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Socorro M Rodríguez-Pinilla,
Carlos Barrionuevo,
Juan García,
María de los Ángeles,
Raquel Pajares,
Sandro Casavilca,
Jaime Montes,
Antonio Martínez,
Santiago Montes-Moreno, Lydia Sánchez,
Miguel Ángel Piris
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ABSTRACT: The World Health Organization lymphoma classification recognizes two different Epstein-Barr virus (EBV)-positive T-cell lymphoproliferative disorders of childhood: systemic EBV-positive T-cell lymphoproliferative disease of childhood, and hydroa vacciniforme-like lymphoma, which is more prevalent in Asia and Latin America. The aim of this study was to characterize six cases of paediatric EBV-positive peripheral T-cell lymphoma with distinct features.
All cases were male, with a median patient age of 9 years (range: 5-17 years). Most of them presented suddenly with fever, weight loss, hepatosplenomegaly, peripheral lymphadenopathy, and high lactate dehydrogenase (LDH) levels. Moreover, gut, lung or soft tissues of the abdominal wall were also affected in four cases. Partial to total replacement of the lymph node by pleomorphic infiltration of atypical neoplastic cells was found in all cases. Vasculitis and geographical areas of necrosis were seen in three and four cases, respectively. Neoplastic cells showed expression of EBV-encoded RNA, T-cell markers (CD2 and CD3), and cytotoxic markers (TIA1, granzyme-B, and perforin). CD56 and T-cell receptor -γ were expressed in one case each. TCR-BF1, CD4, CD8 and anaplastic lymphoma kinase were negative. In all cases, the disease progressed rapidly, causing death of the patient, with a median survival of 7.1 months (range: 1-13 months).
These cases probably represent a solid form of systemic EBV-positive T-cell lymphoproliferative disease of childhood, which requires identification and the development of appropriate therapy.
Histopathology 12/2011; 59(6):1183-93. · 3.08 Impact Factor
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Alberto Cascón,
Carlos Vázquez Huarte-Mendicoa,
L Javier Leandro-García,
Rocío Letón,
Javier Suela,
Alfredo Santana,
Mauro Boronat Costa,
Iñaki Comino-Méndez,
Iñigo Landa, Lydia Sánchez,
Cristina Rodríguez-Antona,
Juan C Cigudosa,
Mercedes Robledo
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ABSTRACT: Hereditary primary hyperparathyroidism (HPT) may develop as a solitary endocrinopathy (FIHP) or as part of multiple endocrine neoplasia Type 1, multiple endocrine neoplasia Type 2A, or hereditary HPT-jaw tumor syndrome. Inactivating germline mutations of the tumor suppressor gene CDC73 account for 14 and 50% of all FIHP and HPT-JT patients, respectively, and have also been found in almost 20% of apparently sporadic parathyroid carcinoma patients. Although more than 60 independent germline mutations have been described, to date no rearrangement affecting the CDC73 locus has been identified. By means of multiplex-PCR we found a large germline deletion affecting the whole gene in a two-generation HPT-JT family. Subsequently array-CGH and specific PCR analysis determined that the mutation spanned ∼ 547 kb, and included four additional genes: TROVE2, GLRX2, B3GALT2, and UCHL5. Although no clear mutation-specific phenotype was found associated to the presence of the mutation, further studies are needed to assess whether the loss of the neighboring genes could modify the phenotype of carriers. There was complete absence of nuclear staining in the two HPT-JT-related tumors available. The finding of the first rearrangement affecting the CDC73 gene warrants screening for this tumor suppressor gene inactivation mechanism not only in high-risk CDC73 point mutation-negative HPT-JT families, but also in FIHP patients.
Genes Chromosomes and Cancer 08/2011; 50(11):922-9. · 3.31 Impact Factor
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Soledad R Alonso,
Lorraine Tracey,
Pablo Ortiz,
Beatriz Pérez-Gómez,
José Palacios,
Marina Pollán,
Juan Linares,
Salvio Serrano,
Ana I Sáez-Castillo, Lydia Sánchez,
Raquel Pajares,
Abel Sánchez-Aguilera,
Maria J Artiga,
Miguel A Piris,
José L Rodríguez-Peralto
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ABSTRACT: Metastatic disease is the primary cause of death in cutaneous malignant melanoma (CMM) patients. To understand the mechanisms of CMM metastasis and identify potential predictive markers, we analyzed gene-expression profiles of 34 vertical growth phase melanoma cases using cDNA microarrays. All patients had a minimum follow-up of 36 months. Twenty-one cases developed nodal metastatic disease and 13 did not. Comparison of gene expression profiling of metastatic and nonmetastatic melanoma cases identified 243 genes with a >2-fold differential expression ratio and a false discovery rate of <0.2 (206 up-regulated and 37 down-regulated). This set of genes included molecules involved in cell cycle and apoptosis regulation, epithelial-mesenchymal transition (EMT), signal transduction, nucleic acid binding and transcription, protein synthesis and degradation, metabolism, and a specific group of melanoma- and neural-related proteins. Validation of these expression data in an independent series of melanomas using tissue microarrays confirmed that the expression of a set of proteins included in the EMT group (N-cadherin, osteopontin, and SPARC/osteonectin) were significantly associated with metastasis development. Our results suggest that EMT-related genes contribute to the promotion of the metastatic phenotype in primary CMM by supporting specific adhesive, invasive, and migratory properties. These data give a better understanding of the biology of this aggressive tumor and may provide new prognostic and patient stratification markers in addition to potential therapeutic targets.
Cancer Research 04/2007; 67(7):3450-60. · 7.86 Impact Factor
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Tomás Alvaro,
Marylène Lejeune,
Francisca I Camacho,
Ma Teresa Salvadó, Lydia Sánchez,
Juan F García,
Carlos Lopez,
Joaquín Jaén,
Ramón Bosch,
Lluis E Pons,
Carmen Bellas,
Miguel A Piris
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ABSTRACT: The presence of tumor-associated macrophages (TAM) is a prognostic factor for survival in follicular lymphoma (FL). Overexpression and/or activation of the signal transducer and activator of transcription 1 (STAT1) in these TAM have also been observed. The aim of this study was to determine the extent to which macrophages are present in FL and to investigate the expression of STAT1 in these cells.
We retrospectively analyzed 211 patients with distinct stages and grades of FL. Expression of the CD68 proteins, chosen as a marker for macrophages, and STAT1 was quantified by immunohistochemistry and double immunofluorescence.
Automated determinations revealed the presence of CD68-positive macrophages in all FL tissues studied (mean 57.6+/-45.1 cells/field), while STAT1 protein was expressed in 29.94% of cases. Double-fluorescence staining confirmed that STAT1 protein co-localized exclusively with CD68, indicating the presence of a subset of STAT1-expressing TAM localized principally in the vicinity of tumor cells. Multivariate analysis showed that, besides the Follicular Lymphoma International Prognostic Index (FLIPI) classification, expression of STAT1 was an important independent prognostic factor for shorter overall survival in FL.
These results demonstrate the presence of STAT1-expressing TAM in FL and their association with an adverse outcome, thus emphasizing the relevance of non-tumor cells in the control of the growth and survival of lymphoma cells.
Haematologica 01/2007; 91(12):1605-12. · 6.42 Impact Factor
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Emiliano Honrado,
Ana Osorio,
José Palacios,
Roger L Milne, Lydia Sánchez,
Orland Díez,
Alicia Cazorla,
Kirsi Syrjakoski,
David Huntsman,
Päivi Heikkilä,
Enrique Lerma,
Anne Kallioniemi,
Carmen Rivas,
William D Foulkes,
Heli Nevanlinna,
Javier Benítez
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ABSTRACT: Morphologic and immunohistochemical studies of familial breast cancers have identified specific characteristics associated with BRCA1 mutation-associated tumors when compared with BRCA2 and non-BRCA1/2 tumors, but have not identified differences between BRCA2 and non-BRCA1/2 tumors. Because BRCA1 and BRCA2 genes participate in the DNA repair pathway, we have performed an immunohistochemical study with markers related to this pathway to establish the profile of the three groups.
We have studied two tissue microarrays that include 103 familial and 104 sporadic breast tumors, with a panel of DNA repair markers including ATM, CHEK2, RAD51, RAD50, XRCC3, and proliferating cell nuclear antigen.
We found more frequent expression of CHEK2 in BRCA1 and BRCA2 tumors than in non-BRCA1/2 and sporadic tumors. We found absence of nuclear expression and presence of cytoplasmic expression of RAD51 in BRCA2 tumors that differentiate them from other familial tumors. We validated these results with a new series of patient cases. The final study with 253 familial patient cases (74 BRCA1, 71 BRCA2, 108 non-BRCA1/2), and 288 sporadic patient cases, has allowed us to confirm our preliminary results. Because BRCA2 tumors present a specific immunohistochemical profile for RAD51 and CHEK2 markers that is different from non-BRCA1/2 tumors, we have built a multivariate model with these markers that distinguish both tumors with an estimated probability of at least 76%.
Our results suggest that BRCA2 tumors demonstrate more cytoplasmic and less nuclear RAD51 staining, and increased CHEK2 staining. This pattern may distinguish BRCA2 from familial non-BRCA1/2 tumors.
Journal of Clinical Oncology 11/2005; 23(30):7503-11. · 18.37 Impact Factor
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Laura Valle,
Alberto Cascón,
Lorenzo Melchor,
Ignacio Otero,
Sandra Rodríguez-Perales, Lydia Sánchez,
Juan Cruz Cigudosa,
Mercedes Robledo,
Barbara Weber,
Miguel Urioste,
Javier Benítez
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ABSTRACT: Conventional renal cell carcinoma (CRCC) may appear in families with germline translocations involving chromosome 3, although a recurrent responsible gene has not been found. We recently described a family with CRCC and a constitutional t(3;8)(p14.1;q24.23), and we demonstrated that no genes were disrupted by the translocation breakpoints. In order to investigate the genetic origin and features of the CRCC tumors that occurred in this family, we have extended the pedigree up to four generations, and analyzed peripheral blood samples from 36 members, CRCC tumors, normal renal tissues, and a gastric tumor. (1) By means of comparative genomic hybridization (CGH), we have detected loss of the derivative chromosome carrying 3p in all CRCC but not in the corresponding normal renal tissue. In addition, by means of the fluorescence in situ hybridization technique, we have observed that not all tumoral cells lose the der(3p), which suggests that, previous to this loss, another hit should occur to initiate the transformation of normal into tumoral cells. (2) All known mechanisms of inactivation of the candidate von Hippel-Lindau (VHL) gene have been studied in the tumors, detecting alterations in 65% of them. This confirms that inactivation of the VHL gene is not always required to develop CRCC, and that (an)other suppressor gene(s) on 3p could be involved. (3) We discard FHIT as an alternative pathway to VHL. We have not found new candidate regions along 3p by using a 1-Mb resolution array-based CGH. (4) The tumorigenesis mechanism of a second gastric tumor developed in the probandus is different from that of CRCC.
European Journal of HumanGenetics 06/2005; 13(5):570-8. · 4.40 Impact Factor
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ABSTRACT: Deoxynucleoside analogs are used in the treatment of a variety of solid tumors. Their transport across the plasma membrane may determine their cytotoxicity and thus nucleoside transporter (NT) expression patterns may be of clinical relevance. Lack of appropriate antibodies for use in paraffin-embedded biopsies has been a bottleneck to undertake high-throughput analysis of NT expression in solid tumors. Here we report the characterization of 2 new antibodies raised against the low-affinity equilibrative NTs, hENT1 and hENT2, suitable for that purpose. These 2 antisera, along with a previously characterized antibody that specifically recognizes the high-affinity Na-dependent concentrative NT, hCNT1, have been used to analyze, using a tissue array approach, NT expression in gynecologic cancers (90 ovarian, 80 endometrial and 118 uterine cervix carcinomas). Human CNT1 was not detected in 33% and 39% of the ovarian and uterine cervix carcinomas, respectively, whereas hENT1 and hENT2 expression was significantly retained in a high percentage of tumors (91% and 96% for hENT1, 84% and 98% for hENT2, in ovarian and cervix carcinomas, respectively). Only a few endometrial carcinomas (15%) were found to be negative for hCNT1, but they all retained hENT1 and hENT2 expression. In ovarian cancer, the loss of all 3 NT proteins was a more common event in the clear cell histologic subtype than in the serous, mucinous and endometrioid histotypes. In uterine cervix tumors, the loss of expression of hCNT1 was significantly associated with the adenocarcinoma subtype. In summary, hCNT1 was by far the isoform whose expression was most frequently reduced or lost in the 3 types of gynecologic tumors analyzed. Moreover, NT expression is related to the type of gynecologic tumor and its specific subtype, hCNT1 protein loss being highly correlated with poor prognosis histotypes. Since hCNT1, hENT1 and hENT2 recognize fluoropyrimidines as substrates, but with different affinities, this study anticipates high variability in drug uptake efficiency in solid tumors.
International Journal of Cancer 01/2005; 112(6):959-66. · 5.44 Impact Factor
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ABSTRACT: p18INK4c is a cyclin-dependent kinase (CDK) inhibitor that interferes with the Rb-kinase activity of CDK6/CDK4. Disruption of p18INK4c in mice impairs B-cell terminal differentiation and confers increased susceptibility to tumor development; however, alterations of p18INK4c in human tumors have rarely been described. We used a tissue-microarray approach to analyze p18INK4c expression in 316 Hodgkin lymphomas (HLs). Nearly half of the HL cases showed absence of p18INK4c protein expression by Reed-Sternberg (RS) cells, in contrast with the regular expression of p18INK4c in normal germinal center cells. To investigate the cause of p18INK4c repression in RS cells, the methylation status of the p18INK4c promoter was analyzed by methylation-specific polymerase chain reaction (PCR) and bisulfite sequencing. Hypermethylation of the p18INK4c promoter was detected in 2 of 4 HL-derived cell lines, but in none of 7 non-Hodgkin lymphoma (NHL)-derived cell lines. We also detected p18INK4c hypermethylation, associated with absence of protein expression, in 5 of 26 HL tumors. The correlation of p18INK4c immunostaining with the follow-up of the patients showed shorter overall survival in negative cases, independent of the International Prognostic Score. These findings suggest that p18INK4c may function as a tumor suppressor gene in HL, and its inactivation may contribute to the cell cycle deregulation and defective terminal differentiation characteristic of the RS cells.
Blood 04/2004; 103(6):2351-7. · 9.90 Impact Factor
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Soledad R Alonso,
Pablo Ortiz,
Marina Pollán,
Beatriz Pérez-Gómez, Lydia Sánchez,
Ma Jesús Acuña,
Raquel Pajares,
Francisco J Martínez-Tello,
Carlos M Hortelano,
Miguel A Piris,
José L Rodríguez-Peralto
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ABSTRACT: Cutaneous malignant melanoma remains the leading cause of skin cancer death in industrialized countries. Clinical and histological variables that predict survival, such as Breslow's index, tumor size, ulceration, or vascular invasion have been identified in malignant melanoma. Nevertheless, the potential relevance of biological variables still awaits an in-depth exploration. Using tissue microarrays (TMAs), we retrospectively analyzed 165 malignant melanoma samples from 88 patients corresponding to distinct histological progression phases, radial, vertical, and metastases. A panel of 39 different antibodies for cell cycle, apoptosis, melanoma antigens, transcription factors, DNA mismatch repair, and other proteins was used. Integrating the information, the study has identified expression profiles distinguishing specific melanoma progression stages. Most of the detected alterations were linked to the control of cell cycle G1/S transition; cyclin D1 was expressed in radial cases 48% (12 of 25) with significant lost of expression in vertical cases 14% (9 of 65), P = 0.002; whereas p16(INK4a) (89% in vertical versus 71% in metastatic cases, P = 0.009) and p27(KIP1) (76% in radial versus 45% in vertical cases, P = 0.010) were diminished in advanced stages. The study also defines a combination of biological markers associated with shorter overall survival in patients with vertical growth phase melanoma, that provided a predictor model with four antibodies (Ki67, p16(INK4a), p21(CIP1), and Bcl-6). This predictor model was validated using an independent series of 72 vertical growth phase melanoma patients.
American Journal Of Pathology 02/2004; 164(1):193-203. · 4.89 Impact Factor
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ABSTRACT: Alterations in the mismatch repair genes (hMLH1 and hMSH2) play an important role in the development of microsatellite instability in sporadic endometrial cancer. Tissue microarray technology allows molecular profiling of tumor samples at the DNA, RNA, and protein levels. We analyzed hMLH1 and hMSH2 expression by immunohistochemistry in a group of atypical endometrial hyperplasias (n = 10), endometrioid endometrial carcinomas (n = 58), and nonendometrioid endometrial carcinomas (n = 27) on tissue microarray. The results were correlated with microsatellite instability status as evaluated by BAT-25 and BAT-26. Overall, 29.4% of lesions showed microsatellite instability. Loss of nuclear hMLH1 and hMSH2 protein expression was seen in 22.3% and 6.5% of cases, respectively. Immunohistochemistry for hMLH1 and hMSH2 showed lack of protein expression in 64% and 16.6% of microsatellite instability-positive endometrial lesions, respectively. Taken together, hMLH1 or hMSH2 protein expression was absent in 18 of 24 microsatellite instability-positive cases (75% sensitivity). A high level of concordance was found between immunohistochemistry for hMLH1 and hMSH2 and microsatellite instability status evaluated by BAT-25 and BAT-26 (kappa value of 0.7). Of the 57 cases found to be microsatellite instability negative, 53 showed normal expression of both proteins (93% specificity). The observed predictive value of absence of expression of hMLH1 for predicting microsatellite instability-positive status was 82%. The predictive value of normal expression of both proteins for predicting microsatellite instability-negative status was 90%. These results are consistent with those previously reported in whole tissue sections. Therefore, immunohistochemical analysis of hMLH1 and hMSH2 expression on tissue microarray provides an accurate technique for screening for tumors with microsatellite instability. Tissue microarrays represent an ideal approach for comparing different diagnostic or predictive markers with one another in consecutive tissue microarray sections.
Modern Pathology 12/2003; 16(11):1148-58. · 4.79 Impact Factor
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José Palacios,
Emiliano Honrado,
Ana Osorio,
Alicia Cazorla,
David Sarrió,
Alicia Barroso,
Sandra Rodríguez,
Juan C Cigudosa,
Orland Diez,
Carmen Alonso,
Enrique Lerma, Lydia Sánchez,
Carmen Rivas,
Javier Benítez
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ABSTRACT: Most familial breast cancers are not associated with BRCA1 or BRCA2 germ-line mutations. Therefore, it is of major importance to define the morphological, immunohistochemical, and molecular features of this group of tumors to improve genetic testing and also gain further insight into the biological characteristics of tumors.
We evaluated the morphological characteristics of 37 tumors arising in women without BRCA1 or BRCA2 mutations, 20 tumors from BRCA1 mutation carriers, and 18 from BRCA2 mutation carriers, all of which were from index patients from breast cancer families. In addition, a tissue microarray was constructed with all tumoral samples to evaluate the immunohistochemical expression of a wide panel of antibodies (11 antibodies) and the amplification of HER-2 and c-MYC genes by fluorescence in situ hybridization. An age-matched group with 50 sporadic breast cancers as controls for non-BRCA1/2 was also included.
Non-BRCA1/2 infiltrating ductal carcinomas (IDCs) showed specific differences from BRCA1 tumors. They were of lower grade (1 and 2); more frequently estrogen receptor, progesterone receptor, BCL2 positive, and p53 negative; had a low proliferation rate (Ki-67 immunostaining < 5%); and did not express P-cadherin. With respect to BRCA2 IDCs and control group, non-BRCA1/2 tumors were of lower grade and had a lower proliferation rate. No cases of HER-2 amplification and/or overexpression were observed except in the control group ( approximately 20%). In contrast, c-MYC amplification was present in 18.2, 62.5, and 12.5% of BRCA1, BRCA2, and non-BRCA1/2 IDCs, respectively, and 31% in the control group.
This study thus reveals distinct morphological and immunohistochemical features in non-BRCA1/2 and BRCA1 tumors, whereas BRCA2 tumors present characteristics intermediate between the two phenotypes. In addition, the study also demonstrates the usefulness of tissue microarray technology in the evaluation of the immunophenotypic features of hereditary breast cancer.
Clinical Cancer Research 09/2003; 9(10 Pt 1):3606-14. · 7.74 Impact Factor
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Juan F García,
Francisca I Camacho,
Manuel Morente,
Máximo Fraga,
Carlos Montalbán,
Tomás Alvaro,
Carmen Bellas,
Angel Castaño,
Ana Díez,
Teresa Flores,
Carmen Martin,
Miguel A Martinez,
Francisco Mazorra,
Javier Menárguez,
Maria J Mestre,
Manuela Mollejo,
Ana I Sáez, Lydia Sánchez,
Miguel A Piris
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ABSTRACT: Tumoral cells in Hodgkin lymphoma (HL) display an increased growth fraction and diminished apoptosis, implying a profound disturbance of the cell cycle and apoptosis regulation. However, limitations of molecular techniques have prevented the analysis of the tumor suppressor pathways and cell-cycle checkpoints. Tissue microarray (TMA) is a powerful tool for analyzing a large number of molecular variables in a large series of tumors, although the feasibility of this technique has not yet been demonstrated in heterogeneous tumors. The expression of 29 genes regulating the cell cycle and apoptosis were analyzed by immunohistochemistry and in situ hybridization in 288 HL biopsies using TMA. The sensitivity of the technique was validated by comparing the results with those obtained in standard tissue sections. The results revealed multiple alterations in different pathways and checkpoints, including G1/S and G2/M transition and apoptosis. Striking findings were the overexpression of cyclin E, CDK2, CDK6, STAT3, Hdm2, Bcl2, Bcl-X(L), survivin, and NF-kappaB proteins. A multiparametric analysis identified proteins associated with increased growth fraction (Hdm2, p53, p21, Rb, cyclins A, B1, D3, and E, CDK2, CDK6, SKP2, Bcl-X(L), survivin, STAT1, and STAT3), and proteins associated with apoptosis (NF-kappaB, STAT1, and RB). The analysis also demonstrated that Epstein-Barr virus (EBV)-positive cases displayed a characteristic profile, confirming the pathogenic role of EBV in HL. Survival probability depends on multiple biologic factors, including overexpression of Bcl2, p53, Bax, Bcl-X(L), MIB1, and apoptotic index. In conclusion, Hodgkin and Reed-Sternberg cells harbor concurrent and overlapping alterations in the major tumor suppressor pathways and cell-cycle checkpoints. This appears to determine the viability of the tumoral cells and the clinical outcome.
Blood 02/2003; 101(2):681-9. · 9.90 Impact Factor
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Inmaculada C Navas,
Patrocinio Algara,
Marisol Mateo,
Pedro Martínez,
Carmen García,
Jose L Rodriguez,
Francisco Vanaclocha,
Nuria Barrientos,
Luis Iglesias, Lydia Sánchez,
Miguel A Piris,
Pablo Ortiz-Romero
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ABSTRACT: Knowledge about the molecular mechanisms involved in the pathogenesis of tumoral progression in mycosis fungoides (MF) is still scarce. Because the 9p21 locus seems to be a good target for a detailed study in MF, this prompted us to compare the mechanisms of inactivation of the p16(INK4a), p15(INK4b), and p14(ARF) genes in aggressive and stable forms of MF, performing microsatellite analysis, methylation-specific polymerase chain reaction, direct sequencing, and p16(INK4a) protein expression by immunohistochemistry. Additionally, the p53 gene was also sequenced in tumoral lesions. Thirty-nine patients with stable MF were studied. Alterations in p16(INK4a) and p15(INK4b) genes were detected in 18% and 5% of the cases, respectively. None of the cases analyzed showed alterations of the p14(ARF) gene. In contrast with these findings, in the 11 patients with aggressive MF, alterations of the p16(INK4a), p15(INK4b), or p14(ARF) genes were found in 8 (73%), 3 (27%), and 2 (18%) cases, respectively. A significant proportion (4/11) of these alterations were already present in the p16(INK4a) gene in the initial plaque lesions in these aggressive forms of MF. Alterations in the p16(INK4a) gene, either methylation or loss of heterozygosity, were clearly more frequent than those in the p15(INK4b) and p14(ARF) genes. These p16(INK4A) alterations were confirmed using immunohistochemistry. None of the nine tumoral lesions analyzed showed mutations in exons 1-2 of the p16(INK4a) gene or in exons 5-8 of the p53 gene. These results seem to suggest that 9p21 alterations, and selectively p16(INK4a) silencing, could be a characteristic phenomenon in MF progression.
Laboratory Investigation 03/2002; 82(2):123-32. · 3.64 Impact Factor
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ABSTRACT: The development of human cancers is frequently associated with the silencing of the two major tumor suppressor pathways represented by retinoblastoma protein and p53. As the incidence of p53 mutations is significantly lower in Hodgkin's lymphoma than in other neoplasias, we investigated whether the malfunction of other proteins in this pathway could be responsible for its inactivation. Because the existence of nucleolar complexes between p14(ARF) and Hdm2 has been described as having a critical effect on p53 function by inhibiting its degradation, we analyzed the expression and subcellular localization of these proteins in 52 cases and in Hodgkin's cell lines. Two of four cell lines revealed loss of p14(ARF) expression secondary to gene promoter methylation, this being mutually exclusive with p53 mutations (1 of 4), illustrating the existence of selective pressure to inactivate the p53 pathway. The majority of Hodgkin's samples showed a strong nucleolar expression of p14(ARF) that was not associated with Hdm2. They also showed the existence of Hdm2/p53 complexes, and the absence of complexes containing either p14(ARF)/Hdm2 or p14(ARF)/p53. The different localization of Hdm2 (nucleoplasm) and p14(ARF) (nucleoli) observed in Hodgkin's tumors and cell lines is associated with the presence of short alternatively spliced transcripts of Hdm2 lacking the ARF-binding region and the nuclear export signal. The absence of these p14(ARF)/Hdm2 nucleolar complexes could be sufficient to inactivate the pathway and may explain the low frequency of p53 mutations in this tumor.
American Journal Of Pathology 03/2002; 160(2):569-78. · 4.89 Impact Factor
