Relaxin receptors 1 and 2 and nuclear receptor subfamily 3, group C, member 1 (glucocorticoid receptor) mRNAs are expressed in oral components of developing mice.

OBJECTIVE: Relaxin is a pleiotropic hormone of the insulin-like peptide hormone family that plays an important role in reproductive physiology as well as in fibrosis, angiogenesis, and bone remodelling. It binds to the relaxin family peptide receptors 1 and 2 (Rxfp1 and Rxfp2) and can, in addition and independently, bind and activate the glucocorticoid receptor Nr3c1. Despite the wide-ranging effect of relaxin, the expression patterns of Rxfp1 and 2 during facial development have not been examined. In this study, we aimed to identify the mRNA expression patterns of Rxfp1, Rxfp2, and Nr3c1 in oral tissues during late mouse facial development in order to pinpoint the structures that could be sensitive to relaxin signalling during this period. DESIGN: Rxfp1, Rxfp2, and Nr3c1 mRNAs were identified by in situ hybridization using digoxigenin-labelled riboprobes on coronal sections of mouse heads from embryonic days 13.5 to 18.5. RESULTS: We found that Rxfp1, Rxfp2, and Nr3c1 mRNAs were expressed on the developing maxilla and mandible, Meckel's cartilage, tongue, and tooth primordia between embryonic days 13.5-18.5. CONCLUSIONS: Receptors that bind relaxin were present in developing oral tissues of mice. This finding suggests that relaxin may be involved in the prenatal development of the face.

Double partial trisomy of 6p23-pter and 9pter-q21.2 in a neonate resulting from 4:2 meiotic segregation of a maternal complex t(6;7;9)(p23;p15;q21.2) translocation.

We report, a newborn presenting multiple congenital abnormalities with karyotype; 47,XY,der(7)t(6;7)(pter-p23::p15-->qter),+der(9)t(7;9)(pter-->p15::q21.2--> pter)t(6;7;9)(p23;p15;q21.2)mat[20]. The mother and her phenotypically normal daughter were carriers of a complex chromosomal rearrangement with karyotypes; 46,XX,t(6;7;9)(p23;p15;q21.2)[20]. Paternal chromosomes were normal. In our case the extra derivative chromosome was the result of a 4:2 segregation of the chromosomes involved in translocation during oogenesis. Double partial trisomy in newborns resulting from 4:2 segregation is a rare event, and double partial trisomies of the 6p23-pter and trisomy 9pter-q22 regions have not reported to date.

HPV type-related chromosomal profiles in high-grade cervical intraepithelial neoplasia.

BACKGROUND: The development of cervical cancer and its high-grade precursor lesions (Cervical Intraepithelial Neoplasia grade 2/3 [CIN2/3]) result from a persistent infection with high-risk human papillomavirus (hrHPV) types and the accumulation of (epi)genetic host cell aberrations. Epidemiological studies have demonstrated variable CIN2/3 and cancer risks between different hrHPV types. Recent genomic profiling studies revealed substantial heterogeneity in the chromosomal aberrations detected in morphologically indistinguishable CIN2/3 suggestive of varying cancer risk. The current study aimed to investigate whether CIN2/3 with different hrHPV types vary with respect to their chromosomal profiles, both in terms of the number of aberrations and chromosomal loci affected. METHODS: Chromosomal profiles were determined of 43 p16INK4a-immunopositive CIN2/3 of women with long-term hrHPV infection (≥ 5 years). Sixteen lesions harboured HPV16, 3 HPV18, 14 HPV31, 1 HPV33, 4 HPV45, 1 HPV51, 2 HPV52 and 2 HPV58. RESULTS: Unsupervised hierarchical clustering analysis of the chromosomal profiles revealed two major clusters, characterised by either few or multiple chromosomal aberrations, respectively. A majority of 87.5% of lesions with HPV16 were in the cluster with relatively few aberrations, whereas no such unbalanced distribution was seen for lesions harbouring other hrHPV types. Analysis of the two most prevalent types (HPV16 and HPV31) in this data set revealed a three-fold increase in the number of losses in lesions with HPV31 compared to HPV16-positive lesions. In particular, losses at chromosomes 2q, 4p, 4q, 6p, 6q, 8q & 17p and gain at 1p & 1q were significantly more frequent in HPV31-positive lesions (FDR < 0.2). CONCLUSIONS: Chromosomal aberrations in CIN2/3 are at least in part related to the hrHPV type present. The relatively low number of chromosomal aberrations observed in HPV16-positive CIN2/3 suggests that the development of these lesions is less dependent on genetic insult than those caused by other types like HPV31.

The prognostic value of Ki-67, p53, epidermal growth factor receptor, 1p36, 9p21, 10q23, and 17p13 in skull base chordomas.

CONTEXT: Skull base chordomas are rare, locally aggressive, notochord-derived neoplasms for which prognostically relevant biomarkers are not well established. OBJECTIVE: To evaluate whether newly discovered molecular alterations in chordomas have prognostic significance similar to what has been described regarding Ki-67 proliferation index. DESIGN: We conducted a retrospective study of 28 cases of primary clival chordomas. RESULTS: Ki-67 proliferation index 5% or more, p53 accumulation, and epidermal growth factor receptor expression were seen in 32%, 44%, and 8% of chordomas, respectively. 1p loss of heterozygosity (LOH) and/or 1p36 hemizygous deletion was seen in 30% of tumors, while 9p LOH and/or 9p21 homozygous deletion was seen in 21% of cases. Loss of heterozygosity at 10q23 and 17p13 were identified in 57% and 52% of cases, respectively. Ki-67 proliferation index 5% or more and 9p LOH were significantly associated with a shorter overall survival, while homozygous deletion at 9p21 via fluorescence in situ hybridization approached significance. No correlation with survival was found for p53 or epidermal growth factor receptor expression, 1p36 hemizygous deletion, or LOH at 1p, 10q23, or 17p13. CONCLUSIONS: Chordomas with elevated Ki-67 proliferation index or deletion at 9p21 may be at risk for a more aggressive clinical course and shorter survival. These biomarkers may thus be used to improve therapeutic stratification.

Association of three genetic loci with uric acid concentration and risk of gout: a genome-wide association study.

BACKGROUND: Hyperuricaemia, a highly heritable trait, is a key risk factor for gout. We aimed to identify novel genes associated with serum uric acid concentration and gout. METHODS: Genome-wide association studies were done for serum uric acid in 7699 participants in the Framingham cohort and in 4148 participants in the Rotterdam cohort. Genome-wide significant single nucleotide polymorphisms (SNPs) were replicated in white (n=11 024) and black (n=3843) individuals who took part in the study of Atherosclerosis Risk in Communities (ARIC). The SNPs that reached genome-wide significant association with uric acid in either the Framingham cohort (p<5.0 x 10(-8)) or the Rotterdam cohort (p<1.0 x 10(-7)) were evaluated with gout. The results obtained in white participants were combined using meta-analysis. FINDINGS: Three loci in the Framingham cohort and two in the Rotterdam cohort showed genome-wide association with uric acid. Top SNPs in each locus were: missense rs16890979 in SLC2A9 (p=7.0 x 10(-168) and 2.9 x 10(-18) for white and black participants, respectively); missense rs2231142 in ABCG2 (p=2.5 x 10(-60) and 9.8 x 10(-4)), and rs1165205 in SLC17A3 (p=3.3 x 10(-26) and 0.33). All SNPs were direction-consistent with gout in white participants: rs16890979 (OR 0.59 per T allele, 95% CI 0.52-0.68, p=7.0 x 10(-14)), rs2231142 (1.74, 1.51-1.99, p=3.3 x 10(-15)), and rs1165205 (0.85, 0.77-0.94, p=0.002). In black participants of the ARIC study, rs2231142 was direction-consistent with gout (1.71, 1.06-2.77, p=0.028). An additive genetic risk score of high-risk alleles at the three loci showed graded associations with uric acid (272-351 mumol/L in the Framingham cohort, 269-386 mumol/L in the Rotterdam cohort, and 303-426 mumol/L in white participants of the ARIC study) and gout (frequency 2-13% in the Framingham cohort, 2-8% in the Rotterdam cohort, and 1-18% in white participants in the ARIC study). INTERPRETATION: We identified three genetic loci associated with uric acid concentration and gout. A score based on genes with a putative role in renal urate handling showed a substantial risk for gout.

Malignant glioma: the involvement of loss of allelic heterozygosity and PTEN mutations in a group of Malay patients.

Frequent loss of heterozygosity (LOH) and mutations of the tumor suppressor gene PTEN (phosphatase and tensin homologue deleted from chromosome 10) have been found in sporadic gliomas. The most documented regions of allelic losses include 9p21, 10q23-25 and 17p1 3 whereas PTEN aberrations are preferentially found in glioblastoma multiformes. This research aimed to detect the incidence of allelic losses on chromosomes 10q, 9p, 17p and 13q and mutations on exons 5, 6 and 8 of PTEN in malignant gliomas. Malignant glioma specimens obtained were classified histopathologically according to the WHO criteria. Each tumor was then subjected to polymerase chain reaction (PCR)-LOH analysis using microsatellite markers and single-stranded conformational polymorphism (SSCP) analysis. Twelve of 23 (52%) malignant glioma cases showed allelic losses whereas 7 of 23 (30%) samples showed aberrant band patterns and mutations of PTEN. Four of these cases showed LOH in 10q23 and mutations of PTEN. The data on LOH indicated the involvement of different genes in the genesis of glioma whereas mutations of PTEN indicated the role of PTEN tumor suppressor gene in the progression of glioma in Malay population.

Renal metanephric adenoma with previously unreported cytogenetic abnormalities: case report and review of the literature.

We report a case of a renal metanephric adenoma in a 10-year-old boy, in which cytogenetic analysis showed a balanced translocation, t(9;15)(p24;q24) and a balanced paracentric inversion of chromosome 12, inv(12)(q13q15). Immunohistochemically, the tumor showed diffuse reactivity for cytokeratin AE1/AE3, CAM5.2, CD57, and WT1; patchy reactivity for CD56; and focal reactivity for cytokeratin 7, epithelial membrane antigen, and CD10. Tumor cells were entirely nonreactive for alpha-methyl acyl coenzyme A racemase. Published cytogenetic data for metanephric adenomas are limited, and this is the first report of these cytogenetic abnormalities. The involvement of the chromosome region 9p24 is particularly interesting because of the recent identification of a tumor suppressor gene, KANK (kidney ankyrin repeat-containing protein), at this locus.

OWEN: aligning long collinear regions of genomes.

OWEN is an interactive tool for aligning two long DNA sequences that represents similarity between them by a chain of collinear local similarities. OWEN employs several methods for constructing and editing local similarities and for resolving conflicts between them. Alignments of sequences of lengths over 10(6) can often be produced in minutes. OWEN requires memory below 20 L, where L is the sum of lengths of the compared sequences.

Fluorescence in situ hybridization to assess transitional changes of aneuploidy for chromosomes 7, 8, 10, 12, 16, X and Y in metastatic prostate cancer following anti-androgen therapy.

There have been few detailed studies conducted on the cell population in relation to cytogenetic changes between the pre- and post-treatment periods in patients with prostate cancer. We investigated numerical chromosome changes associated with anti-androgen therapy, using fluorescence in situ hybridization (FISH). FISH using chromosome-specific centromeric probes was used to assess transitional changes in the frequency of aneuploidy for chromosomes 7, 8, 10, 12, 16, X, and Y in prostate cancer during the pre- and post-treatment periods. Gains of chromosomes 7, 8 and 12 were notable in the pre-treatment samples (8 out of 9 cases in chromosome 7; 8 out of 9 cases in chromosome 8; 7 out of 9 cases in chromosome 12), while a notable reduction in the number of cells with extra copies of these chromosomes was observed in post-treatment specimens. Other chromosomes did not show noticeable change in their FISH signals at each phase of clinical treatment in all 9 cases. Changes in cell number with high ploidies of chromosome 7, 8 and 12 reflect the clinical effects of anti-androgen therapy at the early phase, which might explain the androgen dependency of metastatic prostate cancer cells.

Translocation (3;12) (p21-pter; q24.1-qter) and phenylketonuria.

Cytogenetic karyotyping in mental retardation associated with physical dysmorphism has been regarded as the primary key for the classification of syndromes and other genetic disorders for the predisposition of neoplasia and other fatal diseases. Giemsa-banding of metaphase chromosomes in lymphocytes is a traditional and routine process for the identification of the chromosomal counterpart which can provide a clue for molecular investigation in the subject. An 8-year-old girl showed a diploid karyotype 46, XX, t(3;12) (p21-pter, q24.1-qter) in peripheral blood lymphocyte culture. Biochemical examination of urine labelled her as a case of phenylketonuria. The maternal karyotyping was similar and confirmed the maternal transmission of the translocation.

[Genetic aspects of the etiology of arrhythmia]. / Genetische Aspekte der Arrhythmieentstehung.

Cardiac arrhythmias are common causes of morbidity and mortality in clinical medicine. Much has been learned about cellular mechanisms of arrhythmogenesis in the past but genetic components have only recently been recognized for some heritable forms of arrhythmias. The long QT syndrome and the Brugada syndrome are both caused by molecular defects in ion channel proteins. Cardiac arrhythmias can also be associated with structural heart diseases. For example, sinus node dysfunction or AV-block can precede some forms of inherited dilated cardiomyopathy. A distinct genetic form of hypertrophic cardiomyopathy is associated with the Wolff-Parkinson-White syndrome and maps to chromosome 7q35. Arrhythmogenic right ventricular cardiomyopathy has a strong genetic basis and often manifests with ventricular tachycardia. Atrial fibrillation can also occur as familial disease and may be allelic with dilated cardiomyopathy as both diseases can be closely linked to chromosome 10q2.

[Proliferative activity and chromosomal alterations of smooth muscle cells in atherosclerosis]. / Actividad proliferativa y alteraciones cromosómicas de las células musculares lisas en la ateroesclerosis.

Atherosclerosis is the most frequent cause of death in industrialized countries. Lesions are characterized by lipid deposits, focal thickening of the arterial wall with proliferation of smooth muscle cells (SMC), mononuclear infiltrates and neoformed vessels. In this paper, we studied the proliferative characteristics and cytogenetic alterations of SMC. These cells, expressing specific muscular actin, were diploid with an increased proliferative index for PCNA. A high percentage of SMC showed intense expression of p53. There were signs of chromosomal instability, being the most frequent findings chromosome 7 trisomy and chromosome 11 monosomy. Additionally, the gene for FGF-3 showed a marked amplification. These findings strongly suggest that SMC proliferation is active, and is related to the accumulation or mutation of the p53 oncoprotein. It also presents specific chromosomal alterations in close relation with growth factors. According to these findings SMC hyperplasia in the atherosclerosis plaque may be considered as a cellular clonal expansion.

Dysregulation of HMGIC in a uterine lipoleiomyoma with a complex rearrangement including chromosomes 7, 12, and 14.

Uterine lipoleiomyomas are extremely rare tumors consisting of a mixture of mature adipocytes and smooth muscle cells. Using G-banding and FISH, we characterized a complex rearrangement involving chromosomes 7, 8, 10, 11, 12, and 14 in one of these tumors. The region 14q23-24 was inserted into the long arm of the derivative chromosome 12, between the 3' end of HMGIC and 7q21-22, another region often rearranged in uterine leiomyomas. Other portions of chromosomes 12 and 14 were involved in derivative chromosomes 7, 11, 12, and 14. A chromosome 8 was involved in a three-way rearrangement including the derivative 7, a ring chromosome 10, and a small derivative chromosome 8 bearing segments of chromosomes 10 and 11. No abnormality of chromosome 5 was detected, in contrast to two previously reported cytogenetic analyses of uterine lipoleiomyoma. The consistent finding of chromosomes 12 and 14 on different derivatives indicates that the t(12;14) was a primary event. In addition, immunohistochemical studies showed that HMGI-C was aberrantly expressed in this tumor. These observations suggest that uterine lipoleiomyomas have a pathogenetic origin similar to that of typical leiomyomas. Genes Chromosomes Cancer 27:209-215, 2000.

Actividad proliferativa y alteraciones cromosomicas de las ceculas musculares lisas en la ateroesclerosis / Proliferative activity and chromosomal alterations of smooth muscle cells in atherosclerosis

La causa de muerte más frecuente en los países desarrollados es la ateroesclerosis. Sus lesiones características, además del depósito lipídico, son el engrosamiento focal de la pared arterial con proliferación de células musculares lisas (CML) e infiltración mononuclear y presencia de vasos neoformados. En este trabajo estudiamos el fenómeno proliferativo y las alteraciones citogenéticas de las CML. Estas células, identificadas mediante inmunohistoquímica por su expresión de actina muscular específica, eran dipolides, con un alto índice de proliferación demostrado por expresión de la proteína nuclear PCNA. Un porcentaje elevado de CML expresó intensamente a la oconproteína p53. Además se encontraron claros indicios de inestabilidad cromosómica. Los hallazgos más frecuentes fueron trisomía del cromosoma 11. También se observó ampliación del gen FGF-3. Estos hallazgos permiten inferir que la proliferación de CML es activa, tiene relación con la acumulación o mutación de la oncoproteína p53 y además presenta alteraciones cromosómicas específicas y relacionadas con los factores de crecimiento. La presencia de este tipo de cambios nos lleva a considerar a la hiperplasia de las CML en la placa ateromatosa como una expresión celular de carácter clonal. (AU)

Actividad proliferativa y alteraciones cromosomicas de las ceculas musculares lisas en la ateroesclerosis / Proliferative activity and chromosomal alterations of smooth muscle cells in atherosclerosis

La causa de muerte más frecuente en los países desarrollados es la ateroesclerosis. Sus lesiones características, además del depósito lipídico, son el engrosamiento focal de la pared arterial con proliferación de células musculares lisas (CML) e infiltración mononuclear y presencia de vasos neoformados. En este trabajo estudiamos el fenómeno proliferativo y las alteraciones citogenéticas de las CML. Estas células, identificadas mediante inmunohistoquímica por su expresión de actina muscular específica, eran dipolides, con un alto índice de proliferación demostrado por expresión de la proteína nuclear PCNA. Un porcentaje elevado de CML expresó intensamente a la oconproteína p53. Además se encontraron claros indicios de inestabilidad cromosómica. Los hallazgos más frecuentes fueron trisomía del cromosoma 11. También se observó ampliación del gen FGF-3. Estos hallazgos permiten inferir que la proliferación de CML es activa, tiene relación con la acumulación o mutación de la oncoproteína p53 y además presenta alteraciones cromosómicas específicas y relacionadas con los factores de crecimiento. La presencia de este tipo de cambios nos lleva a considerar a la hiperplasia de las CML en la placa ateromatosa como una expresión celular de carácter clonal.

Assessment of genomic imbalances in malignant fibrous histiocytomas by comparative genomic hybridization.

In order to investigate genomic imbalances, comparative genomic hybridization was applied to 20 malignant fibrous histiocytomas. Deletions were rare and found mainly in chromosomes 2q33-35, 4q32-qter, 8p, 9p21-pter, 12p and 19p, whereas, over-representations frequently affected chromosomes 3, 4q31, 5p, 6, 7, 14q22-ter, 18p, as well as, five distinct amplifications within the regions 12q12-15 and 15q24-qter. The total number of genetic imbalances per tumor was slightly increased in primary tumors when compared to relapses. No relationship was found between the patterns of gain and loss when compared to the histological subtype, tumor grading, the clinical outcome and the p53 mutation status.

Systematic search for uniparental disomy in early fetal losses: the results and a review of the literature.

About 20% of all human conceptuses are estimated to be trisomic and trisomy of all chromosomes remains a common cause of early fetal loss. Uniparental disomy (UPD) has been reported for most human chromosomes and may be an underrecognized contributor to embryonic lethality. To investigate the contribution of UPD to spontaneous abortions, we devised a genome-based screening strategy to identify holochromosomic UPD in 18 fetal losses. No cases of UPD were identified using this approach. Based on our data, UPD does not appear to be a significant contributor to early embryonic lethality. The results of the study are presented along with a review of the cases of UPD reported in the literature by chromosome, parental origin, mode of ascertainment, and phenotypic consequences due to imprinting.

Allelotyping demonstrates common and distinct patterns of chromosomal loss in human lung cancer types.

Allelic loss is a hallmark of tumor suppressor gene (TSG) inactivation. We have allelotyped 29 paired lymphoblastoid and lung cancer cell lines derived from 11 patients with small cell (SCLC) and 18 patients with non-small cell lung carcinomas (NSCLC). Statistical analysis indicated that a threshold of 30% separated non-random allelic loss from the random genetic deletions of malignancy. We have identified non-random allelic loss at 42 of 54 (78%) specific chromosomal regions examined, with 22 regions (52%) common between the two major lung cancer histologic types. There were 3 regions (7%) with allelic loss specific for SCLC and 17 regions (41%) specific for NSCLC. Furthermore, there were significant differences in loss of heterozygosity (LOH) frequencies between NSCLC and SCLC at 13 regions on eight chromosome arms (3p, 5q, 6q, 9p, 10q, 11p, 13q, and 19p). Eight homozygous deletions were present in seven cell lines at four regions, 3p12, 3p14.2, 9p21, and 10q23-25. We have also identified novel sites of chromosomal deletions. In particular, there was frequent loss at 11p13 in SCLC and loss at 6p21.3 and 13q12.3 in NSCLC. In this study, we demonstrate that a) non-random allelic losses in lung cancer involve multiple regions; b) some losses are common to both NSCLC and SCLC subtypes, whereas others are subtype specific; c) there are genetic deletions at novel chromosomal regions; and d) several homozygous deletions have been noted. Our studies demonstrate the usefulness of continuous cell lines for detailed allelotyping, for comparing genetic abnormalities between SCLC and NSCLC, and for identifying homozygous deletions.