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Maria Debiec-Rychter

Publications and source records attributed to Maria Debiec-Rychter.

53 records · Page 3Linked to original sources
PubMed2003

Complex genomic rearrangement of ALK loci associated with integrated human Epstein-Barr virus in a post-transplant myogenic liver tumor.

Epstein-Barr virus (EBV) is a ubiquitous viral agent, well known to be associated with lymphoid, epithelial, and smooth-muscle malignancies in immunocompromised individuals. This report describes a 10-year-old patient with an EBV-related liver tumor occurring after kidney transplantation. The neoplasm presented a phenotypic spectrum, ranging from a smooth-muscle tumor to an inflammatory pseudotumor (IPT). The neoplastic cells failed to disclose CD21, CD35, or ALK expression, the latter confirmed by reverse-transcription polymerase chain reaction. Cytogenetic analysis revealed a single clonal cell population showing 46,XY,del (2)(p23),der(3)t (2;3)(p23;q29),der(21) t(Y;21)(q12;p13) karyotype. By metaphase FISH analysis, the neoplastic cells demonstrated the presence of two molecularly different but related aberrant clones, one with the loss of one ALK allele and the second with translocation of the 3'end of ALK kinase domain on the der(3) chromosome. Using FISH with an EBV-specific and 3'end ALK DNA probes, a co-localization of the viral DNA and the ALK sequences was found on the der(3) chromosome. Metaphases with loss of rearranged ALK did not show integrated virus; instead, viral particles together with an associated 3'end ALK domain formed an ex-chromosomal, episomal-like type configuration. The interphase study, using dual-color 5'/3' end ALK FISH assay, revealed 30% of nuclei with only one fused signal, confirming the total loss of one ALK allele in the subset of tumor cells. A combined immunofluorescence and FISH study indicated this separate clonal variant to correspond to desmin-positive smooth-muscle cells. In contrast, desmin-negative myofibroblasts showed the presence of both normal and rearranged ALK alleles. Our results indicate that ALK locus may be a target of EBV integration, a hitherto unreported finding. Although the sustained clonal expansion in EBV-related smooth-muscle tumors/IPTs may depend on functions provided by the EBV oncogenic proteins, the tumor phenotype may be further modified by the secondary genomic rearrangements imposed by the virus during and/or after the integration event. In this respect, the observed phenotypic heterogeneity most likely reflects divergence during neoplastic progression, with the subsequent expansion of morphologically and molecularly distinct but cytogenetically related clones.

Anaplastic Lymphoma Kinase↗
PubMed2003

Endometrial stromal sarcoma with a sole t(X;17) chromosome change: report of a case and review of the literature.

BACKGROUND: Endometrial stromal sarcomas (ESSs) exhibit varying degrees of malignancy and heterogeneity at the karyotypic level. The biological mechanisms that contribute to tumorigenesis of ESS are still largely unknown. CASE: A 33-year-old woman suffering from ESS was treated primarily surgically. Cytogenetic evaluation of the primary uterine nodule and metastatic tumor showed 46,XX,t(X;17)(p11:q23) karyotype in all metaphases analyzed. Normal endometrial cells exhibited 46,XX karyotype. Fluorescence in situ hybridization analysis confirmed the presence of the reciprocal t(X;17) translocation and allowed for the positioning of the chromosome X breakpoint distal to SSX1 gene loci. CONCLUSIONS: Our report of a previously undescribed sole cytogenetic translocation in an advanced stage of ESS might identify a cytogenetically distinct subgroup of ESS and help to reveal genes involved in ESS tumorigenesis.

Adult↗
PubMed2003

Endometrial stromal sarcoma presenting as postpartum haemorrhage: report of a case with a sole t(10;17)(q22;p13) translocation.

BACKGROUND: Although the clinical picture of endometrial stromal sarcoma (ESS) is variable, it was never reported to present as a postpartum hemorrhage. In addition, ESS is a tumor type of which, due to its rarity, little is known regarding chemosensitivity and genetic changes. CASE: A 28-year-old woman complaining of persistent postpartum bleeding was referred to our hospital, where she was diagnosed with ESS. At laparotomy, the invasion of nervous and vascular pelvic structures rendered her inoperable, and chemotherapy (doxorubicin 50 mg/m(2) for 15 min; ifosfamide 5 g/m(2)/24 h; mesna 5 g/m(2), every 3 weeks) was initiated. The ESS appeared to be chemosensitive because after three treatment cycles the tumor iliac metastase significantly decreased in volume and became surgically removable. Chemosensitivity was confirmed microscopically. Three additional courses of chemotherapy and pelvic irradiation were administered. Cytogenetic evaluation of both the primary as well as the metastatic lesions revealed a t(10;17)(q22;p13) as the sole cytogenetic abnormality. CONCLUSIONS: Three interesting features of this particular case put ESS in a new perspective. First, the fundal ESS permitted normal conception and pregnancy but caused a postpartum haemorrhage. Second, the ESS was clearly chemosensitive. Third, we report a novel cytogenetic aberration in ESS, the molecular characterization of which might lead to the identification of the deregulated pathway(s) triggering tumor development in ESS.

Adult↗
PubMed2003

A unique occurrence of a cerebral atypical teratoid/rhabdoid tumor in an infant and a spinal canal primitive neuroectodermal tumor in her father.

This report describes the clinical, pathological, immunohistochemical and genetic data of two rare malignant neoplasms of the central nervous system (CNS)--a cerebral atypical teratoid/rhabdoid tumor (AT/RT) in a 5-month-old girl and a spinal canal primitive neuroectodermal tumor (PNET) in her father. Despite aggressive treatment, both tumors were fatal, displaying extensive local recurrence and diffuse neoplastic dissemination. The paraffin-embedded tumor tissue samples were analyzed using a dual-color FISH with a locus specific LSI22q (BCR) probe. In the AT/RT tissue, a loss of BCR locus was observed in a significant proportion of the cells in contrast to the PNET specimen where the majority of nuclei did not reveal any loss of the BCR region. No mutations in exon 5 and no changes in SNP of intron 5 of hSNF/INI1 gene were found. In addition, analysis of loss of heterozygosity (LOH) was performed using a panel of 15 microsatellite markers of chromosome 22. No LOH were found in both tumor tissues. In both cases no constitutional mutations of gene TP53 were found. Analysis of the TP53 mutations in the tumor tissues revealed that the PNET, not the AT/RT tumor, was homozygous for a missense mutation at codon 175 (CGC ==> CAC). Thus, our findings emphasize the genetic differences between the two specimens and suggest that the occurrence of these two aggressive tumors of CNS in one family could be coincidental.

Adult↗
PubMed2003

Role of gain of 12p in germ cell tumour development.

Within the human testis, three entities of germ cell tumours are distinguished: the teratomas and yolk sac tumors of newborn and infants, the seminomas and nonseminomas of adolescents and young adults, referred to as testicular germ cell tumours (TGCT), and the spermatocytic seminomas. Characteristic chromosomal anomalies have been reported for each group, supporting their distinct pathogenesis. TGCT are the most common cancer in young adult men. The initiating pathogenetic event of these tumours occurs during embryonal development, affecting a primordial germ cell or gonocyte. Despite this intra-uterine initiation, the tumour will only be clinically manifest after puberty, with carcinoma in situ (IS) as the precursor. All invasive TGCT, both seminomas and nonseminomas, as well as CIS cells are aneuploid. The only consistent (structural) chromosomal abnormalities in invasive TGCT are gains of the short arm of chromosome 12, mostly due to isochromosome (i(12p)) formation. This suggests that an increase in copy number of a gene(s) on 12p is associated with the development of a clinically manifest TGCT. Despite the numerous (positional) candidate gene approaches that have been undertaken thus far, identification of a causative gene(s) has been hampered by the fact that most 12p gains involve rather large genomic intervals, containing unmanageable numbers of candidate genes. Several years ago, we initiated a search for 12p candidate genes using TGCT with a restricted 12p-amplification, cytogenetically identified as 12p11.2-p12.1. This approach is mainly based on identification of candidate genes mapped within the shortest region of overlap of amplification (SROA). In this review, data will be presented, which support the model that gain of 12p-sequences is associated with suppression of apoptosis and Sertoli cell-independence of CIS cells. So far, DAD-R is one of the most likely candidate genes involved in this process, possibly via N-glycosylation. Preliminary results on high through-put DNA- and cDNA array analyses of 12p-sequences will be presented.

Adolescent↗
PubMed2003

Cytogenetic comparison between clear cell sarcoma and a case of acral clear cell melanoma.

BACKGROUND: Clear cell melanoma is a recently described variant of melanoma characterized by prominent clear cell features similar to clear cell sarcoma. PATIENTS AND METHODS: The present report describes a deeply invasive case of clear cell melanoma clinically, histologically, immunohistochemically, ultrastructurally and with the FISH technique and compares these findings with those in clear cell sarcoma. RESULTS: A 68-year-old male presented with an ulcerated, deeply invasive melanoma on the heel, corresponding to Clark level V, with a maximum tumour thickness of more than 14 mm; follow-up revealed inguinal lymph-node and lung metastases. Apart from characteristic histological features of melanoma with intraepidermal involvement, the lesion was immunohistochemically positive for 5100 protein, with HMB45 and A103 (anti-human Melan-A/MART-1), and ultrastructurally showed melanosomes. In deeply invasive parts, the lesion was indistinguishable from clear cell sarcoma, exhibiting nests, fascicles and sheets of pale-staining epithelioid to spindle-shaped cells ('clear cells') with scattered Touton-like multinucleated giant cells. Cytogenetic analysis using the FISH technique revealed a 12q13 chromosomal break in the vicinity of the ATFI gene but without ATF1 disruption. CONCLUSION: These findings may indicate the possible involvement of the ATF1 gene in clear cell melanoma tumorigenesis, similar to clear cell sarcoma with classical t(12;22) translocation.

Activating Transcription Factor 1↗
PubMed2003

Loss of chromosome 22 and proliferative potential in ependymomas.

Fluorescence in situ hybridisation (FISH) analysis using total chromosome 22 painting and locus specific 22q11.2 (bcr locus) probes was performed on sections from archival paraffin-embedded tumours obtained from 28 patients diagnosed with either ependymoma, WHO grade 11 (18 cases) or anaplastic ependymoma, WHO grade 111 (10 cases). The Ki-67 labelling index (LI) analysis was carried out in parallel to estimate the tumours' proliferative potential. Loss of chromosome 22 was revealed in eleven (39%) ependymomas, seven (39%) WHO grade II and four (40%) anaplastic variants. Concurrent cytogenetic analysis was performed on 11 tumours to confirm the loss of chromosome 22 in four cases; clones with a loss of chromosome 22, which was identified by FISH, were not detected by standard cytogenetics in two samples. The loss of chromosome 22 was restricted either to the tumours' site or to sex or age of the patients studied. The Ki-67 LI ranged from 0.1 to 32.0% (mean 4.3%). Low-grade tumours significantly showed a lower mean Ki-67 LI than those classified as anaplastic tumours (3.1% and 6.4%, respectively). Additionally, the mean Ki-67 LI for ependymomas with a loss of chromosome 22 was significantly lower than that for tumours with chromosome 22 disomy (1.6% and 6.0%, respectively, p = 0.05), indicating that loss of chromosome 22 may be associated with the subset of ependymomas characterised by low proliferative capacities.

Adolescent↗
PubMed2002

Atypical lipomatous tumor in a 14-year-old patient: distinction from lipoblastoma using FISH analysis.

Liposarcomas are rare in young age. We present the rare case of an atypical lipomatous tumor (synonym: well-differentiated lipoma-like liposarcoma) in a 14-year-old girl with the differential diagnosis of lipoblastoma which was excluded by fluorescence in situ hybridization (FISH) analysis. The tumor presented as a soft tissue mass at the dorsal part of the right thigh measuring up to 18 cm. Microscopically the lesion consisted of atypical adipocytes with hyperchromatic nuclei and additional multivacuolated lipoblasts. Interphase dual-color FISH performed with chromosome 8 centromeric and YAC164H5 (mapping to exons 2-5 of the PLAG1 gene) probes revealed no rearrangement of PLAG1 oncogene or polysomy of chromosome 8. Additional FISH using an MDM2 gene probe and an BAC534N15 probe (containing sequences specific for the CDK4 gene) showed amplification of the CDK4 gene. These findings indicate that this tumor was no lipoblastoma but an atypical lipomatous tumor, which is of clinical relevance. In young individuals the distinction between lipoblastoma and liposarcoma is often impossible by light microscopy alone. This case shows that FISH can serve as a decisive tool in the differential diagnosis of lipoblastoma and lipoma-like liposarcoma apart from its role in distinction between lipoblastoma and myxoid/round cell liposarcoma.

Adolescent↗
PubMed2002

Molecular cytogenetic analysis of clustered sporadic and familial renal cell carcinoma-associated 3q13 approximately q22 breakpoints.

We describe several relatives within one renal cell cancer (RCC) family sharing a constitutional t(2;3) (q35;q21). Based on molecular studies on several independent primary tumors in this family, a causative role for this translocation in tumor development was suggested. Subsequent positional cloning of the 3q21 chromosomal breakpoint revealed that this breakpoint disrupts a novel gene, DIRC2 (disrupted in renal cancer 2). This gene encodes an evolutionary conserved transmembrane protein and represents a novel member of the MFS superfamily of transporters. To evaluate whether DIRC2 is also targeted in sporadic RCC cases with cytogenetically defined 3q21 breakpoints, fluorescence in situ hybridization analysis was performed on metaphase spreads and/or interphase nuclei of 12 primary sporadic RCC using genomic clones from a 3q21 breakpoint-spanning contig as probes. Three breakpoints were mapped proximal to the familial breakpoint and nine breakpoints were mapped distal to this breakpoint. Two of the latter breakpoints were mapped in the contig within 1 Mb distance from the familial breakpoint. Because these clustered 3q21 breakpoints do not coincide with the familial 3q21 breakpoint, they most likely affect genes distinct from DIRC2.

Carcinoma, Renal Cell↗
PubMed2002

Identification of a karyopherin alpha 2 recognition site in PLAG1, which functions as a nuclear localization signal.

The activation of the pleomorphic adenoma gene 1 (PLAG1) is the most frequent gain-of-function mutation found in pleomorphic adenomas of the salivary glands. To gain more insight into the regulation of PLAG1 function, we searched for PLAG1-interacting proteins. Using the yeast two-hybrid system, we identified karyopherin alpha2 as a PLAG1-interacting protein. Physical interaction between PLAG1 and karyopherin alpha2 was confirmed by an in vitro glutathione S-transferase pull-down assay. Karyopherin alpha2 escorts proteins into the nucleus via interaction with a nuclear localization sequence (NLS) composed of short stretches of basic amino acids. Two putative NLSs were identified in PLAG1. The predicted NLS1 (KRKR) was essential for physical interaction with karyopherin alpha2 in glutathione S-transferase pull-down assay, and its mutation resulted in decreased nuclear import of PLAG1. Moreover, NLS1 was able to drive the nuclear import of the cytoplasmic protein beta-galactosidase. In contrast, predicted NLS2 of PLAG1 (KPRK) was not involved in karyopherin alpha2 binding nor in its nuclear import. The residual nuclear import of PLAG1 after mutation of the NLS1 was assigned to the zinc finger domain of PLAG1. These observations indicate that the nuclear import of PLAG1 is governed by its zinc finger domain and by NLS1, a karyopherin alpha2 recognition site.

Binding Sites↗
PubMed2002

Ring chromosome 6 may represent a cytogenetic subgroup in benign thymoma.

Cytogenetic and fluorescence in situ hybridization analysis of a thymoma revealed the presence of an abnormal clone with a karyotype 46,XY,r(6)(p2?q35?).ish r(6)(p2?q35?)(WCP6+,dJ476O18-,dJ62I11-, PAC59C23+,PAC57H24-),der(21)t(6;21)(p25;q22)(dJ62I11+,cosC9a1-). Histologically, the tumor was encapsulated and classified as thymoma type AB (World Health Organization classification) or mixed thymoma (Muller-Hermelink classification), composed of well-formed lobules with sharp demarcation of both the spindly type A and lymphocyte-rich type B components. This finding, together with literature data, strongly suggests that terminal deletion of the short arm of chromosome 6 is a recurrent aberration in thymoma.

Aged↗
PubMed2002

PRCC-TFE3 renal carcinomas: morphologic, immunohistochemical, ultrastructural, and molecular analysis of an entity associated with the t(X;1)(p11.2;q21).

The reappraisal of genetically defined subsets of renal tumors can help to highlight the key pathologic features of specific neoplastic entities. We report the morphologic, immunophenotypic, ultrastructural, and molecular features of 11 renal carcinomas bearing a t(X;1)(p11.2;q21) and/or the resulting PRCC-TFE3 gene fusion. The male/female ratio was 4:7. Ten patients were in the age range of 9-29 years and one was 64 years old (mean 21.3 years, median 15 years). The predominant histologic pattern was nested, with islands of tumor cells compartmentalized by thin-walled capillary vasculature. Minor variations on this pattern yielded solid, acinar, alveolar, and tubular architecture. Papillary architecture was seen in nine cases, usually as a minor component. Neoplastic cells were typically characterized by irregularly shaped nuclei with vesicular chromatin and small nucleoli not visible with a 10x objective, and cytoplasm that ranged from clear to densely granular and eosinophilic. Mitoses were extremely rare; 5 were found in 900 high power fields examined from the 11 neoplasms. The most distinctive immunohistochemical feature of these neoplasms was moderate to intense nuclear labeling for TFE3 protein. These tumors were also consistently immunoreactive for the RCC antigen (10 of 11) and CD10 (9 of 9), whereas cytokeratin and epithelial membrane antigen were negative in four cases and were positive focally in the others. Ultrastructurally, all of the six neoplasms examined showed features consistent with conventional-type (clear cell) renal carcinoma, although two demonstrated distinctive intracisternal microtubules. Both tumors tested contained PRCC-TFE3 fusion transcripts. The differential diagnosis includes conventional-type papillary renal cell carcinoma, conventional-type (clear cell) renal carcinoma, and the ASPL-TFE3 renal carcinomas associated with the t(X;17)(p11.2;q25), with the latter two being morphologically the most similar to the t(X;1) renal carcinomas. Aside from their distinctive clinicopathologic features described here, there is experimental evidence suggesting that these tumors may show differential sensitivity to certain chemotherapeutic agents.

Adolescent↗
PubMed2002

Complex genetic alterations in gastrointestinal stromal tumors with autonomic nerve differentiation.

Gastrointestinal stromal tumors (GISTs) with neurogenic differentiation, also referred to as "gastrointestinal autonomic nerve tumors (GANTs)," form an ultrastructurally distinctive subgroup of mesenchymal neoplasms of gastrointestinal tract. Cytogenetic and molecular data of these tumors are limited. In the current study, c-KIT gene sequenc-ing analysis, comparative genomic hybridization (CGH), and interphase fluorescence in situ hybrid- ization (FISH) analysis, utilizing chromosome 14- and 22-specific probes, were performed on five primary ultrastructurally confirmed GANTs. FISH and CGH analysis revealed loss of a whole or part of chromosome 14q in two tumors and of chromo- some 22q, with the common overlapping area of loss at q13, in all five tumors evaluated. c-KIT mu- tations were found in all cases; three tumors carried point mutation and/or deletions of exon 11, and in two tumors, insertion in exon 9 was found. These findings suggest that accumulated genetic changes contribute to the pathogenesis of GANTs and that 22q13 loss may be a characteristic feature of these tumors.

Adult↗
PubMedDate not supplied

Post-irradiation sarcoma after external beam radiation therapy for localized adenocarcinoma of the prostate.

We report a case of postirradiation sarcoma that arose in the right inguinal region 8 years after completion of external beam radiation therapy for a localized adenocarcinoma of the prostate. The patient was treated in 1995 with a "mixed-beams" technique (18 MV photons and 65 MeV fast neutrons). Eight years after the end of treatment, he presented with a radio-induced, high-grade spindle-cell sarcoma. Cytogenetic analysis was performed to confirm the diagnosis. Although the use of external beam radiation therapy for the treatment of prostate cancer has been common practice for decades, postirradiation sarcomas have been reported to be rare sequelae of irradiation and, to our knowledge, only a few of them were cytogenetically investigated.

Adenocarcinoma↗
PubMedDate not supplied

Correlation of the genotypes for N-acetyltransferases 1 and 2 with double bladder and prostate cancers in a case-comparison study.

BACKGROUND: The arylamine N-acetyltransferases play a major role in the metabolic activation of carcinogenic amines that are present in cigarette smoke and a variety of other exogenous sources. The objective of this study was to determine the association of rapid or slow arylamine N-acetyltransferase (NAT) genotypes with smoking history and the risk for developing both bladder and prostate cancer. PATIENTS AND METHODS: The subjects analyzed were a case group of 17 double-cancer patients and 34 age-matched controls who had benign prostatic hypertrophy, but were asymptomatic for prostate or bladder cancers. Genotyping of NAT1 and NAT2 alleles was done by restriction fragment length polymorphism and/or sequencing of NAT genes amplified from genomic DNAs by the polymerase chain reaction (PCR). RESULTS: No significant correlation was found between NAT1 genotypes, double cancer, and smoking history. While NAT2-smoking interaction gave an odds ratio of only 1.70 (p = 0.117), a disproportionate number of cancer cases were genotypically rapid: 12 of 17 cancer cases vs. 13 of 34 controls (odds ratio 3.88; p = 0.040). CONCLUSION: Rapid NAT2 genotype correlated significantly with the development of double prostate-bladder cancer.

Acetyltransferases↗
PubMedDate not supplied

Establishment of a mouse gastrointestinal stromal tumour model and evaluation of response to imatinib by small animal positron emission tomography.

BACKGROUND: Gastrointestinal stromal tumours (GIST) predominantly express activating mutations of the KIT tyrosine kinase receptor and are successfully treated with imatinib mesylate, a KIT inhibitor. As resistance to imatinib causes therapy failure, our aim was to develop an in vivo GIST model to evaluate KIT inhibitors and monitor therapy with small animal positron emission tomography (PET). MATERIALS AND METHODS: The first mouse model of GIST xenografts was successfully established by injecting GIST882 cells subcutaneously into nude mice. RESULTS: Using the small animal PET, FDG up-take in xenografts was significantly decreased after 24 h of treatment with imatinib, which correlated with a response to treatment, e.g., with a decrease in tumour volume, the inhibition of KIT and downstream intermediate phosphorylation and arrest of tumour cell proliferation as evaluated after 7 days of treatment. CONCLUSION: This model is useful to study imatinib resistance and to evaluate novel targeted therapies.

Animals↗