currently, cancer risks for individuals with HNPCC are based on data from clinically ascertained families. The purpose of this study was to re-examine the penetrance in HNPCC using a comprehensive dataset from a geographically defined region. Methods: A combined dataset of 70 HNPCC families ascertained by traditional high-risk criteria and by molecular screening comprising 88 probands and 373 mutation-positive family members was used. Statistical methods were modified survival analysis techniques. Results: In mutation-positive relatives (excluding probands), the median age at diagnosis of CRC was 61.2 years (confidence interval [CI], 56.3- 68.0 y). The lifetime risk for CRC was 68.7% (CI, 58.6% - 78.9% ) for men and 52.2% (CI, 37.6% - 66.9% ) for women. Considering only probands, the median age at diagnosis of CRC was 44.0 years (CI, 41.0- 46.3 y). Median age of onset of EC was 62.0 years (CI, 55.9 y to an upper limit too high to calculate)with a lifetime cancer risk of 54% (CI, 41.9% - 66.1% ). Conclusions: A markedly later age of onset for CRC at 61 y than previously reported (? 44 y) is suggested, resulting mainly from a more rigorous method of analysis in which all gene-positive individuals (both affected and unaffected with cancer) are considered. Lifetime cancer risks may be lower for CRC and endometrial cancer than presently assumed. If confirmed, these data suggest a need to alter counseling practices, and to consider HNPCC in older individuals than before.展开更多
We report an apparently benign familial 9p subtelomere deletion identified using chromosome-arm-specific subtelomere probes in a patient with multiple congenital anomalies. Our experience demonstrated that the discove...We report an apparently benign familial 9p subtelomere deletion identified using chromosome-arm-specific subtelomere probes in a patient with multiple congenital anomalies. Our experience demonstrated that the discovery of a subtelomeric deletion and/or duplication does not always guarantee the identification of the etiology for the patient’s phenotype and a positive finding with subtelomere probes should always be followed by parental study with the same probe in order to distinguish a disease causing alteration from a benign familial polymorphism.展开更多
The most frequent chromosomal rearrangement reported in acute promyelocytic leukemia (APL) is t(15;17)(q22;q21). The t(15;17) generates the PML/RARA fusion gene that blocks the transcription of genes involved in myelo...The most frequent chromosomal rearrangement reported in acute promyelocytic leukemia (APL) is t(15;17)(q22;q21). The t(15;17) generates the PML/RARA fusion gene that blocks the transcription of genes involved in myeloid cell differentiation. A small number of simple and complex variants of the classical t(15;17) have been reported. We report two complex three-way translocation variants,t(3;17;15)(q27;q21;q22) and t(8;17;15)(q24.3;q12;q22) in which the PML/RARA fusion gene has been created on the derivative 15 chromosomes. Many of these variant translocations are suspected by conventional cytogenetics but need to be confirmed with additional molecular testing. We discuss the importance of supplementing conventional cytogenetic testing with FISH and RT-PCR to accurately diagnose APL variant patients.展开更多
基金supported in part by the grants R01 AR45585 and R01 AR056292 from the National Institutes of Health,USA
文摘Vitiligo is an acquired disease characterized principally by patchy depigmentation of skin and overlying hair. Generalized vitiligo （GV）, the predominant form of the disorder, results from autoimmune loss of melanocytes from affected regions. GV is a ＂complex trait＂, inherited in a non-Mendelian polygenic, multifactorial manner. GV is epidemiologically associated with other autoimmune diseases, both in GV patients and in their close relatives, suggesting that shared genes underlie susceptibility to this group of diseases. Early candidate gene association studies yielded a few successes, such as PTPN22, but most such reports now appear to be false-positives. Subsequent genomewide linkage studies identified NLRP1 and XBP1, apparent true GV susceptibility genes involved in immune regulation, and recent genome-wide association studies （GWAS） of GV in Caucasian and Chinese populations have yielded a large number of additional validated GV susceptibility genes. Together, these genes highlight biological systems and pathways that reach from the immune cells to the melanocyte, and provide insights into both disease pathogenesis and potential new targets for both treatment and even prevention of GV and other autoimmune diseases in genetically susceptible individuals.
基金supported in part by National Institutes of Health grants U01ES015986, U54 CA113001 and R01CA069065This TL1 award was funded by Award Number KL2 RR025754 from the National Center for Research Resources
文摘Epigenetic mechanisms, including DNA methylation, are responsible for determining and maintaining cell fate, stably differentiating the various tissues in our bodies. Increasing evidence shows that DNA methylation plays a significant role in cancer, from the silencing of tumor suppressors to the activation of oncogenes and the promotion of metastasis. Recent studies also suggest a role for DNA methylation in drug resistance. This perspective article discusses how DNA methylation may contribute to the development of acquired endocrine resistance, with a focus on breast cancer. In addition, we discuss DNA methylome profiling and how recent developments in this field are shedding new light on the role of epigenetics in endocrine resistance. Hormone ablation is the therapy of choice for hormone-sensitive breast tumors, yet as many as 40% of patients inevitably relapse, and these hormone refractory tumors often have a poor prognosis. Epigenetic studies could provide DNA methylation biomarkers to predict and diagnose acquired resistance in response to treatment. Elucidation of epigenetic mechanisms may also lead to the development of new treatments that specifically target epigenetic abnormalities or vulnerabilities in cancer cells. Expectations must be tempered by the fact that epigenetic mechanisms of endocrine resistance remain poorly understood, and further study is required to better understand how altering epigenetic pathways with therapeutics can promote or inhibit endocrine resistance in different contexts. Going forward, DNA methylome profiling will become increasingly central to epigenetic research, heralding a network-based approach to epigenetics that promises to advance our understanding of the etiology of cancer in ways not previously possible.
文摘The epithelium of the human epididymis maintains an appropriate luminal environment for sperm maturation that is essential for male fertility. Regional expression of small noncoding RNAs such as microRNAs contributes to segment-specific gene expression and differentiated functions. MicroRNA profiles were reported in human epididymal tissues but not specifically in the epithelial cells derived from those regions. Here, we reveal miRNA signatures of primary cultures of caput, corpus, and cauda epididymis epithelial cells and of the tissues from which they were derived. We identify 324 epithelial cell-derived microRNAs and 259 tissue-derived microRNAs in the epididymis, some of which displayed regionalized expression patterns in cells and/or tissues. Caput cell-enriched miRNAs included miR-573 and miR-155. Cauda cell-enriched miRNAs included miR-1204 and miR-770. Next, we determined the gene ontology pathways associated with in silico predicted target genes of the differentially expressed miRNAs. The effect of androgen receptor stimulation on miRNA expression was also investigated. These data show novel epithelial cell-derived miRNAs that may regulate the expression of important gene networks that are responsible for the regionalized gene expression and function of the epididymis.
基金supported by the grant DE13571 from the National Institutes of Health (R.A.S.),USAthe support from Rotaplast International, Inc. (M.M.T.),USA
文摘Non-syndromic cleft lip with or without cleft palate （nsCL/P） is among the most common major birth defects, with complex inheritance involving multiple genes and environmental factors. Numerous studies of MTHFR, encoding methylenetetrahydrofolate reductase, which catalyzes the rate-limiting step of folic acid biosynthesis, have shown inconsistent association of two common hypomorphic allelic variants, C677T and A1298C, in nsCL/P patients and, in some cases, their mothers. We have studied the MTHFR C677T and A1298C polymorphisms in nsCL/P patients, their mothers, and population-matched controls from northern Venezuela. We found no evidence for contribution of the MTHFR C677T and A1298C variants to the risk of nsCL/P in northern Venezuela. Overall, our findings fail to support a causal role of either the MTHFR C677T or A 1298C variants in the pathogenesis of nsCL/P in northern Venezuela.
基金Supported by The Instituto de Salud Carlos Ⅲ, Ministerio de Sanidad y Consumo (FIS01-04, project P047-04)
文摘AIM:To characterize clinicopathological and familial features of early-onset colorectal cancer(CRC) and compare features of tumors with and without microsatellite instability(MSI).METHODS:Forty-five patients with CRC aged 45 or younger were included in the study.Clinical information,a three-generation family history,and tumor samples were obtained.MSI status was analyzed and mismatch repair genes were examined in the MSI families.Tumors were included in a tissue microarray and an immunohistochemical study was carried out with a panel of selected antibodies.RESULTS:Early onset CRC is characterized by advanced stage at diagnosis,right colon location,low-grade of differentiation,mucin production,and presence of polyps.Hereditary forms represent at least 21% of cases.Eighty-one percent of patients who died during followup showed a lack of expression of cyclin E,which could be a marker of poor prognosis.β-catenin expression was normal in a high percentage of tumors.CONCLUSION:Early-onset CRC has an important familial component,with a high proportion of tumors showing microsatellite stable.Cyclin E might be a poor prognosis factor.
文摘Background & Aims: Mutations in the mismatch repair genes cause hereditary nonpolyposis colorectal cancer (HNPCC) syndrome and convey high lifetime cancer risks for colorectal (CRC) and endometrial cancer. Currently, cancer risks for individuals with HNPCC are based on data from clinically ascertained families. The purpose of this study was to re-examine the penetrance in HNPCC using a comprehensive dataset from a geographically defined region. Methods: A combined dataset of 70 HNPCC families ascertained by traditional high-risk criteria and by molecular screening comprising 88 probands and 373 mutation-positive family members was used. Statistical methods were modified survival analysis techniques. Results: In mutation-positive relatives (excluding probands), the median age at diagnosis of CRC was 61.2 years (confidence interval [CI], 56.3- 68.0 y). The lifetime risk for CRC was 68.7% (CI, 58.6% - 78.9% ) for men and 52.2% (CI, 37.6% - 66.9% ) for women. Considering only probands, the median age at diagnosis of CRC was 44.0 years (CI, 41.0- 46.3 y). Median age of onset of EC was 62.0 years (CI, 55.9 y to an upper limit too high to calculate)with a lifetime cancer risk of 54% (CI, 41.9% - 66.1% ). Conclusions: A markedly later age of onset for CRC at 61 y than previously reported (? 44 y) is suggested, resulting mainly from a more rigorous method of analysis in which all gene-positive individuals (both affected and unaffected with cancer) are considered. Lifetime cancer risks may be lower for CRC and endometrial cancer than presently assumed. If confirmed, these data suggest a need to alter counseling practices, and to consider HNPCC in older individuals than before.
文摘We report an apparently benign familial 9p subtelomere deletion identified using chromosome-arm-specific subtelomere probes in a patient with multiple congenital anomalies. Our experience demonstrated that the discovery of a subtelomeric deletion and/or duplication does not always guarantee the identification of the etiology for the patient’s phenotype and a positive finding with subtelomere probes should always be followed by parental study with the same probe in order to distinguish a disease causing alteration from a benign familial polymorphism.
文摘The most frequent chromosomal rearrangement reported in acute promyelocytic leukemia (APL) is t(15;17)(q22;q21). The t(15;17) generates the PML/RARA fusion gene that blocks the transcription of genes involved in myeloid cell differentiation. A small number of simple and complex variants of the classical t(15;17) have been reported. We report two complex three-way translocation variants,t(3;17;15)(q27;q21;q22) and t(8;17;15)(q24.3;q12;q22) in which the PML/RARA fusion gene has been created on the derivative 15 chromosomes. Many of these variant translocations are suspected by conventional cytogenetics but need to be confirmed with additional molecular testing. We discuss the importance of supplementing conventional cytogenetic testing with FISH and RT-PCR to accurately diagnose APL variant patients.
