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Irina Golovleva

Publications and source records attributed to Irina Golovleva.

12 recordsLinked to original sources
PubMed2006

Characterisation of dic(9;20)(p11-13;q11) in childhood B-cell precursor acute lymphoblastic leukaemia by tiling resolution array-based comparative genomic hybridisation reveals clustered breakpoints at 9p13.2 and 20q11.2.

Although the dic(9;20)(p11-13;q11) is a recurrent chromosomal abnormality in paediatric B-cell precursor acute lymphoblastic leukaemia (BCP ALL), occurring in approximately 2% of the cases, its molecular genetic consequences have not been elucidated. In the present study, high-resolution genome-wide array-based comparative genomic hybridisation (array-CGH) and fluorescence in situ hybridisation (FISH) were used to characterise the 9p and 20q breakpoints (BPs) in seven childhood BCP ALLs with dic(9;20), which was shown to be unbalanced in all of them, resulting in loss of 9p13.2-pter. Five of the cases had loss of 20q11.2-qter, whereas two displayed gain of 20cen-pter. All BPs on 9p clustered in a 1.5 Mb segment of the sub-band 9p13.2; in three of the cases, the 20q BPs mapped to three adjacent clones covering a distance of 350 kb at 20q11.2. Thus, the aberration should be designated dic(9;20)(p13.2;q11.2). One of the ALLs, shown to have a complex dic(9;20), was further investigated by FISH, revealing a rearrangement of the haemapoietic cell kinase isoform p61 (HCK) gene at 20q11. The disruption of HCK may result in a fusion gene or in loss of function. Unfortunately, lack of material precluded further analyses of HCK. Thus, it remains to be elucidated whether dic(9;20)(p13.2;q11.2) leads to a chimaeric gene or whether the functionally important outcome is loss of 9p and 20q material.

Adolescent↗
PubMed2005

hTERT gene copy number is not associated with hTERT RNA expression or telomerase activity in colorectal cancer.

In a majority of malignant human tumors telomerase activity can be detected, suggesting an immortal phenotype. Expression of the reverse transcriptase subunit, hTERT, in the human telomerase complex is required for telomerase activity. The regulation of hTERT, from gene level to a fully functional protein, is still a poorly understood process. Increased copy number of the hTERT gene has been demonstrated in a significant portion of established cell lines and tumors of different origin but its relevance for telomerase activity levels is unclear. In the present study, we examined the hTERT gene copy number using fluorescence in situ hybridization (FISH) in samples from 64 colorectal carcinomas and an increased copy number (> or = 3 hTERT gene copies/nucleus) was observed in 31 cases (48%). No statistical association existed between hTERT gene copy number and hTERT RNA expression or telomerase activity. However, a significant relationship was found between an increase in hTERT gene copy number and p53 protein accumulation (p = 0.002) and aneuploidy (p = 0.036). Only 4 tumors showed microsatellite instability, 3 of which had a normal hTERT gene copy number. The data indicated that the increased copy number of the hTERT gene in colorectal carcinoma was a result of genomic instability with no obvious consequence for telomerase activity levels.

Aneuploidy↗
PubMed2005

Increased copy number at 3p14 in breast cancer.

INTRODUCTION: The present study was conducted to investigate if chromosome band 3p14 is of any pathogenic significance in the malignant process of breast cancer. Genetic studies have implicated a tumour suppressor gene on chromosome arm 3p and we have proposed LRIG1 at 3p14 as a candidate tumour suppressor. The LRIG1 gene encodes an integral membrane protein that counteracts signalling by receptor tyrosine kinases belonging to the ERBB family. LRIG1 mRNA and protein are expressed in many tissues, including breast tissue. METHODS: In the present report we analysed the LRIG1 gene by fluorescence in situ hybridisation (FISH), LRIG1 mRNA by quantitative RT-PCR, and LRIG1 protein by western blot analysis. Two tumour series were analysed; one series consisted of 19 tumour samples collected between 1987 and 1995 and the other series consisted of 9 tumour samples with corresponding non-neoplastic breast tissues collected consecutively. RESULTS: The LRIG1 gene showed increased copy number in 11 out of 28 tumours (39%) and only one tumour showed a deletion at this locus. Increased LRIG1 copy number was associated with increased levels of LRIG1 mRNA (two of three tumours) and protein (four of four tumours) in the tumours compared to matched non-neoplastic breast tissue, as assessed by RT-PCR and western blot analysis. CONCLUSION: The molecular function of LRIG1 as a negative regulator of ERBB receptors questions the biological significance of increased LRIG1 copy number in breast cancer. We propose that a common, but hitherto unrecognised, breast cancer linked gene is located within an amplicon containing the LRIG1 locus at 3p14.3.

Breast Neoplasms↗
PubMed2004

Characterization and tissue-specific expression of human LRIG2.

We have recently identified and cloned the human LRIG1 gene (formerly LIG1). LRIG1 is a predicted integral membrane protein with a domain organization reminiscent of the Drosophila epidermal growth factor (EGF)-receptor antagonist Kekkon-1. We have searched for additional members of the human LRIG family and identified LRIG2 (). The LRIG2 gene was localized to chromosome 1p13 and had an open reading frame of 1065 amino acids. The LRIG2 protein was predicted to have the same domain organization as LRIG1 with a signal peptide, an extracellular part containing15 leucine-rich repeats and three immunoglobulin-like domains, a transmembrane domain, and a cytoplasmic tail. The LRIG2 amino acid sequence was 47% identical to human LRIG1 and mouse Lrig1 (also known as Lig-1). Northern blotting and RT-PCR revealed LRIG2 transcripts in all tissues analyzed. Quantitative real-time RT-PCR showed the most prominent RNA expression in skin, uterus, ovary, kidney, brain, small intestine, adrenal gland, and stomach. Immunoblotting of COS-7 cell lysates demonstrated that heterologously expressed human LRIG2 had an apparent molecular weight of 132 kDa under reducing gel-running conditions. N-glycosidase F treatment resulted in a reduction of the apparent molecular weight to 107 kDa, showing that LRIG2 was a glycoprotein carrying N-linked oligosaccharides. Cell surface biotinylation experiments and confocal fluorescence laser microscopy demonstrated expression of LRIG2 both at the cell surface and in the cytoplasm. LRIG2 was detected in tissue lysates from stomach, prostate, lung, and fetal brain by immunoblotting. In conclusion, LRIG2 was found to be a glycoprotein which was encoded by a gene on human chromosome 1p13 and its mRNA was present in all tissues analyzed.

Amino Acid Sequence↗
PubMed2004

Mutation analysis of the MLH1, MSH2 and MSH6 genes in patients with double primary cancers of the colorectum and the endometrium: a population-based study in northern Sweden.

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant disorder that predisposes to predominantly colorectal and endometrial cancers due to germline mutations in DNA mismatch repair genes, mainly MLH1, MSH2 and in families with excess endometrial cancer also MSH6. In this population-based study, we analysed the mutation spectrum of the MLH1, MSH2 and MSH6 genes in a cohort of patients with microsatellite unstable double primary tumours of the colorectum and the endometrium by PCR, DHPLC and sequencing. Fourteen of the 23 patients (61%) had sequence variants in MLH1, MSH2 or MSH6 that likely affect the protein function. A majority (10/14) of the mutations was found among probands diagnosed before age 50. Five of the mutations (36%) were located in MLH1, 3 (21%) in MSH2 and 6 (43%) in MSH6. MSH6 seem to have larger impact in our population than in other populations, due to a founder effect since all of the MSH6 families originate from the same geographical area. MSH6 mutation carriers have later age of onset of both colorectal cancer (62 vs. 51 years) and endometrial cancer (58 vs. 48 years) and a larger proportion of endometrial cancer than MLH1 or MSH2 mutation carriers. We can conclude that patients with microsatellite unstable double primary cancers of the colorectum and the endometrium have a very high risk of carrying a mutation not only in MLH1 or MSH2 but also in MSH6, especially if they get their first cancer diagnosis before the age of 50.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Spontaneously immortalized human T lymphocytes develop gain of chromosomal region 2p13-24 as an early and common genetic event.

To gain further insight into the molecular events responsible for the extended life span and immortalization of human lymphoid cells, we analyzed a series of spontaneously immortalized, IL2-dependent human T-cell lines using molecular cytogenetic techniques. Two of the cell lines were derived from normal spleen and three from patients with Nijmegen breakage syndrome (NBS), a recessive disorder characterized by a high incidence of lymphoid malignancies. Here we show that spontaneous immortalization of the five T-cell lines was associated with the acquisition of copy number gains involving chromosomal region 2p13-24 as common early alterations. In addition, we found an amplification of 8q21-24 after prolonged propagations in all three NBS-derived cell lines as well as early development of near-tetraploidy in two of these lines. Gains involving the short arm of chromosome 2 recently were found in several lymphoid malignancies. Therefore, the cell lines described here can be used for identification and characterization of genes involved in the pathogenesis of lymphoid neoplasms and would also provide a useful tool for better understanding the mechanisms responsible for cell immortalization.

Cell Line, Transformed↗
PubMed2003

Disease-causing mutations in the cellular retinaldehyde binding protein tighten and abolish ligand interactions.

Mutations in the human cellular retinaldehyde binding protein (CRALBP) gene cause retinal pathology. To understand the molecular basis of impaired CRALBP function, we have characterized human recombinant CRALBP containing the disease causing mutations R233W or M225K. Protein structures were verified by amino acid analysis and mass spectrometry, retinoid binding properties were evaluated by UV-visible and fluorescence spectroscopy and substrate carrier functions were assayed for recombinant 11-cis-retinol dehydrogenase (rRDH5). The M225K mutant was less soluble than the R233W mutant and lacked retinoid binding capability and substrate carrier function. In contrast, the R233W mutant exhibited solubility comparable to wild type rCRALBP and bound stoichiometric amounts of 11-cis- and 9-cis-retinal with at least 2-fold higher affinity than wild type rCRALBP. Holo-R233W significantly decreased the apparent affinity of rRDH5 for 11-cis-retinoid relative to wild type rCRALBP. Analyses by heteronuclear single quantum correlation NMR demonstrated that the R233W protein exhibits a different conformation than wild type rCRALBP, including a different retinoid-binding pocket conformation. The R233W mutant also undergoes less extensive structural changes upon photoisomerization of bound ligand, suggesting a more constrained structure than that of the wild type protein. Overall, the results show that the M225K mutation abolishes and the R233W mutation tightens retinoid binding and both impair CRALBP function in the visual cycle as an 11-cis-retinol acceptor and as a substrate carrier.

Alcohol Oxidoreductases↗
PubMed2003

Retinal function in Bothnia dystrophy. An electrophysiological study.

Using prolonged dark adaptometry, standard dark adaptation (DA) and prolonged DA full-field electroretinograms (ERGs), we analysed the retinal function in patients with Bothnia dystrophy (BD), a variant of recessive retinitis punctata albescens (RPA). A compromised rod and cone function, a likely dysfunction of the Müller cells, and indications of disturbed neuronal function of the inner retina, were found. With prolonged DA, a gradual increase in retinal sensitivity to light and an improvement of the ERG components occurred. The findings indicate a prolonged synthesis of photopigments, retardation of the visual process in the retinal pigment epithelium (RPE), and a loss of retinal cells, probably starting at a relatively early age in BD.

Adolescent↗
PubMed2003

Emergence of Philadelphia positive chronic myeloid leukaemia during treatment with hydroxyurea for Philadelphia negative essential thrombocythaemia.

A 58-yr-old male patient with essential thrombocythaemia (ET) developed chronic myeloid leukaemia (CML) after continuous uneventful treatment with hydroxyurea for 18 yr. G-banding analyses of bone marrow cells had repeatedly demonstrated normal male karyotype before this event, but t(9;22)(q34;q11) was demonstrated after the event. An unrelated allogeneic stem cell transplantation was performed. Blood and bone marrow morphology, and the karyotype were normalised and the patient is in good health 1 yr post-transplant. There are no previous reports in the literature about the emergence of CML during treatment with hydroxyurea.

Antineoplastic Agents↗
PubMed2002

Improved outcome in adult acute myeloid leukemia is almost entirely restricted to young patients and associated with stem cell transplantation.

Prognostic factors were studied in a series of 318 patients with acute myeloid leukemia (AML), 17-90 yr old, treated at a single centre during 1982-98, and representing 79% of the total number of cases registered in the area during this period. Risk group stratification based on cytogenetics, occurrence of antecedent hematological disorder, and leukocyte count could be performed in 93%. Five percent were allocated to the favourable risk group, 40% to standard risk, and 55% to adverse risk. Complete remission (CR) was attained in 52%. The CR rate was higher in the favourable (80%) and standard risk groups (69%) than in the adverse risk group (37%). The CR rate increased from 44% in the 1980s to 60% in the 1990s. The 5-yr survival rate for all patients was only 12%. Low age, promyelocytic leukaemia, treatment in the 1990s, high induction treatment intensity, and non-adverse risk group were favourably associated with survival. The median survival time increased from 115 to 349 d between the 1980s and the 1990s, but the 5-yr survival rate was only 11% for patients over 55 yr of age even in the last decade. For the younger patients, the 5-yr overall survival rate increased from 9% to 35% in the last decade. The median time in first remission was 365 d. Age below 56 yr, allogeneic and autologous transplants, and non-adverse risk group were associated with prolonged response duration. The duration of response among all patients increased from 250 d in the 1980s to 451 d in the 1990s, but event-free survival time did not improve significantly in patients above 55 yr of age. Among patients below 56 yr of age, overall survival and event-free survival were significantly better for those who received allogeneic or autologous transplants in first remission than for those who were treated with chemotherapy only. Overall survival times did not improve from the 1980s to the 1990s among those patients below 56 yr who were treated with chemotherapy only in first remission, in spite of the use of transplants in second remission.

Acute Disease↗