D R Lohmann

University Hospital Essen, Essen, North Rhine-Westphalia, Germany

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Publications (62)255.92 Total impact

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    ABSTRACT: Retinoblastoma is the most common intraocular childhood tumour. Although mortality is low in Western countries, long-term sequelae, including secondary tumours, compromised vision or loss of one or both eyes are common. Chemoreduction combined with focal treatment is currently the leading conservative treatment for retinoblastoma, with success rates of 50-75% reported. We assessed a new chemoreduction protocol using intravenous cyclophosphamide with reduced dose of carboplatin on eye retention in patients with retinoblastoma. The 40 patients with retinoblastomas in 56 eyes were treated between 1995 and 2004 at the German Retinoblastoma Reference Centre Essen. The 6-cycle chemotherapy used vincristine (days 1, 22, 43, 64, 85, 106), etoposide (days 22, 43, 85, 106), carboplatin (days 1, 43, 64, 106), and cyclophosphamide (days 1, 22, 64, 85). Mean follow-up was 101 months. Most patients received additional hyperthermia, some received local treatment with laser coagulation, cryotherapy and/or β-ray brachytherapy. Therapy failure was defined as progression requiring enucleation or external beam radiotherapy (EBRT). Primary chemotherapy was successful in 42 of 56 eyes (75%). Therapy success and visual acuity at age 6 years correlated with the International Classification of Retinoblastoma (ICRB) group. Age at diagnosis (> or <6 months) correlated with relapse, but not with therapy failure or visual acuity at 6 years of age. ICRB group did not correlate with occurrence of relapse. In this retrospective single-centre study, chemoreduction, including cyclophosphamide, with or without focal treatment, effectively controlled retinoblastoma progression without requiring enucleation or EBRT. Addition of cyclophosphamide is safe, and allows reduction of carboplatin.
    The British journal of ophthalmology 07/2013; · 2.92 Impact Factor
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    ABSTRACT: Uveal melanoma is the most common primary intraocular tumour in Caucasians. There are approximately 500 new cases of uveal melanoma in Germany per year and the incidence rate peaks at the age of 70 years. Half of all uveal melanoma patients develop metastatic disease, which can be observed even many years after successful treatment of the primary tumour. In most cases the liver is the location of first manifestation. Based on the chromosome 3 status uveal melanomas can be divided into two major classes that differ in their metastatic potential. Tumours with a high risk to metastasise usually show monosomy 3, whereas tumours showing disomy 3 rarely metastasise. If a patient wishes to know about his individual risk, prognostic testing of the primary tumour tissue can be performed after obtaining tumour material via transscleral or transretinal biopsy, or by enucleation. To date results of prognostic testing do not influence therapeutic strategies. Recently, major key genes involved in uveal melanoma development, GNAQ, GNA11, BAP1, SF3B1 and EIF1AX, have been identified. Mutation profiling, in addition to chromosomal 3 analysis, will further refine the classification or subclassification of uveal melanomas and will hopefully influence diagnostic or therapeutic concepts. Hereditary mutations in tumour suppressor gene BAP1 are associated with an increased risk for different tumour entities. Detection of germ line mutations in this tumour suppressor gene should implicate further general screening examinations of the patient to be able to detect these tumour entities. Moreover relatives of these patients should be offered a screening for BAP1 mutation.
    Klinische Monatsblätter für Augenheilkunde 07/2013; 230(7):686-91. · 0.70 Impact Factor
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    ABSTRACT: Elevated levels of cell-free DNA (cfDNA) are frequently observed in tumor patients. Activating mutations in exon 4 (R183) and exon 5 (Q209) of GNAQ and GNA 11 are almost exclusively found in uveal melanoma, thus providing a highly specific marker for the presence of circulating tumor DNA (ctDNA). To establish a reliable, noninvasive assay that might allow early detection and monitoring of metastatic disease, we determined the proportion of GNAQ or GNA 11 mutant reads in cfDNA of uveal melanoma patients by ultradeep sequencing. Cell-free DNA from 28 uveal melanoma patients with metastases or extraocular growth was isolated and quantified by real-time polymerase chain reaction (PCR) (7-1550 ng DNA/mL plasma). GNAQ and GNA 11 regions of interest were amplified in 22 of 28 patients and ultradeep sequencing of amplicons was performed to detect even low proportions of mutant reads. We detected Q209 mutations (2-38% mutant reads) in either GNAQ or GNA 11 in the plasma of 9 of 22 metastasized patients. No correlation between the proportion of mutant reads and the concentration of cfDNA could be detected. Among the nine ctDNA-positive patients, four had metastases in bone, whereas no metastases were detected in the 13 ctDNA-negative patients at this location (P = 0.025). Furthermore, ctDNA-positive patients tended to be younger at initial diagnosis and show larger metastases. The results show that ultradeep amplicon sequencing can be used to detect tumor DNA in plasma of metastasized uveal melanoma patients. It remains to be shown if this approach can be used for early detection of disseminated tumor disease.
    Cancer Medicine 04/2013; 2(2):208-15.
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    ABSTRACT: BACKGROUND: Retinoblastoma is the childhood retinal cancer that defined tumour-suppressor genes. Previous work shows that mutation of both alleles of the RB1 retinoblastoma suppressor gene initiates disease. We aimed to characterise non-familial retinoblastoma tumours with no detectable RB1 mutations. METHODS: Of 1068 unilateral non-familial retinoblastoma tumours, we compared those with no evidence of RB1 mutations (RB1(+/+)) with tumours carrying a mutation in both alleles (RB1(-/-)). We analysed genomic copy number, RB1 gene expression and protein function, retinal gene expression, histological features, and clinical data. FINDINGS: No RB1 mutations (RB1(+/+)) were reported in 29 (2·7%) of 1068 unilateral retinoblastoma tumours. 15 of the 29 RB1(+/+) tumours had high-level MYCN oncogene amplification (28-121 copies; RB1(+/+)MYCN(A)), whereas none of 93 RB1(-/-) primary tumours tested showed MYCN amplification (p<0·0001). RB1(+/+)MYCN(A) tumours expressed functional RB1 protein, had fewer overall genomic copy-number changes in genes characteristic of retinoblastoma than did RB1(-/-) tumours, and showed distinct aggressive histological features. MYCN amplification was the sole copy-number change in one RB1(+/+)MYCN(A) retinoblastoma. One additional MYCN(A) tumour was discovered after the initial frequencies were determined, and this is included in further analyses. Median age at diagnosis of the 17 children with RB1(+/+)MYCN(A) tumours was 4·5 months (IQR 3·5-10), compared with 24 months (15-37) for 79 children with non-familial unilateral RB1(-/-) retinoblastoma. INTERPRETATION: Amplification of the MYCN oncogene might initiate retinoblastoma in the presence of non-mutated RB1 genes. These unilateral RB1(+/+)MYCN(A) retinoblastomas are characterised by distinct histological features, only a few of the genomic copy-number changes that are characteristic of retinoblastoma, and very early age of diagnosis. FUNDING: National Cancer Institute-National Institutes of Health, Canadian Institutes of Health Research, German Research Foundation, Canadian Retinoblastoma Society, Hyland Foundation, Toronto Netralaya and Doctors Lions Clubs, Ontario Ministry of Health and Long Term Care, UK-Essen, and Foundations Avanti-STR and KiKa.
    The Lancet Oncology 03/2013; · 25.12 Impact Factor
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    ABSTRACT: Germline loss of function mutations in tumor suppressor genes RB1 and LKB1/STK11 are associated with the autosomal dominant cancer predisposing syndromes familial retinoblastoma and Peutz-Jeghers syndrome (PJS), respectively. We present a rare case of a young woman with trilateral retinoblastoma diagnosed as an infant who survived and was then diagnosed with PJS as a teenager. There was no family history of either disorder. Analysis of the LKB1/STK11 gene sequence identified a germline frameshift mutation (c.107del) leading to a nonsense mutation near the N-terminus of the protein, confirming a clinical diagnosis of Peutz-Jeghers syndrome. Extensive RB1 gene analysis failed to detect germline mutations or deletions, and immunohistochemical analysis of her ocular tumors demonstrated nuclear staining of immunoreactive pRB. This result suggests that the RB1 gene is intact. We estimate the chance of trilateral retinoblastoma and PJS occurring in the same individual at approximately 1 in 134 billion live births, and we discuss the possibility that this case could be explained by a putative modifier of pRB action that is associated with the LKB1/STK11 pathway. © 2013 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 03/2013; · 2.30 Impact Factor
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    Epigenetics & Chromatin 03/2013; 6(1). · 4.19 Impact Factor
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    ABSTRACT: There are approximately 40 new cases of retinoblastoma in Germany per year. Children in whom the tumour is detected when still intraocular have an excellent overall survival rate (> 95 %). However, the prognosis of metastasised retinoblastoma remains poor. About 40 % of retinoblastoma patients have tumours in both eyes. For these children in particular it is important to save the eye and visual function as much as possible. There are several options for conservative treatment of localised retinoblastoma including laser coagulation, thermotherapy, cryotherapy, brachytherapy and chemotherapy. In recent years, systemic chemotherapy has become the established standard for primary treatment of intraocular retinoblastoma. In case series, intra-arterial, intravitreal and periocular applications of chemotherapy were also shown to be effective in treating intraocular retinoblastoma. Genetic testing is an integral part of the routine diagnostics of all patients. Mutation analysis of tumour material is invaluable for identification of somatic mutations including mutational mosaicism. Genetic testing also identifies children with heritable retinoblastoma, which represent 50 % of cases. These children also have a predisposition for the development of tumours outside of the eye (second primary neoplasm). To adequately address these and other late effects in survivors of retinoblastoma, a multidisciplinary approach is needed that optimises therapy and long-term follow-up. Upcoming multicentre clinical trials will evaluate treatment concepts for localised and metastasised retinoblastoma to improve survival rates and quality of life of children with retinoblastoma. This article was translated and modified and was primarily published in Klin Padiatr 2012; 224: 339-347.
    Klinische Monatsblätter für Augenheilkunde 03/2013; 230(3):232-242. · 0.70 Impact Factor
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    ABSTRACT: The human retinoblastoma gene (RB1) is imprinted; the mouse Rb1 gene is not. Imprinted expression of RB1 is due to differential methylation of a CpG island (CpG85), which is located in the pseudogene PPP1R26P1 in intron 2 of RB1. CpG85 serves as promoter for an alternative RB1 transcript, which is expressed from the unmethylated paternal allele only and is thought to suppress expression of the full-length RB1 transcript in cis. PPP1R26P1 contains another CpG island (CpG42), which is biallelically methylated. To determine the influence of PPP1R26P1 on RB1 expression, we generated an in vitro murine embryonic stem cell model by introducing human PPP1R26P1 into mouse Rb1. Next generation bisulfite sequencing of CpG85 and CpG42 revealed differences in their susceptibility to DNA methylation, gaining methylation at a median level of 4% and 18%, respectively. We showed binding of RNA polymerase II at and transcription from the unmethylated CpG85 in PPP1R26P1 and observed reduced expression of full-length Rb1 from the targeted allele. Our results identify human PPP1R26P1 as a cis-repressive element and support a connection between retrotransposition of PPP1R26P1 into human RB1 and the reduced expression of RB1 on the paternal allele.
    PLoS ONE 01/2013; 8(9):e74159. · 3.53 Impact Factor
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    ABSTRACT: The human RB1 gene is imprinted due to a differentially methylated CpG island in intron 2. This CpG island is part of PPP1R26P1, a truncated retrocopy of PPP1R26, and serves as a promoter for an alternative RB1 transcript. We show here by in silico analyses that the parental PPP1R26 gene is present in the analysed members of Haplorrhini, which comprise Catarrhini (Old World Monkeys, Small apes, Great Apes and Human), Platyrrhini (New World Monkeys) and tarsier, and Strepsirrhini (galago). Interestingly, we detected the retrocopy, PPP1R26P1, in all Anthropoidea (Catarrhini and Platyrrhini) that we studied but not in tarsier or galago. Additional retrocopies are present in human and chimpanzee on chromosome 22, but their distinct composition indicates that they are the result of independent retrotransposition events. Chimpanzee and marmoset have further retrocopies on chromosome 8 and chromosome 4, respectively. To examine the origin of the RB1 imprint, we compared the methylation patterns of the parental PPP1R26 gene and its retrocopies in different primates (human, chimpanzee, orangutan, rhesus macaque, marmoset and galago). Methylation analysis by deep bisulfite sequencing showed that PPP1R26 is methylated whereas the retrocopy in RB1 intron 2 is differentially methylated in all primates studied. All other retrocopies are fully methylated, except for the additional retrocopy on marmoset chromosome 4, which is also differentially methylated. Using an informative SNP for the methylation analysis in marmoset, we could show that the differential methylation pattern of the retrocopy on chromosome 4 is allele-specific. We conclude that the epigenetic fate of a PPP1R26 retrocopy after integration depends on the DNA sequence and selective forces at the integration site.
    PLoS ONE 01/2013; 8(11):e81502. · 3.53 Impact Factor
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    ABSTRACT: Retinoblastoma affects approximately 40 children in Germany per year. Most children are diagnosed early with localized intraocular disease, and the overall survival rate exceeds 95%. However, the prognosis of metastasized retinoblastoma remains poor. In 40% of the patients, retinoblastoma occurs bilaterally and, especially for these children, the salvage of the eye and visual function is of major importance. The variety of conservative treatment options for localized retinoblastoma includes laser coagulation, thermotherapy, cryotherapy, brachytherapy and chemotherapy. While systemic chemotherapy has nearly completely replaced external beam radiotherapy in the primary treatment of intraocular retinoblastoma, intra-arterial, intravitreal and periocular application of chemotherapy was also shown to be effective in treating intraocular retinoblastoma in case series. Genetic testing is an integral part of the routine diagnostics of all patients. Available tumor material should be analyzed to detect mutational mosaicism, that affects >10% of children with unilateral retinoblastoma. Genetic testing also identifies children with heritable (50% of patients) retinoblastoma. These children have a genetic predisposition for second malignancies. For this reason, late effects are an increasing concern and the care of patients with retinoblastoma requires a multidisciplinary approach to tailor therapy and long-term follow-up. Multicenter clinical trials are being developed to evaluate evidence-based treatment concepts for localized and metastasized retinoblastoma to improve survival rates and quality of life of children with retinoblastoma.
    Klinische Pädiatrie 10/2012; 224(6):339-347. · 1.90 Impact Factor
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    ABSTRACT: In uveal melanoma (UM), the most frequent primary intraocular tumour in adults, loss of one entire chromosome 3 (monosomy 3 (M3)) is observed in ~50% of tumours and is significantly associated with metastatic disease. The strong association of metastatic disease with M3 offers the opportunity for molecular prognostic testing of UM patients. To re-evaluate M3 as prognostic marker in our clinical and laboratory setting and to determine the metastatic potential of rare tumours with partial M3, we performed a comprehensive study on 374 UM patients treated by enucleation in our clinic within 10 consecutive years, starting in 1998. Genotyping of all tumours was performed by microsatellite analysis. Median follow-up time was 5.2 years. The disease-specific mortality rates (death by UM metastases) for tumours with disomy 3 (D3) and M3 were 13.2% and 75.1%, respectively. The disease-specific survival was worse when M3 was observed together with chromosome 8 alterations (P=0.020). Death of UM metastases was also observed in 12 patients (9%) with D3 tumours. The metastasising D3 tumours showed a larger basal tumour diameter (P=0.007), and were more frequently of mixed or epitheloid cell type (P<0.0001) than D3 tumours that did not metastasise. Mortality rate of tumours showing partial M3 (8.3%) was as low as that for tumours with D3. This shows that large tumours with disomy 3 have an increased risk to develop metastases. On the basis of these results, our clinic offers routine prognostic testing of UM patients by chromosome 3 typing.
    British Journal of Cancer 02/2012; 106(6):1171-6. · 5.08 Impact Factor
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    ABSTRACT: Treacher Collins syndrome (TCS) is a rare craniofacial disorder characterized by facial anomalies and ear defects. TCS is caused by mutations in the TCOF1 gene and follows autosomal dominant inheritance. Recently, mutations in the POLR1D and POLR1C genes have also been identified to cause TCS. However, in a subset of patients no causative mutation could be found yet. Inter- and intrafamilial phenotypic variability is high as is the variety of mainly family-specific mutations identified throughout TCOF1. No obvious correlation between pheno- and genotype could be observed. The majority of described point mutations, small insertions and deletions comprising only a few nucleotides within TCOF1 lead to a premature termination codon. We investigated a cohort of 112 patients with a tentative clinical diagnosis of TCS by multiplex ligation-dependent probe amplification (MLPA) to search for larger deletions not detectable with other methods used. All patients were selected after negative screening for mutations in TCOF1, POLR1D and POLR1C. In 1 patient with an unequivocal clinical diagnosis of TCS, we identified a 3.367 kb deletion. This deletion abolishes exon 3 and is the first described single exon deletion within TCOF1. On RNA level we observed loss of this exon which supposedly leads to haploinsufficiency of TREACLE, the nucleolar phosphoprotein encoded by TCOF1.
    Molecular syndromology 01/2012; 2(2):53-59.
  • Klinische Pädiatrie 01/2012; 224:339–347. · 1.90 Impact Factor
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    ABSTRACT: Retinoblastomas are the most frequent primary malignant intraocular tumours worldwide. Conventional and new treatment modalities have significantly improved the chance for survival and preservation of vision. The armamentarium of treatment modalities has been broadened recently by new techniques like intraarterial chemotherapy, which still has to be considered as experimental since long-term follow-up results are not yet available. The excellent prognosis for retinoblastomas in countries with a well developed health system is contrasted by the miserable prognosis for retinoblastomas in developing countries, which must be changed by a joint effort of all centres.
    Klinische Monatsblätter für Augenheilkunde 07/2011; 228(7):593-8. · 0.70 Impact Factor
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    ABSTRACT: Patients with an interstitial 13q deletion that contains the RB1 gene show retinoblastoma and variable clinical features. Relationship between phenotypic expression and loss of specific neighboring genes are unresolved, yet. We obtained clinical, cytogenetic and molecular data in 63 patients with an interstitial 13q deletion involving RB1. Whole-genome array analysis or customized high-resolution array analysis for 13q14.11q14.3 was performed in 38 patients, and cytogenetic analysis was performed in 54 patients. Deletion sizes ranged between 4.2 kb and more than 33.43 Mb; breakpoints were non-recurrent. Sequence analysis of deletion junctions in five patients revealed microhomology and insertion of 2-34 base pairs suggestive of non-homologous end joining. Milder phenotypic expression of retinoblastoma was observed in patients with deletions larger than 1 Mb, which contained the MED4 gene. Clinical features were compared between patients with small (within 13q14), medium (within 13q12.3q21.2) and large (within 13q12q31.2) deletions. Patients with a small deletion can show macrocephaly, tall stature, obesity, motor and/or speech delay. Patients with a medium deletion show characteristic facial features, mild to moderate psychomotor delay, short stature and microcephaly. Patients with a large deletion have characteristic craniofacial dysmorphism, short stature, microcephaly, mild to severe psychomotor delay, hypotonia, constipation and feeding problems. Additional features included deafness, seizures and brain and heart anomalies. We found no correlation between clinical features and parental origin of the deletion. Our data suggest that hemizygous loss of NUFIP1 and PCDH8 may contribute to psychomotor delay, deletion of MTLR1 to microcephaly and loss of EDNRB to feeding difficulties and deafness.
    European journal of human genetics: EJHG 04/2011; 19(9):947-58. · 3.56 Impact Factor
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    European journal of human genetics: EJHG 03/2011; 19(3). · 3.56 Impact Factor
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    ABSTRACT: Recent data have revealed that the paradigmatic tumour suppressor gene RB1 on chromosome 13 is preferentially expressed from the maternal allele. Imprinted expression of RB1 is linked to a differentially methylated CpG island in intron 2 of this gene (CpG 85). On the paternal chromosome, CpG 85 is unmethylated and acts as a weak promoter of an alternative RB1 transcript. Paternal mRNA levels are probably reduced as the result of transcriptional interference of the regular promoter and the alternative promoter on this chromosome. CpG 85 is part of a truncated processed pseudogene (KIAA0649P) that integrated into the RB1 gene prior to the speciation of extant primates. It is plausible that differential penetrance and variation of age at diagnosis, which have been observed in patients with hereditary and non-hereditary retinoblastoma, respectively, are a consequence of imprinted expression of the RB1 gene. Interestingly, RB1 is imprinted in the same direction as CDKN1C, which operates upstream of RB1. The imprinting of two components of the same pathway indicates that there has been strong evolutionary selection for maternal inhibition of cell proliferation.
    Briefings in functional genomics 07/2010; 9(4):347-53. · 4.21 Impact Factor
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    ABSTRACT: The GFI1 gene encodes a transcriptional repressor, which regulates myeloid differentiation. In the mouse, Gfi1 deficiency causes neutropenia and an accumulation of granulomonocytic precursor cells that is reminiscent of a myelodysplastic syndrome. We report here that a variant allele of GFI1 (GFI1(36N)) is associated with acute myeloid leukemia (AML) in white subjects with an odds ratio of 1.6 (P < 8 x 10(-5)). The GFI1(36N) variant occurred in 1806 AML patients with an allele frequency of 0.055 compared with 0.035 in 1691 healthy control patients in 2 independent cohorts. We observed that both GFI1 variants maintain the same activity as transcriptional repressors but differ in their regulation by the AML1/ETO (RUNX1/RUNX1T1) fusion protein produced in AML patients with a t(8;21) translocation. AML1/ETO interacts and colocalizes with the more common GFI1(36S) form in the nucleus and inhibits its repressor activity. However, the variant GFI1(36N) protein has a different subnuclear localization than GFI1(36S). As a consequence, AML1/ETO does not colocalize with GFI1(36N) and is unable to inhibit its repressor activity. We conclude that both variants of GFI1 differ in their ability to be regulated by interacting proteins and that the GFI1(36N) variant form exhibits distinct biochemical features that may confer a predisposition to AML.
    Blood 03/2010; 115(12):2462-72. · 9.78 Impact Factor
  • Dietmar Lohmann
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    ABSTRACT: Retinoblastoma (Rb) is a malignant tumor that originates from developing retina. Diagnosis based on clinical signs and symptoms and is usually made in children under the age of five years. Mutations in both alleles of the RB1 gene are a prerequisite for this tumor to develop. In most patients with sporadic unilateral Rb, both RB1 gene mutations occur in somatic cells and are not passed over to offspring (nonhereditary Rb). Almost all patients with sporadic bilateral and virtually all patients with familial Rb are heterozygous for RB1 gene mutations that cause predisposition to Rb (hereditary Rb). In families, Rb predisposition is transmitted as an autosomal dominant trait (familial Rb). In addition to Rb, patients with hereditary disease also have an increased risk of tumors outside the eye (second cancer). This risk is enhanced in patients who have received external beam radiotherapy. Analysis of genotype-phenotype associations has shown that the mean number of tumor foci that develop in carriers of mutant RB1 alleles is variable depending on which functions of the normal allele are retained and to what extent. Moreover, phenotypic expression of hereditary retinoblastoma is subject to genetic modification. Identification of the genetic factors that underlie these effects will not only help to arrive at a more precise prognosis but may also point to mechanisms that can be used to reduce the risk of tumor development.
    Advances in experimental medicine and biology 01/2010; 685:220-7. · 1.83 Impact Factor
  • D. Lohmann
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    ABSTRACT: Mutationen beider Allele des Retinoblastomgens (RB1) sind Voraussetzung für die Entstehung des Retinoblastoms. Dieser Augentumor kann auf der Grundlage einer autosomal-dominanten Disposition entstehen, die durch Keimbahnmutationen im RB1-Gen verursacht wird. Die Entstehung eines Tumorherds wird durch eine somatische Mutation des anderen RB1-Allels ausgelöst. Bei Patienten mit der nichterblichen Form sind beide RB1-Mutationen somatisch. Beim erblichen und beim nichterblichen Retinoblastom können Elterneffekte beobachtet werden. Diesen ist gemeinsam, dass die onkogene Wirkung der ersten Mutation höher ist, wenn sie das RB1-Allel paternaler Herkunft betrifft. Das RB1-Gen des Menschen unterliegt dem Imprinting: Als indirekte Folge differenzieller Methylierung einer CpG-Insel im Intron2 überwiegt die Expression der mit Exon1 beginnenden Transkripte vom maternalen, methylierten Allel. Ob und wie das Imprinting dieser CpG-Insel zu den beobachteten Elterneffekten führt, ist noch ungeklärt. Mutations in both alleles of the retinoblastoma gene (RB1) are required for the development of retinoblastoma, a childhood tumor of the eye. Hereditary predisposition to this tumor is caused by heterozygous RB1 gene mutations. A tumor focus is initiated by a second somatic mutation that inactivates the remaining RB1 allele. In non-hereditary retinoblastoma both the first and second mutation occur in somatic cells. The human RB1 gene is imprinted. It contains a CpG island in intron2 that is methylated on the paternal allele only and, mediated by promoting expression of an alternative transcript, reduces expression of the regular paternal relative to the maternal RB1 transcript. Parent-of-origin effects have been identified in hereditary and in non-hereditary retinoblastoma. These effects have in common that the oncogenic effect of the first mutation is higher if a paternal allele is hit. It is plausible that some mechanisms link differential methylation of the CpG island and the observed parent-of-origin effects. SchlüsselwörterRetinoblastomgene-Allele-„Loss of heterozygosity“-Genetisches Imprinting-Genetische Prädisposition KeywordsRetinoblastoma genes-Alleles-Loss of heterozygosity-Genetic imprinting-Genetic predisposition
    Medizinische Genetik 01/2010; 22(4):429-433. · 0.09 Impact Factor

Publication Stats

1k Citations
255.92 Total Impact Points

Institutions

  • 1994–2013
    • University Hospital Essen
      • • Klinik für Kinderheilkunde II
      • • Institut für Humangenetik
      Essen, North Rhine-Westphalia, Germany
  • 1997–2011
    • University of Duisburg-Essen
      • Faculty of Medicine
      Essen, North Rhine-Westphalia, Germany
  • 2001
    • The Catholic University of America
      Washington, Washington, D.C., United States
  • 1993
    • Technische Universität München
      München, Bavaria, Germany
    • University of Hamburg
      • Center for Internal Medicine
      Hamburg, Hamburg, Germany