High frequency of the X-chromosome inactivation in young female patients with high-grade glioma
- Gang Li†1, 5,
- Zhiguo Zhang†1,
- Tianbo Jin†2,
- Hongjuan Liang1,
- Yanyang Tu3,
- Li Gong4,
- Zhongping Chen5Email author and
- Guodong Gao1Email author
© Li et al.; licensee BioMed Central Ltd. 2013
Received: 30 April 2013
Accepted: 9 June 2013
Published: 19 June 2013
Gliomas are common tumors and high-grade ones account for 62% of primary malignant brain tumors. Though current evidence have suggested that inherited risks play a role in glioma susceptibility, it was conveyed that glioma was such a complex disease, and the direct genetic contribution to glioma risk factors and its relation to other factors should be discussed more deeply. X-chromosome inactivation (XCI) is the mechanism by which gene dosage equivalence is achieved between female mammals with two X chromosomes and male mammals with a single X chromosome. As skewed XCI has been linked to development of some solid tumors, including ovarian, breast, and pulmonary and esophageal carcinomas, it is challenging to elucidate the relation of skewed XCI to high-grade gliomas development.
The present study aimed to determine the general concordance between XCI pattern in blood cells and brain tissues, and SXCI frequencies in female patients with high-grade glioma compared to healthy controls.
1,103 Chinese females without a detectable tumor and 173 female high-grade glioma patients, were detected in the study. Normal brain tissues surrounding the lesions in gliomas were obtained from 49 patients among the 173 ones, with the microdissection using a laser microdissection microscope Genomic DNA was extracted from the peripheral blood cells and the normal brain tissues from the subjects. Exon 1 of androgen receptor (AR) gene was amplified, and its products of different alleles were resolved on denaturing polyacrylamide gels and visualized after silver staining. The corrected ratios (CR) of the products before and after Hpa II digestion were calculated.
Occurrence of SXCI was detected in both the patients and controls at similar frequencies. However, the phenomenon, as defined as CR ≥ 3, was more frequent in the patients aging ≤40 (23.6%) compared to the corresponding reference group (5.1%, P <0.0001). When CR ≥ 10 was adopted, the frequencies were 5.5% and 1.6%, respectively. Their difference did not attain statistical significance (P = 0.10). When detected, both blood cells and brain tissue were compared after determination of a high concordance of XCI between blood cells and brain tissue collected from the same individuals (n = 48, r =0.57, P <0.01).
The data from the current study demonstrated that SXCI may be a predisposing factor for development of high-grade glioma in young female patients and further study will verify its suitability as a biomarker to assess susceptibility of young female patients to high-grade glioma.
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1935066233982578
KeywordsSkewed X-chromosome inactivation Androgen receptor gene Glioma High-grade Cancer predisposition Laser microdissection
The incidence of brain tumors is approximately 18.71 per 100,000 person-years (i.e., 11.52 per 100,000 for benign tumors and 7.19 per 100,000 person-years for malignant tumors) worldwide . In comparison, in Shanghai core city, one of the most developed areas of China, in 2007 the overall age-specific incidence of primary central nervous system tumors was 80 per 100,000 person-years (i.e., 42 per 100,000 person-years for males, and 38 per 100,000 person-years for females, respectively) (unpublished data). Glioma is one such common malignancy, accounting for up to 30% of all brain tumors and 80% of the primary malignant brain tumors .
To date, the causes and mechanisms of gliomas remain to be elucidated, while hereditary genetic disorders such as neurofibromatoses (type 1 and type 2) and tuberous sclerosis complex are known to predispose to development of glioma . However, glioma is a very complex disease and high-grade gliomas, including anaplastic gliomas and glioblastomas, account for the majority of gliomas, representing 62% of cases . Thus, novel approaches are needed to identify susceptibility genes for association with glioma risk and the molecular mechanisms responsiable for glioma development . Towards this end, Wrench et al.  in 2009 reported genome-wide screening data on association with glioma susceptibility and thereafter, a number of such association studies have been carried out for gliomas [5, 7, 8]. These explorations involved identification of susceptibility genes for glioma development and to date, eight glioma susceptibility loci have been identified by candidate gene-association studies . Altered genes, gene promoters, and single-nucleotide polymorphisms (SNPs) could induce susceptibility to glioma development , while detection of gene mutations, deletions and translocations using DNA sequencing can identify genomic regions responsible for developing glioma . A number of molecular alterations, such as EGFR, TP53, RPA3, PTEN, and CDKN2A have therefore been detected [11–13] and SNPs of some genes have also been identified in gliomas [5–8, 14, 15]. These studies have improved our knowledge and understanding of glioma development.
Our research is focused on skewing X-chromosome inactivation (SXCI). It is well known that in female mammals there are two X chromosomes, one of which is silenced epigenetically during early embryo development, thereby making female X-chromosome gene dosage largely equivalent to that of males [16–18], which occurs randomly . Because of this random process, adult female tissues are cellular mosaics, wherein half of the cells contain an active maternal X chromosome (Xm) and the other half contain an active paternal X chromosome (Xp) . This random moderate skewing might occur by chance due to the small number of stem cells undergoing X-inactivation during embryogenesis and results in a Gaussian distribution of X-chromosome inactivation ratios with a mean of 1 to 1. However, skewed inactivation ratios of ≥3 to 10 were infrequently detected in cord blood cells of neonates and, importantly, heritability of skewed X-chromosome inactivation patterns (XCIP) is a highly uncommon event [19, 20]. Previous studies have shown that SXCI is associated with the development of breast [21–23], ovarian , lung  and esophageal cancers . In glioma, an age-standardized incidence rate was higher among females than males . Thus, this study investigated whether the imbalanced inactivation of X chromosomes in female somatic cells associates with an increased risk of glioma development.
Subjects and methods
Clinicopathological features of patients with glioma ( n = 173)
Mean Age (yrs.)
Gross total resection
Radiotherapy and Chemotherapy combination
Moreover, a random 1,103 healthy unrelated female individuals were recruited between June 2006 and August 2012 from the Medical Examination Center at Tangdu hospital. All of the chosen healthy subjects were Han Chinese living in Xi’an city and its surrounding areas. The median age was 55 years (range between 16 and 96 years old). A detailed recruitment and exclusion criteria was used, i.e., subjects with chronic diseases and conditions involving vital organs such as the heart, lung, liver, kidney and brain, and/or had severe endocrinological, metabolic or nutritional diseases were excluded from this study. The use of human tissues and blood samples in this study was approved by the Human Research Committee of the Fourth Military Medical University for Approval of Research Involving Human Subjects. A written informed consent was obtained from all the subjects or their custodians. All specimens were handled and made anonymous according to the ethical and legal standards.
Demographic and clinical data
Demographic and personal data were collected through an in-person interview using a standardized epidemiological questionnaire, including age, sex, ethnicity, residential region, tobacco smoking, alcohol consumption, education levels, and family history of cancer. For patients, detailed clinical information was also collected through a medical chart review or consultation with treating physicians. Levels of plasma carcinoembryonic antigen and alpha-fetoprotein were detemrined in all control subjects to make sure that they were healthy and without any cancers.
Blood samples collection, tissue laser microdissection, and DNA extraction
Peripheral blood was taken from the elbow vein or the head superficial vein, and treated immediately with an anticoagulant containing sodium citrate (22 g/L) and sodium chloride (8.5 g/L) from all 173 glioma patients and 1,103 healthy controls. The blood samples were then stored at −70°C until use.
Analysis of skewed X chromosome inactivation (SXCI)
The analysis is based on differential inactivation of X chromosomes of female somatic tissues and the CAG short-tandem repeat (STR) polymorphism at the AR gene exon 1 . There are two Hha I and two Hpa II restriction sites at the locus 100 bp upstream to the CAG STR with a heterozygosity frequency of around 90% [31, 32]. X-chromosome inactivation is associated with methylation of these restriction sites, i.e., if these sites are methylated, indicating the inactive X chromosome, this gene can not be transcribed, whereas if unmethylated, indicating the active X chromosome in females or male X chromosome, the gene can be transcribed .
Thus, we used this pricinple to digest DNA with methylation-sensitive endonucleases, followed by PCR with primers flanking these restriction sites and the highly polymorphic STR, to distinguish between the transcriptionally active and inactive X chromosome in heterozygous female subjects. In females with random X-chromosome inactivation, the amplification products from both alleles should be equal, with a ratio of approximately 1 to 1. In the neoplastic tissues, most of which originate from single cell clones [25, 26], the ratio will change markedly compared with the surrounding normal tissues. It is worth noting that a remarkable deviation of the ratio has been observed in apparently non-neoplastic cell populations, such as peripheral blood cells from female subjects, which is defined as SXCI [33, 34].
Genomic DNA (1 μg) was digested with 0.5 μL of Hpa II (10 U/μL; Promega, Madison, WI, USA) in 2 μL of 10 mol/L reaction buffer, 0.2 μL of 10 g/L bovine serum albumin and 7.3 μL of deionized water at 37°C for 4 hours. The reaction was then terminated by incubation of the sample mixture at room temperature for 30 minutes as suggested by the manufacturer. After that, a nested PCR was conducted as described previously [25, 26]. A negative and water-blank control was included in each batch of PCR. The reaction fidelity of Hpa II digestion was guaranteed by parallel negative controls with the enzyme omitted from the reaction mixture. In addition, the whole assay was repeated twice.
After that, the amplification efficacy was demonstrated by electrophoresis of 2% agarose gels. The amplification products (4 μL of each) were mixed with the same volume of the loading buffer (1 g/L xylene cyanole, 1 g/L bromophenol blue, in formamide), loaded onto the 10% polyacrylamide gel containing 8 mol/L urea, resolved through electrophoresis with the Mini-VE system (Amersham Biosciences Corp., San Francisco, CA) at a voltage of 80 v for 8 hours, and then visualized after silver staining as described previously . For the samples whose allelic differences at the CAG STR were small (one or two repeats), a longer gel (26-cm long and 0.75-mm thick) was used for the resolution with the SE660 system (Amersham). The results were recorded, and the intensities of the products from both alleles were analyzed by using an image-analyzing system (LabWorks 3.0, UVP, Cambridge, UK). To avoid the potential interference of possible preferential amplification of one of the alleles, we used the corrected ratio (CR) to evaluate the X-chromosome inactivation pattern by comparing the allelic difference of a sample before and after Hpa II digestion. CR was derived by dividing the ratio of the upper-band intensity to the lower-band intensity of the sample after digestion by that of the same sample before digestion. If CR was <1, the reciprocal value was considered. In the present study, CR ≥3, which indicated the expression of the same allele in more than 75% of the cells examined, was used to define SXCI. In addition, we also used CR ≥10 as a more stringent criterion for defining SXCI.
Statistical analysis was performed using an SPSS package for Windows (Version 13.0; SPSS Inc., Chicago, IL, USA). The likelihood ratio test was used to determine the difference in SXCI frequency among various age groups. The χ2 test was used to compare categorical variables. Pearson’s correlation analysis was performed on XCI corrected ratio (CR) data obtained from the 49 glioma patients whose blood and brain tissues samples were accessible simultaneously. A P value of <0.05 (two-tailed) was considered statistically significant.
Skewed X-chromosomal inactivation frequencies in glioma patients of various age groups and the corresponding controls
Age range (median: ys)
Numbers with CR ≥ 3(%)
Numbers with CR ≥ 10(%)
The relationship between SXCI in blood cells and clinical stages of the cancer was also assessed. With the criterion of CR ≥ 3 adopted, the frequencies for the cases of WHO grades III and IV were 20% (11/55) and 18.9% (21/111), respectively. There was no significant difference among them (P > 0.05).
In the current study, we extracted genomic DNA from the peripheral blood or brain tissue samples from 1,103 Chinese female control subjects and 173 female patients with high-grade glioma. We then amplified androgen receptor (AR) exon 1 and digested it with Hpa II to assess X-chromosome inactivation. We found that similar SXCI frequencies occurred in both patients and controls. However, SXCI (with an adopted CR ≥ 3) frequency was 23.6% in patients with an age of 40 years or younger compared to the healthy controls (5.1%). Moreover, SXCI frequencies showed a high concordance of XCI between blood cells and brain tissues. These data demonstrated that SXCI was a predisposing factor for development of high-grade glioma in young female patients.
Despite recent advancement in therapy for glioma, such as surgery, radiotherapy, photodynamic therapy, and chemotherapy, the clinical outcome of patients with high-grade glioma remains poor, especially in patients with WHO IV glioma (9.8% 5-year survival rate) . Thus, it is held widely that early detection of glioma could prolong the survival of glioma patients, and some detected biomarks have been verified their suitability to assist significantly in the evaluation of biological activity in gliomas and even have prognostic value [35, 36]. Furthermore, some correlated studies have shown that inherited risk factors do play a significant role in glioma susceptibility, and that a heritable component of glioma had a twofold elevated risk in individuals with a positive family history [37, 38], and rare genetic syndromes increased the risk of glioma . GWAS studies have identified common susceptibility variants at 5p15.33 (TERT), 8q24.21 (CCDC26), 9q21.3(CDKN2A-CDKN2B), 20q13.33(RTEL1) and 11q23.3 (PHLDB1) [5–8]. These fingings could help us to understand the altered genes and their expressions which are involved in the development of glioma. Meanwhile other studies, including our current study, have investigated gene SNPs or chromosome levels of alterations as a means of predicting genetic susceptibility for glioma development. Our current data showed that SXCI occurred more frequently in glioma patients with an age of 40 years or younger compared to the healthy controls, which could be further evaluated as a biomarker for glioma susceptibility in young patients.
A number of studies have reported on the association between XCI skewing and developmental disorders in females [21–26]. These studies usually examined XCI patterns in blood samples because tissues of the organ of interest (e.g., CNS) were either unavailable or difficult to obtain. Thus, in the current study, we compared SXCI frequencies between blood cells and the brain tissues and found that SXCI frequencies had a high concordance between blood cells and brain tissues. This finding suggests that blood is a useful surrogate brain tissue for such an analysis.
Previous studies showed that SXCI occurrence in blood cells was associated with autoimmune diseases [40–43] and linked to the development of certain female cancers . For example, in 1999, Buller et al. reported that patients with invasive ovarian cancer had an increased frequency of SXCI compared to those without ovarian tumor . In a study by Kristiansen et al., SXCI (CR ≥ 10) frequency was shown to be markedly increased in young patients (≤ 45 years old) with breast cancer (13%) compared to that of the control group (1%) . A similar phenomenon was also observed in familial breast cancer patients without a detectable BRCA-1 or BRCA-2 mutation , lung cancer  and esophageal carcinomas .
In the current study, SXCI (CR ≥ 3) frequency was determined to be as high as 23.6% in young patients (≤40 years) with gliomas, which was significantly higher than that in the corresponding control subjects (5.1%). Moreover, the average age at diagnosis in the cancer patients with SXCI was 11 years younger than that in patients without SXCI. However, SXCI was first described in 1987 during a clonality assay based on AR gene polymorphism in tissue samples . To date, the mechanism of SXCI is largely unknown and was believed to be due to selection for, or against, alleles on the active X chromosome. Such selection may depend upon gene expression of the gene or the interaction with other genes . SXCI may also occur when the size of the pool of the embryonic precursor cells undergoing X-chromosome inactivation is too small to avoid stochastic variation . Moreover, SXCI may be attributable to relatively small selective advantages, such as X-chromosome rearrangements and mutations in X-linked genes [45, 46].
In addition, our current study did address some aspects in this field of study. For example, the previous studies raised a question whether the XCI pattern in different tissues could be predicted by testing haematopoietic cells. Our current study showed a general concordance of XCI pattern between blood cells and brain tissues. Moreover, it is known that population admixture may cause type-I error (false positive) for association studies. In our study, all the samples we used were from the same hospital to avoid two or more definite selection bias which is why they did not differ in geographical distributions or genotype frequencies. The race of all participants was limited to Han Chinese who lived in Xi’an city or nearby areas; thus, substantial population admixture can be ignored in our study. In addition, it has long been recognized from a theroretical perspective that an additional explanational for SXCI ratios might include mutations in the X-inactivation process itself, which causes one chromosome to be chosen over another at the time of X inactivation in the early embryo [47, 48]. Mutations of the X-inactivation pathway genes are thought to be rare, but studies of individuals with such mutations may provide more information regarding the regulation of the X-inactivation pathway.
In this study, we observed an excellent concordance of SXCI frequency between blood cells and brain tissues. SXCI is a predisposing factor for the development of high-grade glioma in young female patients. However, further study is needed to verify whether SXCI is useful as a biomarker for prediction of glioma development in young female patients.
This work is supported in part by grants from the National Natural Science Foundation of China (No. 81272776), China Postdoctoral Science Foundation (No. 20100471628 and No. 201104634), Wu Jieping Medical Foundation (320.6750.12161), Shaanxi Province Programs of Science and Technology Development (No. 2012 K 13-01-13 and 2011 K12-47), the Innovation Project 2012 and the Talents Program 2010 of Tangdu hospital, The Fourth Military Medical University. We thank all the patients and individuals for their participation and the clinicians and hospital staff for help in collection of blood samples and data for this study. Additionally, we thank Aassociate Professor Yu Yao of the Department of Neurosurgery, Huashan hospital, Fudan University, China, for his sharing of data on primary central nervous system (CNS) tumors in Shanghai core city, China.
- Ostrom QT, Barnholtz-Sloan JS: Current state of our knowledge on brain tumor epidemiology. Curr Neurol Neurosci Rep. 2011, 11: 329-335. 10.1007/s11910-011-0189-8.View ArticlePubMedGoogle Scholar
- Kohler BA, Ward E, McCarthy BJ, Schymura MJ, Ries LA, Eheman C, Jemal A, Anderson RN, Ajani UA, Edwards BK: Annual report to the nation on the status of cancer, 1975–2007, featuring tumors of the brain and other nervous system. J Natl Cancer Inst. 2011, 103: 714-736. 10.1093/jnci/djr077.PubMed CentralView ArticlePubMedGoogle Scholar
- Reuss D, Von Deimling A: Hereditary tumor syndromes and gliomas. Recent Results Cancer Res. 2009, 171: 83-102. 10.1007/978-3-540-31206-2_5.View ArticlePubMedGoogle Scholar
- Zinn PO, Colen RR, Kasper EM, Burkhardt JK: Extent of resection and radiotherapy in GBM: A 1973 to 2007 surveillance, epidemiology and end results analysis of 21,783 patients. Int J Oncol. 2013, 42: 929-434.PubMedGoogle Scholar
- Rajaraman P, Melin BS, Wang Z, McKean-Cowdin R, Michaud DS, Wang SS, Bondy M, Houlston R, Jenkins RB, Wrensch M, Yeager M, Ahlbom A, Albanes D, Andersson U, Freeman LE, Buring JE, Butler MA, Braganza M, Carreon T, Feychting M, Fleming SJ, Gapstur SM, Gaziano JM, Giles GG, Hallmans G, Henriksson R, Hoffman-Bolton J, Inskip PD, Johansen C, Kitahara CM, et al.: Genome-wide association study of glioma and meta-analysis. Hum Genet. 2012, 131: 1877-1888. 10.1007/s00439-012-1212-0.PubMed CentralView ArticlePubMedGoogle Scholar
- Wrensch M, Jenkins RB, Chang JS, Yeh RF, Xiao Y, Decker PA, Ballman KV, Berger M, Buckner JC, Chang S, Giannini C, Halder C, Kollmeyer TM, Kosel ML, LaChance DH, McCoy L, O'Neill BP, Patoka J, Pico AR, Prados M, Quesenberry C, Rice T, Rynearson AL, Smirnov I, Tihan T, Wiemels J, Yang P, Wiencke JK: Variants in the CDKN2B and RTEL1 regions are associated with high-grade glioma susceptibility. Nat Genet. 2009, 41: 905-908. 10.1038/ng.408.PubMed CentralView ArticlePubMedGoogle Scholar
- Shete S, Hosking FJ, Robertson LB, Dobbins SE, Sanson M, Malmer B, Simon M, Marie Y, Boisselier B, Delattre JY, Hoang-Xuan K, El Hallani S, Idbaih A, Zelenika D, Andersson U, Henriksson R, Bergenheim AT, Feychting M, Lönn S, Ahlbom A, Schramm J, Linnebank M, Hemminki K, Kumar R, Hepworth SJ, Price A, Armstrong G, Liu Y, Gu X, Yu R, Lau C, Schoemaker M, Muir K, Swerdlow A, Lathrop M, Bondy M, Houlston RS: Genome-wide association study identifies five susceptibility loci for glioma. Nat Genet. 2009, 41: 899-904. 10.1038/ng.407.PubMed CentralView ArticlePubMedGoogle Scholar
- Sanson M, Hosking FJ, Shete S, Zelenika D, Dobbins SE, Ma Y, Enciso- Mora V, Idbaih A, Delattre JY, Hoang-Xuan K, Marie Y, Boisselier B, Carpentier C, Wang XW, Di Stefano AL, Labussiere M, Gousias K, Schramm J, Boland A, Lechner D, Gut I, Armstrong G, Liu Y, Yu R, Lau C, Di Bernardo MC, Robertson LB, Muir K, Hepworth S, Swerdlow A, et al.: Chromosome 7p11.2 (EGFR) variation influences glioma risk. Hum Mol Genet. 2011, 20: 2897-2904. 10.1093/hmg/ddr192.PubMed CentralView ArticlePubMedGoogle Scholar
- Liu Y, Shete S, Hosking F, Robertson L, Houlston R, Bondy M: Genetic advances in glioma: susceptibility genes and networks. Curr Opin Genet Dev. 2010, 20: 239-244. 10.1016/j.gde.2010.02.001.PubMed CentralView ArticlePubMedGoogle Scholar
- Yang TH, Kon M, Hung JH, Delisi C: Combinations of newly confirmed Glioma-Associated loci link regions on chromosomes 1 and 9 to increased disease risk. BMC Med Genomics. 2011, 4: 63-10.1186/1755-8794-4-63.PubMed CentralView ArticlePubMedGoogle Scholar
- Jin TB, Zhang JY, Li G, Li SQ, Yang B, Chen C, Cai LB: TP53 and RPA3 gene variations were associated with risk of glioma in a Chinese Han population. Cancer Biother Radiopharm. 2013, 28: 248-253. 10.1089/cbr.2012.1291.View ArticlePubMedGoogle Scholar
- Hartmann C, Mueller W, Von Deimling A: Pathology and molecular genetics of oligodendroglial tumors. J Mol Med(Berl). 2004, 82: 638-655.View ArticleGoogle Scholar
- Reifenberger G, Collins VP: Pathology and molecular genetics of astrocytic gliomas. J Mol Med (Berl). 2004, 82: 656-670. 10.1007/s00109-004-0564-x.View ArticleGoogle Scholar
- Song X, Zhou K, Zhao Y, Huai C, Zhao Y, Yu H, Chen Y, Chen G, Chen H, Fan W, Lu D, Mao Y: Fine mapping analysis of a region of 20q13.33 identified five independent susceptibility loci for glioma in a Chinese Han population. Carcinogenesis. 2012, 33: 1065-1071. 10.1093/carcin/bgs117.View ArticlePubMedGoogle Scholar
- Chen H, Chen Y, Zhao Y, Fan W, Zhou K, Liu Y, Zhou L, Mao Y, Wei Q, Xu J, Lu D: Association of sequence variants on chromosomes 20, 11, and 5 (20q13.33, 11q23.3, and 5p15.33) with glioma susceptibility in a Chinese population. Am J Epidemiol. 2011, 173: 915-922. 10.1093/aje/kwq457.View ArticlePubMedGoogle Scholar
- Lyon MF: Gene action in the X-chromosome of the mouse [Mus musculus L]. Nature. 1961, 190: 372-373. 10.1038/190372a0.View ArticlePubMedGoogle Scholar
- Carrel L, Willard HF: X inactivation profile reveals extensive variability in X-linked gene expression. Nature. 2005, 434: 400-404. 10.1038/nature03479.View ArticlePubMedGoogle Scholar
- Lyon MF: X-chromosome inactivation and developmental pattern in mammals. Biol Rev. 1971, 47: 1-35.View ArticleGoogle Scholar
- Bolduc V, Chagnon P, Provost S, Dube MP, Belisle C, Gingras M, Mollica L, Busque L: No evidence that skewing of X chromosome inactivation patterns is transmitted to offspring in humans. J Clin Invest. 2008, 118: 333-341. 10.1172/JCI33166.PubMed CentralView ArticlePubMedGoogle Scholar
- Minks J, Robinson WP, Brown CJ: A skewed view of X chromosome inactivation. J Clin Invest. 2008, 118: 20-23. 10.1172/JCI34470.PubMed CentralView ArticlePubMedGoogle Scholar
- Zheng J, Deng J, Jiang L, Yang L, You Y, Hu M, Li N, Wu H, Li W, Li H, Lu J, Zhou Y: Heterozygous Genetic Variations of FOXP3 in Xp11.23 Elevate breast cancer risk in Chinese population via skewed X-chromosome inactivation. Hum Mutat. 2013, 34: 619-628.PubMedGoogle Scholar
- Kristiansen M, Langerod A, Knudsen GP, Weber BL, Borresen-Dale AL, Ørstavik KH: High frequency of skewed X inactivation in young breast cancer patients. J Med Genet. 2002, 39: 30-33. 10.1136/jmg.39.1.30.PubMed CentralView ArticlePubMedGoogle Scholar
- Kristiansen M, Knudsen GP, Maguire P, Margolin S, Pedersen J, Lindblom A, Ørstavik KH: High incidence of skewed X chromosome inactivation in young patients with familial non-BRCA1/BRCA2 breast cancer. J Med Genet. 2005, 42: 877-880. 10.1136/jmg.2005.032433.PubMed CentralView ArticlePubMedGoogle Scholar
- Buller RE, Sood AK, Lallas T, Buekers T, Skilling JS: Association between non-random X-chromosome inactivation and BRCA1 mutation in germline DNA of patients with ovarian cancer. J Natl Cancer Inst. 1999, 91: 339-346. 10.1093/jnci/91.4.339.View ArticlePubMedGoogle Scholar
- Li G, Su Q, Liu GQ, Gong L, Zhang W, Wang SF, Zhu SJ, Zhang HL, Feng YM, Zhang YH: Skewed X-chromosome inactivation of bood cells is associated with early development of lung cancer in females. Oncol Rep. 2006, 16: 859-864.PubMedGoogle Scholar
- Li G, Jin TB, Liang HJ, Zhang W, Gong L, Su Q, Gao GD: Skewed X-chromosome inactivation in patients with esophageal carcinoma. Diagn Pathol. 2013, 8: 55-10.1186/1746-1596-8-55.PubMed CentralView ArticlePubMedGoogle Scholar
- Gigineishvili D, Shengelia N, Shalashvili G, Rohrmann S, Tsiskaridze A, Shakarishvili R: Primary brain tumour epidemiology in Georgia: first-year results of a population-based study. J Neurooncol. 2013, 112: 241-246. 10.1007/s11060-013-1054-1.View ArticlePubMedGoogle Scholar
- Scheithauer BW, Kleihues P: The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007, 114: 97-109. 10.1007/s00401-007-0243-4.PubMed CentralView ArticlePubMedGoogle Scholar
- Gong L, Li YH, Su Q, Li G, Zhang WD, Zhang W: Use of X-chromosome inactivationpattern and laser microdissection to determine the clonal origin of focal nodular hyperplasia of the liver. Pathology. 2009, 40: 348-355.View ArticleGoogle Scholar
- Gong L, Zhang WD, Li YH, Liu XY, Yao L, Han XJ, Zhu SJ, Lan M, Zhang W: Clonal Status and Clinicopathological Features of Langerhans Cell Histiocytosis. J Int Med Res. 2010, 38: 1099-1105. 10.1177/147323001003800338.View ArticlePubMedGoogle Scholar
- Allen RC, Zoghbi HY, Moseley AB: Methylation of Hpa II and Hha I sites near the polymorphic CAG repeat in the human androgen receptor gene correlates with X chromosome inactivation. Am J Hum Genet. 1992, 51: 1229-1239.PubMed CentralPubMedGoogle Scholar
- Lucas DR, Shroyer KR, McCarthy PJ, Markham NE, Fujita M, Enomoto TE: Desmoid tumor is a clonal cellular proliferation: PCR amplification of HUMARA for analysis of patterns of X-chromosome inactivation. Am J Surg Pathol. 1997, 21: 306-311. 10.1097/00000478-199703000-00006.View ArticlePubMedGoogle Scholar
- Vogelstein B, Fearon ER, Hamilton SR, Preisinger AC, Willard HF, Michelson AM, Riggs AD, Orkin S: Clonal analysis using recombinant DNA probes from the X-chromosome. Cancer Res. 1987, 47: 4806-4813.PubMedGoogle Scholar
- Gale RE, Wheadon H, Linch DC: X-chromosome inactivation patterns using HPRT and PGK polymorphisms in haematologically normal and post-chemotherapy females. Br J Haematol. 1991, 79: 193-197. 10.1111/j.1365-2141.1991.tb04521.x.View ArticlePubMedGoogle Scholar
- Lind-Landström T, Varughese RK, Sundstrøm S, Torp SH: Expression and clinical significance of the proliferation marker minichromosome maintenance protein 2 (Mcm2) in diffuse astrocytomas WHO grade II. Diagn Pathol. 2013, 8: 67-10.1186/1746-1596-8-67.PubMed CentralView ArticlePubMedGoogle Scholar
- Habberstad AH, Gulati S, Torp SH: Evaluation of the proliferation markers Ki-67/MIB-1, mitosin, survivin, pHH3, and DNA topoisomerase IIα in human anaplastic astrocytomas–an immunohistochemical study. Diagn Pathol. 2011, 6: 43-10.1186/1746-1596-6-43.PubMed CentralView ArticlePubMedGoogle Scholar
- Hemminki K, Tretli S, Sundquist J, Johannesen TB, Granstrom C: Familial risks in nervous-system tumours: a histologyspecific analysis from Sweden and Norway. Lancet Oncol. 2009, 10: 481-488. 10.1016/S1470-2045(09)70076-2.View ArticlePubMedGoogle Scholar
- Scheurer ME, Etzel CJ, Liu M, El-Zein R, Airewele GE, Malmer B, Aldape KD, Weinberg JS, Yung WK, Bondy ML: Aggregation of cancer in first- degree relatives of patients with glioma. Cancer Epidemiol Biomarkers Prev. 2007, 16: 2491-2495. 10.1158/1055-9965.EPI-07-0576.PubMed CentralView ArticlePubMedGoogle Scholar
- Farrell CJ, Plotkin SR: Genetic causes of brain tumors: neurofibromatosis, tuberous sclerosis, von Hippel-Lindau, and other syndromes. Neurol Clin. 2007, 25 (viii): 925-946.View ArticlePubMedGoogle Scholar
- Seidel MG, Rami B, Item C, Schober E, Zeitlhofer P, Huber WD, Heitger A, Bodamer OA, Haas OA: Concurrent FOXP3- and CTLA4-associated genetic predisposition and skewed X chromosome inactivation in an autoimmune disease-prone family. Eur J Endocrinol. 2012, 167: 131-134. 10.1530/EJE-12-0197.View ArticlePubMedGoogle Scholar
- Brix TH, Hegedüs L: Twin studies as a model for exploring the aetiology of autoimmune thyroid disease. Clin Endocrinol (Oxf). 2012, 76: 457-464. 10.1111/j.1365-2265.2011.04318.x.View ArticleGoogle Scholar
- Płoski R, Szymański K, Bednarczuk T: The genetic basis of graves' disease. Curr Genomics. 2011, 12: 542-563. 10.2174/138920211798120772.PubMed CentralView ArticlePubMedGoogle Scholar
- Brix TH, Hegedüs L: Twins as a tool for evaluating the influence of genetic susceptibility in thyroid autoimmunity. Ann Endocrinol (Paris). 2011, 72: 103-107. 10.1016/j.ando.2011.03.013.View ArticleGoogle Scholar
- Medema RH, Burgering BM: The X factor: skewing X inactivation towards cancer. Cell. 2007, 129: 1253-1254. 10.1016/j.cell.2007.06.008.View ArticlePubMedGoogle Scholar
- Swierczek SI, Agarwal N, Nussenzveig RH, Rothstein G, Wilson A, Artz A, Prchal JT: Hematopoiesis is not clonal in healthy elderly women. Blood. 2008, 112: 3186-3193. 10.1182/blood-2008-03-143925.PubMed CentralView ArticlePubMedGoogle Scholar
- Aruna M, Dasgupta S, Sirisha PV, Andal Bhaskar S, Tarakeswari S, Singh L, Reddy BM: Role of androgen receptor CAG repeat polymorphism and X-inactivation in the manifestation of recurrent spontaneous abortions in Indian women. PLoS One. 2011, 6 (3): e17718-10.1371/ journal. pone. 0017718.PubMed CentralView ArticlePubMedGoogle Scholar
- Hafner C, Toll A, Fernández-Casado A, Earl J, Marqués M, Acquadro F, Méndez-Pertuz M, Urioste M, Malats N, Burns JE, Knowles MA, Cigudosa JC, Hartmann A, Vogt T, Landthaler M, Pujol RM, Real FX: Multiple oncogenic mutations and clonal relationship in spatially distinct benign human epidermal tumors. Proc Natl Acad Sci USA. 2010, 107: 20780-20785. 10.1073/pnas.1008365107.PubMed CentralView ArticlePubMedGoogle Scholar
- Gontan C, Achame EM, Demmers J, Barakat TS, Rentmeester E, van IJcken W, Grootegoed JA, Gribnau J: RNF12 initiates X-chromosome inactivation by targeting REX1 for degradation. Nature. 2012, 485: 386-390. 10.1038/nature11070.View ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.