26 results on '"Knuutila S"'
Search Results
2. Monosomy of chromosome 17 in breast cancer during interpretation of HER2 gene amplification
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Brunelli, M., Nottegar, A., Bogina, G., Caliò, A., Cima, L., Eccher, A., Vicentini, C., Marcolini, L., Aldo Scarpa, Pedron, S., Brunello, E., Knuutila, S., Sapino, A., Marchiò, C., Bria, E., Molino, A., Carbognin, L., Tortora, G., Jasani, B., Miller, K., Merdol, I., Zanatta, L., Laurino, L., Wirtanen, T., Zamboni, G., Marconi, M., Chilosi, M., Manfrin, E., Martignoni, G., and Bonetti, F.
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false positive ,double probes ,Breast carcinoma ,aCGH method ,monosomy ,Original Article ,HER 2 amplification ,chromosome 17 ,FISH analysis ,ratio (HER2/CEP 17) ,single signals - Abstract
Monosomy of chromosome 17 may affect the assessment of HER2 amplification. Notably, the prevalence ranges from 1% up to 49% due to lack of consensus in recognition. We sought to investigate the impact of monosomy of chromosome 17 to interpretation of HER2 gene status. 201 breast carcinoma were reviewed for HER2 gene amplification and chromosome 17 status. FISH analysis was performed by using double probes (LSI/CEP). Absolute gene copy number was also scored per each probe. HER2 FISH test was repeated on serial tissue sections, ranging in thickness from 3 to 20 µm. Ratio was scored and subsequently corrected by monosomy after gold control test using the aCGH method to overcome false interpretation due to artefactual nuclear truncation. HER2 immunotests was performed on all cases. 26/201 cases were amplified (13%). Single signals per CEP17 were revealed in 7/201 (3.5%) cases. Five out of 7 cases appeared monosomic with aCGH (overall, 5/201, 2.5%) and evidenced single signals in >60% of nuclei after second-look on FISH when matching both techniques. Among 5, one case showed amplification with a pattern 7/1 (HER2/CEP17>2) of copies (3+ at immunotest); three cases revealed single signals per both probes (LSI/CEP=1) and one case revealed a 3:1 ratio; all last 4 cases showed 0/1+ immunoscore. We concluded that: 1) monosomy of chromosome 17 may be observed in 2.5% of breast carcinoma; 2) monosomy of chromosome 17 due to biological reasons rather than nuclear truncation was observed when using the cut-off of 60% of nuclei harboring single signals; 3) the skewing of the ratio due to single centromeric 17 probe may lead to false positive evaluation; 4) breast carcinomas showing a 3:1 ratio (HER2/CEP17) usually show negative 0/1+ immunoscore and
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- 2015
3. miRNA signature predicts survival of Ewing’s sarcoma patients and miR34a directly influences cell chemosensitivity and malignancy
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Nakatani F., Manara M. C., VENTURA, SELENA, del Monaco V., Ferrari S., Alberghini M., Grilli A., Knuutila S., Schaefer K. L., Mattia G., Negrini M., Picci P., Serra M., Scotlandi K., FERRACIN, MANUELA, Nakatani F., Ferracin M., Manara M.C., Ventura S., del Monaco V., Ferrari S., Alberghini M., Grilli A., Knuutila S., Schaefer K.L., Mattia G., Negrini M., Picci P., Serra M., and Scotlandi K.
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p53 ,Prognostic biomarkers ,Ewing's sarcoma ,miR-34a ,miRNA - Abstract
Identification of factors to detect chemotherapy-resistant tumours at diagnosis is a first priority for risk-adapted therapy in children and young adults oncology where more individualized, effective and less toxic treatments are highly desirable. In this study, we analyzed the miRNAs discriminating Ewing's sarcoma (EWS) patients with different clinical outcome in order to identify new indicators of prognosis. miRNA expression was investigated in 49 primary EWS by using the Agilent Human miRNA microarray v.2 and/or qRT-PCR. Statistical power of samples studied for miRNA expression was verified, indicating adequate sample size. Microarray analysis defined a signature of 5 miRNAs (miR-34a, miR-23a, miR-92a, miR-490-3p, and miR-130b) as an independent predictor of risk to disease progression and survival. Validation analysis in the extended samples set indicated that both miR-34a and miR490-3p achieved sufficient statistical power to predict prognosis. Results were particularly robust for miR-34a, which appeared associated to either event-free or overall survival and emerged as significant predictor also after multivariate analysis. Patients with the highest expression of miR-34a did not experience adverse events in 5 years; in contrast, patients with the lowest expression recurred within two years. High expression of miR34a can be detected also in paraffin-embedded tissues by in situ hybridization, thus contributing to an easy routinely evaluation of this miRNA. Functional analysis of miR-34a in EWS cell lines indicated that when miR-34a expression was enforced cells were less proliferative, less malignant and sensitized to doxorubicin and vincristine. Expression of miR-34a could be increased in p53wt cells by treatment with Nutlin-3a. Accordingly, Nutlin-3a synergizes with doxorubicin. Overall, our data indicate that miR-34a expression is a strong predictor of outcome in EWS. Restoration of miR-34a activity may be useful to decrease malignancy and increase tumour sensitivity to current drugs, so sparing excessive long-term toxicity to EWS patients.
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- 2012
4. Copy Number Alterations and Neoplasia-Specific Mutations in MELK, PDCD1LG2, TLN1, and PAX5 at 9p in Different Neoplasias
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Sarhadi, V.K., Lahti, L.M., Scheinin, I., Ellonen, P., Kettunen, E., Serra, M., Scotlandi, K., Picci, P., Knuutila, S., Pathology, and CCA - Disease profiling
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Microbiologie ,expression ,comparative genomic hybridization ,identification ,aquaporin 1 ,array cgh ,lung-cancer cells ,wide association ,acute lymphoblastic-leukemia ,Microbiology ,breast-cancer ,susceptibility loci - Abstract
Genetic alterations affecting 9p are commonly present in many cancer types and many cancer-related genes are located in this chromosomal region. We sequenced all of the genes located in a 32Mb region of 9p by targeted next generation sequencing (NGS) in 96 patients with different cancer types, including acute lymphoblastic leukemia, bone malignant fibrous histiocytoma/undifferentiated pleomorphic sarcoma, fibrosarcoma, Ewing's sarcoma, and lung carcinoma. Copy number alterations (CNA), and mutations were studied from the NGS data. We detected a deletion at the CDKN2A locus as being the most frequent genetic alteration in all cancer types. In addition to this locus, NGS also identified other small regions of copy number loss and gain. However, different cancer types did not reveal any statistically significant differences with regard to CNA frequency or type. Of the 191 genes within the target region, two novel recurrent mutations were found in the MELK and PDCD1LG2 genes. The most commonly mutated gene in sarcomas was TLN1 (8%) and PAX5 in ALL (9%). Mutations in PAX5, and RUSC2, were seen exclusively in ALL patients and those in KIAA1432, CA9, TLN1, and MELK only in sarcomas (MFH, FS, EFT). Thus using targeted NGS of the 9p region, in addition to commonly deleted CDKN2A locus, we were able to identify a number of small deletions and gains, as well as novel recurrent mutations in different cancer types. (c) 2014 Wiley Periodicals, Inc.
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- 2014
- Full Text
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5. Integrated gene copy number and expression microarray analysis of gastric cancer highlights potential target genes
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Myllykangas S., Junnila S., Kokkola A., Autio R., Scheinin I., Kiviluoto T., Karjalainen-Lindsberg M.-L., Hollmen J., Knuutila S., and Puolakkainen P.
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- 2008
- Full Text
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6. Expression of ZAP-70, RAF-1 and C-MYC in B-cell lymphomas and chronic leukaemia. Overexpression of ZAP70 predicts poor survival in mantle cell lymphoma
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Nagy, B, Galimberti, Sara, Vilpo, J., Elonen, E., Franssila, K., and Knuutila, S.
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- 2007
7. DNA copy number amplifications in human neoplasms: review of comparative genomic hybridization studies
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Knuutila, S., Björkqvist, A. M., Autio, K., Tarkkanen, M., Wolf, M., Monni, O., Szymanska, J., Larramendy, M. L., Tapper, J., Pere, H., El-Rifai, W., Hemmer, S., Wasenius, V. M., Vidgren, V., and Zhu, Y.
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Research Article - Abstract
This review summarizes reports of recurrent DNA sequence copy number amplifications in human neoplasms detected by comparative genomic hybridization. Some of the chromosomal areas with recurrent DNA copy number amplifications (amplicons) of 1p22-p31, 1p32-p36, 1q, 2p13-p16, 2p23-p25, 2q31-q33, 3q, 5p, 6p12-pter, 7p12-p13, 7q11.2, 7q21-q22, 8p11-p12, 8q, 11q13-q14, 12p, 12q13-q21, 13q14, 13q22-qter, 14q13-q21, 15q24-qter, 17p11.2-p12, 17q12-q21, 17q22-qter, 18q, 19p13.2-pter, 19cen-q13.3, 20p11.2-p12, 20q, Xp11.2-p21, and Xp11-q13 and genes therein are presented in more detail. The paper with more than 150 references and two tables can be accessed from our web site http://www.helsinki.fi/lglvwww/CMG.html. The data will be updated biannually until the year 2001.
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- 1998
8. Prognostic value of metaphase-fluorescence in situ hybridization in follow-up of patients with acute myeloid leukemia in remission
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El-Rifai W, Ruutu T, Elonen E, Liisa Volin, and Knuutila S
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Adult ,Chromosome Aberrations ,Male ,Antineoplastic Agents ,Middle Aged ,Prognosis ,Disease-Free Survival ,Translocation, Genetic ,Leukemia, Myeloid, Acute ,Bone Marrow ,Karyotyping ,Chromosomes, Human ,Humans ,Female ,Chromosome Deletion ,In Situ Hybridization, Fluorescence ,Metaphase ,Aged ,Bone Marrow Transplantation ,Follow-Up Studies - Abstract
The presence of residual leukemic cells was studied using metaphase-fluorescence in situ hybridization (FISH) in 22 patients with acute myeloid leukemia treated with chemotherapy only or chemotherapy followed by allogeneic bone marrow transplantation. The patients were followed up during their complete remission (CR) for 4 to 108 months (median, 21 months). A total of 88 BM samples was studied. In most of the samples more than 1,000 metaphase cells were analyzed. Residual leukemic cells were detected in 9 of 22 patients (41%). All patients who had an increasing and/or persisting level of abnormal cells in two or more subsequent samples or whose initial samples contained more than 1% of abnormal cells relapsed with one exception, in whom the later subsequent samples showed disappearance of abnormal cells. The time span before the first positive sample seems to be insignificant with regard to the outcome of relapse. Absence or single occurrence of abnormal cells followed by their disappearance was in agreement with CR in all the cases (16 patients). Our results indicate that metaphase-FISH is a reliable tool in the quantitation of residual leukemic cells and provides valuable prognostic information for patients with AML.
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- 1997
9. MAC technique (morphology antibody chromosomes) in phenotypic identification of proliferating NK and T cells in interleukin-2-stimulated lymphocyte cultures
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Kovanen, P E, Timonen, T, Seppälä, I, and Knuutila, S
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Immunoenzyme Techniques ,Killer Cells, Natural ,T-Lymphocytes ,Humans ,Interleukin-2 ,Mitosis ,Lymphocyte Activation ,Cells, Cultured ,Research Article - Abstract
Human peripheral blood lymphocytes were activated with recombinant interleukin 2 (rIL-2) and cultured in fetal calf serum (FCS)- or human-AB-serum-supplemented media. Proliferative cells were identified by the MAC technique (morphology antibody chromosomes) which enables the immunoenzymatic identification of both mitotic and non-proliferating cells in unfractionated lymphocyte populations. The results indicate that the phenotype of more than 90% of proliferative lymphocytes can be characterized by using antibodies against T cells and NK cells. Substantial mitotic activity of CD4-positive (CD4+) T cells was observed only in FCS-supplemented cultures, whereas in serum-free or human-AB-serum-supplemented cultures mostly CD8+ T cells and NK cells proliferated. The proportion of NK cells among all mitotic cells varied between 14 and 32%. Interestingly, in unfractionated cultures approximately 13% NK cells entered mitoses in the presence of rIL-2, suggesting that the poor proliferative capacity of purified NK cells demonstrated previously may be due to the lack of accessory stimulatory signals. The proliferation of B cells was minimal in all experiments. The MAC technique is a useful addition to the techniques by which lymphocyte growth regulation is monitored.
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- 1989
10. In situ hybridization using a Y-specific probe--a sensitive method for distinguishing residual male recipient cells from female donor cells in bone marrow transplantation
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Wessman M, Ruutu T, Liisa Volin, and Knuutila S
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Adult ,Male ,Adolescent ,Bone Marrow ,Karyotyping ,Y Chromosome ,Humans ,Nucleic Acid Hybridization ,Bone Marrow Cells ,Female ,DNA Probes ,Tissue Donors ,Bone Marrow Transplantation - Abstract
A non-radioactive in situ hybridization method was used to detect residual host cells after bone marrow transplantation (BMT). A biotinylated Y-specific DNA probe was hybridized to bone marrow cells of three male patients who had received a bone marrow graft from their sisters for the treatment of acute leukaemia. Host cells were detected in two of the three patients, both in clinical remission, in six and seven cells out of 1000 cells analysed, respectively. Only one of a total of 3000 cells from three female controls showed a 'Y-signal'; 2580 cells out of a total of 3000 cells from three male controls showed a positive signal. These results indicate that in situ hybridization is a reliable and sensitive method for the detection of host cells after BMT.
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- 1989
11. t(1;3)(p36;q21) in acute nonlymphocytic leukemia: a new cytogenetic-clinicopathologic association
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Cd, Bloomfield, Om, Garson, Liisa Volin, Knuutila S, and de la Chapelle A
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Adult ,Cell Nucleus ,Male ,Leukemia ,Chromosomes, Human, 1-3 ,Erythrocytes, Abnormal ,Anemia ,Middle Aged ,Translocation, Genetic ,Chromosome Banding ,Karyotyping ,Acute Disease ,Humans ,Female ,Megakaryocytes - Abstract
A number of specific chromosomal abnormalities have been associated with distinctive clinical and/or morphological subtypes of acute nonlymphocytic leukemia (ANLL) in recent years. We have studied three patients with ANLL and t(1;3)(p36;q21). Each had weakness as their major complaint, a moderately severe anemia and, for ANLL, a relatively high platelet count. All three demonstrated abnormalities of the megakaryocytic, erythroid and granulocytic lineages. Most striking was the dysmegakaryocytopoiesis. The blasts in all three patients showed relatively few azurophilic granules, one to four prominent nucleoli, and rare peroxidase positivity. No patient had Auer rods. No patient responded to standard chemotherapy regimens. The data suggest that t(1;3)(p36;q21) identifies a new cytogenetic-clinicopathologic subtype of ANLL.
12. ACUTE MYELOGENOUS LEUKEMIA WITH C-MYC AMPLIFICATION AND DOUBLE MINUTE CHROMOSOMES
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Kari Alitalo, Winqvist, R., Keskioja, J., Ilvonen, M., Saksela, K., Alitalo, R., Laiho, M., Knuutila, S., and Delachapelle, A.
13. Loss of 10p14-pter and gains of 8q24 and 15q25-qter in pancreatic adenocarcinoma observed by comparative genomic hybridization
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Knuutila, S., Lluís, F., Capellà, G., CABALLIN MARIA ROSA, and Gemma Armengol
14. Monocytic involvement by monosomy 7 preceded acute myelomonocytic leukemia in a patient with myelodysplastic syndrome
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Juha Kere, Knuutila S, Ruutu T, Leskinen R, and de la Chapelle A
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Anemia, Refractory, with Excess of Blasts ,Erythrocytes ,Monosomy ,Myelodysplastic Syndromes ,Leukemia, Monocytic, Acute ,Biomarkers, Tumor ,Humans ,Female ,Chromosome Deletion ,Middle Aged ,Chromosomes, Human, Pair 7 ,Monocytes - Abstract
Novel techniques were used to detect which cell lineages were affected by monosomy 7 in a patient who had myelodysplastic syndrome and later developed acute leukemia. The patient had had paroxysmal nocturnal hemoglobinuria for 20 years before developing refractory anemia with excess of blasts. Cytogenetic analysis at the myelodysplastic stage disclosed monosomy 7 in bone marrow mitoses. Restriction fragment length polymorphism analysis of fractionated white blood cells with the chromosome 7-specific probes MetH and MetD revealed that blood monocytes and most bone marrow erythroblasts but not blood granulocytes or lymphocytes were affected by monosomy 7. The patient later developed acute myelomonocytic leukemia with blast cells positive for markers of the myelomonocytic lineage but negative for granulocytic markers in a standard surface marker analysis. The leukemic blast cells had monosomy 7 as determined by direct cytogenetic investigation. Thus, the monocytes were found to be affected by monosomy 7 in this patient 8 months before her myelodysplastic syndrome progressed to acute myelomonocytic leukemia, and the affected cells had the same biologic markers at both stages of the disease.
15. Comparative genomic hybridization of malignant fibrous histiocytoma reveals a novel prognostic marker
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Larramendy, M. L., Tarkkanen, M., Carl Blomqvist, Virolainen, M., Wiklund, T., Asko-Seljavaara, S., Elomaa, I., and Knuutila, S.
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Adult ,Aged, 80 and over ,Chromosome Aberrations ,Male ,Histiocytoma, Benign Fibrous ,Gene Amplification ,Chromosome Mapping ,Nucleic Acid Hybridization ,Soft Tissue Neoplasms ,DNA, Neoplasm ,Middle Aged ,Prognosis ,Survival Analysis ,Biomarkers, Tumor ,Humans ,Female ,In Situ Hybridization, Fluorescence ,Research Article ,Aged - Abstract
DNA sequence copy number changes were studied by comparative genomic hybridization (CGH) along all chromosomes in 58 samples of malignant fibrous histiocytoma (MFH). The material consisted of 43 primary tumors (9 of myxoid and 34 of storiform-pleomorphic subtype), 13 local recurrences (2 myxoid and 11 storiform-pleomorphic), and 2 metastases (1 myxoid and 1 storiform-pleomorphic). Genetic aberrations, with a mean of 5.5 changes per sample (range, 0 to 22), were detected in 47 of 58 samples (81%). The minimal common regions of the most frequent gains were 1p31 (33%), 9q31 (29%), 5p14-pter (26%), 7q32 (24%), and 7p15-pter (22%). High-level amplifications were detected in 16 of the 58 samples (28%). High-level amplification of 13q31-qter was seen in four tumors (7%); other high-level amplifications were more sporadic. Losses of DNA sequences were less frequent than gains. The minimal common regions of the most common losses were 13q21 (21%) and 13q22 (21%). Statistically significant correlation was found between gain of 7q32 and the rates of worse metastasis-free survival (P = 0.01) and overall survival (P = 0.004). The gain of 7q32 retained its prognostic significance also in a multivariate analysis with tumor size and grade. Gain of 1p31 was associated with a trend to decreased overall survival. Gains of 5p14-pter and 9q31 and losses of 13q21 and/or 13q22 did not have any prognostic value; neither did the total number of aberrations, total number of gains, or total number of losses per sample.
16. Few FH mutations in sporadic counterparts of tumor types observed in hereditary leiomyomatosis and renal cell cancer families
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Kiuru M, Lehtonen R, Arola J, Salovaara R, Järvinen H, Aittomäki K, Sjöberg J, Tapio Visakorpi, Knuutila S, Isola J, Delahunt B, Herva R, Launonen V, and La, Aaltonen
17. Expression Analysis of Previously Verified Fecal and Plasma Dow-regulated MicroRNAs (miR-4478, 1295-3p, 142-3p and 26a-5p), in FFPE Tissue Samples of CRC Patients
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Ghanbari, R., Rezasoltani, S., Javad Hashemi, Mohamadkhani, A., Tahmasebifar, A., Arefian, E., Mobarra, N., Asadi, J., Nazemalhosseini Mojarad, E., Yazdani, Y., Knuutila, S., and Malekzadeh, R.
18. Detection of residual host cells after bone marrow transplantation using non-isotopic in situ hybridization and karyotype analysis
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Wessman M, Popp S, Ruutu T, Liisa Volin, Cremer T, and Knuutila S
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Adult ,Male ,Leukemia ,Adolescent ,Cell Survival ,Chimera ,Bone Marrow Purging ,Graft Survival ,Remission Induction ,Middle Aged ,Nuclear Family ,Treatment Outcome ,Bone Marrow ,Karyotyping ,Y Chromosome ,Humans ,Transplantation, Homologous ,Female ,Biomarkers ,In Situ Hybridization ,Bone Marrow Transplantation - Abstract
Karyotype analysis and interphase cytogenetics by means of non-radioactive in situ hybridization (NISH) with Y and X-specific probes were used to detect residual host cells in BM of 18 male patients who had received a BMT from their sisters. All patients but one had a malignant blood disease; 17 patients were clinically in continuous remission at the time of the investigations and throughout the follow-up period. No host cells were detected by karyotype analysis in patients who were in clinical remission. NISH with a biotinylated Y-specific probe showed residual host cells in 16 of the 17 patients in clinical remission. In samples from three patients the existence of host cells was further confirmed by revealing the XY-containing cells with two-color fluorescence in situ hybridization (FISH) using X- and Y-specific probes on direct BM smears showed3% residual host cells in 50% of the samples studied at or later than 2 months post-BMT. On conventional cytogenetic preparations1% Y-specific cells were detected in all but two samples ator = 2 months post-BMT. There was no difference in the proportion of host cells between patients conditioned with total body irradiation and CY and those who received busulphan and CY. The recipient's stromal or epithelial cells in the aspirates probably account for most of the host cells detected. In conclusion, small numbers of residual host cells detected by interphase cytogenetics with a Y-specific probe do not indicate an imminent relapse.(ABSTRACT TRUNCATED AT 250 WORDS)
19. 35th Annual Meeting of the European Association for the Study of Diabetes : Brussels, Belgium, 28 September-2 October 1999
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Melander, A., Olsson, J., Lindberg, G., Salzman, A., Howard, T., Stang, P., Lydick, E., Emslie-Smith, A., Boyle, D. I. R., Evans, J. M. M., Macdonald, T. M., Bain, J., Sullivan, F., Ad Darts Memo, Morris For The Collaboration, Juhl, C., Porksen, N., Sturis, J., Hollingdal, M., Pincus, S., Veldhuis, J., Dejgaard, A., Schmitz, O., Kristensen, J. S., Frandsen, K. B., Bayer, Th, Muller, P., Dunning, B. E., Paladini, S., Gutierrez, C., Deacon, R., Valentin, M., Grunberger, G., Weston, W. M., Patwardhan, R., Rappaport, E. B., Sargeant, L. A., Wareham, N. J., Khaw, K. T., Zethelius, Bjorn, Lithell, Hans, Hales, C. Nicholas, Berne, Christian, Lakka, H-M, Oksanen, L., Tuomainen, T-P, Kontula, K., Salonen, J. T., Dekker, J. M., Boks, P., Vegt, F., Stehouwer, C. D. A., Nijpels, G., Bouter, L. M., Heine, R. J., Bruno, G., Cavallo-Perin, P., Bargero, G., D Errico, N., Borra, M., Macchia, G., Pagano, G., Newton, R. W., Ruta, D. A., New, J. P., Wallace, C., Roxburgh, M. A., Young, R. J., Vaughan, N. J. A., Elliott, P., Brennan, G., Devers, M., Macalpine, R., Steinke, D., Lawson, D. H., Decallonne, B., Casteels, K., Gysemans, C., Bouillon, R., Mathieu, C., Linn, Thomas, Strate, Christine, Schneider, Kerstin, Funda, D. P., Jirsa, M. Jr, Kozakova, H., Kaas, A., Kofronova, O., Tlaskalova-Hogenova, H., Buschard, K., Wanka, H., Hartmann, A., Kuttler, B., Rasmussen, S. B., Sorensen, T. S., Markholst, H., Petersen, J. S., Karounos, D., Dyrberg, T., Mabley, J. G., Hasko, G., Szabo, C., Seissler, J., Nguyen, T. B. T., Steinbrenner, H., Scherbaum, W. A., Cipriani, R., Gabriele, A., Sensi, M., Guidobaldi, L., Pantellini, F., Cerrito, M. G., Scarpa, S., Di Mario, U., Morano, S., Ceolotto, G., Iori, E., Baritono, E., Del Prato, S., Semplicini, A., Trevisan, R., Zerbini, G., Meregalli, G., Asnaghi, V., Tentori, F., Maestroni, A., Mangili, R., Marescotti, C., Vedovato, M., Tiengo, A., Tadjieva, J., Mankovsky, B. N., Aken, S., Raes, A., Vande Walle, J., Matthys, D., Craen, M., Hansen, H. P., Lund, S. S., Rossing, P., Jensen, T., Parving, H-H, Genediab, Study Group, Andersen, S., Tarnow, L., Hansen, B. V., Trautner, C., Haastert, B., Ennenbach, N., Willich, S., Tabak, A. Gy, Orchard, T. J., Spranger, J., Preissner, K. T., Schatz, H., Pfeiffer, A., Canton, A., Burgos, R., Hernandez, C., Lecube, A., Mesa, J., Segura, R. M., Mateo, C., Simo, R., Fathallah, L., Greene, D. A., Obrosova, I., Gilbert, R. E., Kelly, D. J., Cox, A. J., Berka-Wilkinson, J. L., Taylor, H. R., Panagiotopoulos, S., Lee, V., Jerums, G., Cooper, M. E., Hitman, G. A., Aganna, E., Ogunkolade, W. B., Rema, M., Deepa, R., Shanthi-Rani, C. S., Barakat, K., Kumarajeewa, T. R., Cassell, P. G., Mcdermott, M. F., Mohan, V., Ways, K., Bursell, S., Devries, T., Woodworth, J., Alatorre, C., King, G., Aiello, L. P., Karisen, A. E., Pavlovic, D., Nielsen, K., Jensen, J., Andersen, H. U., Pociot, F., Mandrup-Poulsen, T., Eizirik, D. L., Nerup, J., Lortz, S., Tiedge, M., Lenzen, S., Lally, F. J., Bone, A. J., Darville, M. I., Ho, Y-S, Sternesjo, J., Sandler, S., Chen, M-C, Schuit, F., Pipeleers, D. G., Merezak, S., Hardikar, A., Hoet, J. J., Remacle, C., Reusens, B., Breant, B., Garofano, A., Czernichow, P., Kubota, N., Terauchi, Y., Miki, H., Tamemoto, H., Yamauchi, T., Nakano, R., Komeda, K., Eto, K., Tobe, K., Kimura, S., Kadowaki, T., Ide, T., Murakami, K., Tsunoda, M., Mochizuki, T., Ozanne, S. E., Nave, B. T., Wang, C. L., Dorling, M. W., Petry, C. J., Koopmans, S. J., Bent, C., Que, I., Radder, J. K., Sebokova, E., Sana, A. K., Klimes, I., Ruderman, N., Morviducci, L., Pastore, L., Morelli, S., Sagratella, E., Zorretta, D., Buongiomo, A., Tamburrano, G., Giaccari, A., Martinenghi, Sabina, Angelis, Gabriella Cusella, Ravasi, Flavio, Bifari, Francesco, Bordignon, Claudio, Falqui, Luca, Kessler, A., Dransfeld, O., Sasson, S., Tomas, E., Zorzano, A., Eckel, J., Thorsby, P., Rosenfalck, A. M., Kjems, L., Hanssen, K. F., Madsbad, S., Birkeland, K. I., Hamilton-Wessler, M., Markussen, J., Bergman, R. N., Melki, V., Hanaire-Broutin, H., Bessieres-Lacombe, S., Gedec, Study Group, Tauber, J-P, Home, P. D., Lindholm, A., Riis, A., European Insulin Aspart Study Group, Rosenstock, J., Schwartz, S., Clark, C., Edwards, M., Donley, D., Us Dm, Study Group Of Insulin Glargine In Type, Swift, P., Mortensen, H. B., Lynggaard, H., Hougaard, P., Hvidore Study group on Childhood Diabetes, Cull, C. A., Neil, H. A. W., Frighi, V., Manley, S. E., Holman, R. R., Turner, R. C., Ukpds, Group, Steiner, G., Dais, Project Group, Davis, W. A., Weeraratna, T., Bruce, D. G., Davis, T. M. E., Verges, B., Duvillard, L., Pont, F., Florentin, E., Gambert, Ph, Benko, B., Ljubic, S., Turk, Z., Granic, M., Marz, W., Wollschlager, H., Klein, G., Neiss, A., Wehling, M., Huxtable, S. J., Saker, P. J., Walker, M., Frayling, T. M., Levy, J. C., O Rahilly, S., Hattersley, A. T., Mccarthy, M. 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20. Genetic changes in inherited and sporadic ovarian carcinomas by comparative genomic hybridization: extensive similarity except for a difference at chromosome 2q24-q32
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Tapper J, Sarantaus L, Vahteristo P, Heli Nevanlinna, Hemmer S, Seppälä M, Knuutila S, and Butzow R
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Adult ,Ovarian Neoplasms ,Adolescent ,Genes, BRCA1 ,Nucleic Acid Hybridization ,DNA, Neoplasm ,Middle Aged ,Chromosomes, Human, Pair 2 ,Karyotyping ,Humans ,Point Mutation ,Female ,Genes, Tumor Suppressor ,Aged - Abstract
Germ-line mutations in the BRCA1 and BRCA2 genes confer a predisposition to breast as well as ovarian carcinoma. Except for loss of the respective wild-type allele, somatic genetic changes needed for the progression of inherited ovarian tumors are unknown. A genome-wide search for such alterations was performed by comparative genomic hybridization analysis on BRCA1 and BRCA2 mutation-positive (n = 20) ovarian carcinoma specimens. Comparison with sporadic ovarian carcinomas (n = 20) revealed extensive genetic similarity between the inherited and sporadic carcinomas with the sole exception of a frequent gain of 2q24-q32 in the inherited group, suggesting the presence of an oncogene at 2q24-q32 operating in the absence of BRCA1 function. The overall similarity of gains and losses by comparative genomic hybridization suggests a common main pathway in tumor progression of both inherited and sporadic ovarian carcinomas.
21. Monosomy of chromosome 17 in breast cancer during interpretation of HER2 gene amplification
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Brunelli M, Nottegar A, Bogina G, Caliò A, Cima L, Eccher A, Vicentini C, Marcolini L, Scarpa A, Pedron S, Brunello E, Knuutila S, Sapino A, Marchiò C, Bria E, Molino A, Luisa Carbognin, Tortora G, Jasani B, and Miller K
22. Reprofiling Metastatic Samples for Chromosome 9p and 14q Aberrations as a Strategy to Overcome Tumor Heterogeneity in Clear-cell Renal Cell Carcinoma
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Massari F, Ciccarese C, Bria E, Porta C, La Russa F, Knuutila S, Artibani W, Antonio Porcaro, Bimbatti D, Modena A, Sava T, Tortora G, Cheng L, Eccher A, Cima L, Pedron S, Ghimenton C, Martignoni G, and Brunelli M
23. Preeclampsia does not share common risk alleles in 9p21 with coronary artery disease and type 2 diabetes
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Kaartokallio T, Ai, Lokki, Peterson H, Kivinen K, Hiltunen L, Salmela E, Lappalainen T, Maanselkä P, Heino S, Knuutila S, Sayed A, Poston L, Shaun Brennecke, Mp, Johnson, Morgan L, Ek, Moses, Kere J, and Laivuori H
24. Wide spetcrum mutational analysis of metastatic renal cell cancer: a retrospective next generation sequencing approach
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Annalisa Altimari, Riccardo Schiavina, Sarhadi Virinder, Andrea Ardizzoni, Chiara Ciccarese, Davide Bimbatti, Matteo Brunelli, Sakari Knuutila, Michelangelo Fiorentino, Aldo Scarpa, Camillo Porta, Francesca Giunchi, Elisa Gruppioni, Francesco Massari, Guido Martignoni, Roberto Iacovelli, Giampaolo Tortora, Walter Artibani, Fiorentino, M, Gruppioni, E, Massari, F, Giunchi, F, Altimari, A, Ciccarese, C, Bimbatti, D, Scarpa, A, Iacovelli, R, Porta, C, Virinder, S, Tortora, G, Artibani, W, Schiavina, R, Ardizzoni, A, Brunelli, M, Knuutila, S, Martignoni, G, Medicum, and Department of Pathology
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Male ,0301 basic medicine ,Oncology ,Pathology ,DNA Mutational Analysis ,Wide spetcrum mutational analysis of metastatic renal cell cancer: a retrospective next generation sequencing approach ,TARGETED THERAPY ,0302 clinical medicine ,CDKN2A ,Renal cell carcinoma ,Medicine ,Precision Medicine ,next generation sequencing ,Molecular pathology ,Sunitinib ,High-Throughput Nucleotide Sequencing ,Middle Aged ,Kidney Neoplasms ,Temsirolimus ,3. Good health ,Phenotype ,Treatment Outcome ,Italy ,030220 oncology & carcinogenesis ,Pathology Section ,VHL ,metastatic disease ,renal cell carcinoma ,target therapy ,Female ,medicine.drug ,Adult ,Sorafenib ,medicine.medical_specialty ,CARCINOMA ,3122 Cancers ,Antineoplastic Agents ,03 medical and health sciences ,Predictive Value of Tests ,Internal medicine ,Biomarkers, Tumor ,Humans ,Genetic Predisposition to Disease ,Carcinoma, Renal Cell ,Protein Kinase Inhibitors ,Aged ,Retrospective Studies ,business.industry ,Patient Selection ,Cancer ,Precision medicine ,medicine.disease ,Research Paper: Pathology ,030104 developmental biology ,Mutation ,3111 Biomedicine ,business - Abstract
// Michelangelo Fiorentino 1 , Elisa Gruppioni 1 , Francesco Massari 2 , Francesca Giunchi 1 , Annalisa Altimari 1 , Chiara Ciccarese 7 , Davide Bimbatti 6 , Aldo Scarpa 8 , Roberto Iacovelli 7 , Camillo Porta 9 , Sarhadi Virinder 4 , Giampaolo Tortora 7 , Walter Artibani 6 , Riccardo Schiavina 3 , Andrea Ardizzoni 2 , Matteo Brunelli 5 , Sakari Knuutila 4,* and Guido Martignoni 5,* 1 Laboratory of Oncologic Molecular Pathology, S.Orsola-Malpighi Hospital, Bologna, Italy 2 Department of Medical Oncology, S.Orsola-Malpighi Hospital, Bologna, Italy 3 Department of Urology, S.Orsola-Malpighi Hospital, Bologna, Italy 4 Department of Pathology, University of Helsinki, Faculty of Medicine, Helsinki, Finland 5 Department of Pathology, Diagnostics and Public Health University of Verona, Verona, Italy 6 Department of Urology, Diagnostics and Public Health University of Verona, Verona, Italy 7 Department of Medical Oncology, Diagnostics and Public Health University of Verona, Verona, Italy 8 Diagnostics and Public Health University of Verona, Verona, Italy 9 Department of Medical Oncology, University of Pavia, Pavia, Italy * These authors co-shared senior authorship Correspondence to: Michelangelo Fiorentino, email: // Keywords : renal cell carcinoma, next generation sequencing, target therapy, metastatic disease, VHL, Pathology Section Received : July 06, 2016 Accepted : September 21, 2016 Published : October 10, 2016 Abstract Renal cell cancer (RCC) is characterized by histological and molecular heterogeneity that may account for variable response to targeted therapies. We evaluated retrospectively with a next generation sequencing (NGS) approach using a pre-designed cancer panel the mutation burden of 32 lesions from 22 metastatic RCC patients treated with at least one tyrosine kinase or mTOR inhibitor. We identified mutations in the VHL, PTEN, JAK3, MET, ERBB4, APC, CDKN2A, FGFR3, EGFR, RB1, TP53 genes. Somatic alterations were correlated with response to therapy. Most mutations hit VHL1 (31,8%) followed by PTEN (13,6%), JAK3, FGFR and TP53 (9% each). Eight (36%) patients were wild-type at least for the genes included in the panel. A genotype concordance between primary RCC and its secondary lesion was found in 3/6 cases. Patients were treated with Sorafenib, Sunitinib and Temsirolimus with partial responses in 4 (18,2%) and disease stabilization in 7 (31,8%). Among the 4 partial responders, 1 (25%) was wild-type and 3 (75%) harbored different VHL1 variants. Among the 7 patients with disease stabilization 2 (29%) were wild-type, 2 (29%) PTEN mutated, and single patients (14% each) displayed mutations in VHL1, JAK3 and APC/CDKN2A . Among the 11 non-responders 7 (64%) were wild-type, 2 (18%) were p53 mutated and 2 (18%) VHL1 mutated. No significant associations were found among RCC histotype, mutation variants and response to therapies. In the absence of predictive biomarkers for metastatic RCC treatment, a NGS approach may address single patients to basket clinical trials according to actionable molecular specific alterations.
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- 2017
25. Overcoming resistance to conventional drugs in Ewing sarcoma and identification of molecular predictors of outcome
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Massimo Serra, Mirko Francesconi, Daniel Remondini, Gastone Castellani, Anna Maria Caccuri, Maria Cristina Manara, Lara Cantiani, Filippo Nardi, Piero Picci, Sakari Knuutila, Katia Scotlandi, Mario Mercuri, Scotlandi K., Remondini D., Castellani G., Manara MC., Nardi F., Cantiani L., Francesconi M., Mercuri M., Caccuri AM., Serra M., Knuutila S., and Picci P.
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Oncology ,Drug ,Male ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,media_common.quotation_subject ,Drug Resistance ,Antineoplastic Agents ,Bone Neoplasms ,Drug resistance ,Sarcoma, Ewing ,Cell Line ,law.invention ,law ,Internal medicine ,Cell Line, Tumor ,medicine ,Humans ,Settore BIO/10 ,Polymerase chain reaction ,media_common ,Glutathione Transferase ,Prognosis ,Gene Expression Profiling ,Female ,Oxadiazoles ,Principal Component Analysis ,Sarcoma, Ewing's ,Drug Resistance, Neoplasm ,Glutathione S-Transferase pi ,Chemotherapy ,Tumor ,business.industry ,Cancer ,Sarcoma ,medicine.disease ,Gene expression profiling ,Immunology ,Gene chip analysis ,Ewing's ,Neoplasm ,business - Abstract
Purpose The improvement of Ewing sarcoma (EWS) therapy is currently linked to the discovery of strategies to select patients with poor and good prognosis and of modified treatment regimens. In this study, we analyzed the molecular factors governing EWS response to chemotherapy to identify genetic signatures to be used for risk-adapted therapy. Patients and Methods Microarray technology was used for profiling 30 primary tumors and seven metastases of patients who were classified according to event-free survival. For selected genes, real-time polymerase chain reaction was applied in 42 EWS primary tumors as validation assay. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test was used to evaluate in vitro drug sensitivity. Results We identified molecular signatures that reflect tumor resistance to chemotherapy. Annotation analysis was applied to reveal the biologic functions that critically influenced clinical outcome. The prognostic relevance of glutathione metabolism pathway was validated. The expression of MGST1, the microsomal glutathione S-transferase (GST), was found to clearly predict EWS prognosis. MGST1 expression was associated with doxorubicin chemosensitivity. This prompted us to assess the in vitro effectiveness of 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX), a new anticancer agent that efficiently inhibits GST enzymes. Six cell lines were found to be sensitive to this new drug. Conclusion Classification of EWS patients into high- and low-risk groups is feasible with restricted molecular signatures that may have practical value at diagnosis for selecting patients with EWS who are unresponsive to current treatments. Glutathione metabolism pathway emerged as one of the most significantly altered prognosis-associated pathway. NBDHEX is proposed as a new potential therapeutic possibility.
- Published
- 2009
26. Molecular mechanisms of CD99-induced caspase-independent cell death and cell-cell adhesion in Ewing's sarcoma cells: actin and zyxin as key intracellular mediators
- Author
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Piero Picci, Bálint Nagy, Ghislaine Bernard, Maria Cristina Manara, Stefania Perdichizzi, Sakari Knuutila, Mario P. Colombo, Vanessa Cerisano, P. Preda, Giovanna Lattanzi, Yan Aalto, Stefania Benini, Katia Scotlandi, Giovanna Cenacchi, Alain Bernard, CERISANO V, AALTO Y, PERDICHIZZI S, BERNARD G, MANARA MC, BENINI S, CENACCHI G., PREDA P, LATTANZI G, NAGY B, KNUUTILA S, COLOMBO MP, BERNARD A, PICCI P, and SCOTLANDI K.
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Cancer Research ,Arp2/3 complex ,Sarcoma, Ewing ,Biology ,Zyxin ,Adherens junction ,03 medical and health sciences ,0302 clinical medicine ,Tumor Cells, Cultured ,Genetics ,Humans ,Cell adhesion ,Cytoskeleton ,Molecular Biology ,Actin ,Cell Aggregation ,Glycoproteins ,030304 developmental biology ,0303 health sciences ,Cell Death ,Actin cytoskeleton ,Actins ,Cell aggregation ,Cell biology ,Cytoskeletal Proteins ,Caspases ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Signal Transduction - Abstract
CD99 is a unique 32-kDa cell surface molecule with broad cellular expression but still poorly understood biological functions. In cancer cells, CD99 is highly expressed in virtually all Ewing's sarcoma (ES). Engagement of CD99 induces fast homotypic aggregation of ES cells and caspase-independent apoptosis. In this study, we analysed signal transduction after CD99 engagement on ES cells. Findings obtained with selective inhibitors indicated that only actin cytoskeleton integrity was essential for cell-cell adhesion and apoptosis of ES cells. Indeed, CD99 stimulation induced actin repolymerization, further supporting the role of cytoskeleton in CD99 signaling. Gene expression profiling of ES cells after CD99 engagement showed modulation in the expression of 32 genes. Among the pool of upregulated genes reported to be involved in cell adhesion, we chose to analyse the role of zyxin, a cytoplasmic adherens junction protein found to play a role in the regulation of the actin cytoskeleton. Overexpression of zyxin after CD99 ligation was confirmed by real-time PCR and Western blot. Treatment of ES cells with zyxin antisense oligonucleotides inhibited CD99-induced cell aggregation and apoptosis, suggesting a functional role for this protein. Therefore, our findings indicate that CD99 functions occur through reorganization of cytoskeleton and identify actin and zyxin as the early signaling events driven by CD99 engagement.
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- 2004
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