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1. An optimized five-gene multi-platform predictor of hormone receptor negative and triple negative breast cancer metastatic risk

Author

Esserman, Laura, Yau, C, Sninsky, J, Kwok, S, Wang, A, Degnim, A, Ingle, JN, Gillett, C, Tutt, A, Waldman, F, and Moore, D

Abstract

Introduction: Outcome predictors in use today are prognostic only for hormone receptor-positive (HRpos) breast cancer. Although microarray-derived multigene predictors of hormone receptor-negative (HRneg) and/or triple negative (Tneg) breast cancer recurre

Published
2013

2. TP53, EGFR, and KRAS mutations in relation to VHL inactivation and lifestyle risk factors in renal-cell carcinoma from central and eastern Europe

Author

Szymańska, K., Moore, L.E., Rothman, N., Chow, W.H., Waldman, F., Jaeger, E., Waterboer, T., Foretova, L., Navratilova, M., Janout, V., Kollarova, H., Zaridze, D., Matveev, V., Mates, D., Szeszenia-Dabrowska, N., Holcatova, I., Bencko, V., Le Calvez-Kelm, F., Villar, S., Pawlita, M., Boffetta, P., Hainaut, P., and Brennan, P.

Published
2010
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8. Abstracts for the Tenth International Conference on Brain Tumour Research and Therapy: Stalheim Hotel, Voss, Norway, September 6–9, 1993

Author

Abrahamsen, Tore G., Wesenberg, Finn, Mørk, Sverre, Allen, Jeffrey, Hayes, Roberta, DaRosso, Robert, Nirenberg, Anita, Ali-Osman, Francis, Akande, Nike, Amberger, V., Seulberger, H., Paganetti, P. A., Schwab, M. E., Schwab, M. E., Arita N., Ohnishi T., Hiraga S., Yamamoto H., Taki T., Izumoto S., Higuchi M., Hayakawa T., Kusakabe M., Sakakura T., Baldwin, N. G., Rice, C. D., Merchant, R. E., Ashmore, Sally M., Darling, J. L., Bailey, C. C., Balmaceda C., Diez B., Villablanca J., Walker R., Finlay J., Bergenheim, A. Tommy, Hartman, Magdalena, Bergh, Jonas, Ridderheim, PerÅke, Henriksson, Roger, Berens, Michael E., Rief, Monique D., Giese, Alf, Zackrisson, Björn, Elfversson, Jörgen, Bernstein, Mark, Cabantog, Alberto, Glen, Jennifer, Mikulis, David, Bjerkvig, Rolf, Pedersen, Paal-Henning, Mathisen, Berit, Mahesparan, Rupavathana, Haugland, Hans Kristian, Bernstein, Mark, Laperriere, Normand, Thomason, Cindy, Leung, Phil, Bobola M. S., Berger M. S., Silber J. R., Bongcam-Rudloff, Erik, Wang, Jia-Lun, Nistér, Monica, Westermark, Bengt, Brem, Steven, Breslow, Gary, Ho, Jason, Gately, Stephen, Takano, Shingo, Ward, William, Brada, M., Laing, R., Warrington, J., Brem, Steven, Engelhard, Herbert, Takano, Shingo, Gately, Stephen, Brem, Steven, Landau, Barry, Kwaan, Hau, Verrusio, Elaine, Buckner, J. C., Cascino, T. L., Schomberg, P. S., O'Fallon, J. R., Dinapoli, R. P., Burch, P. A., Shaw, E. G., Broaddus, William C., Hager-Loudon, Kathryn, Merchant, Randall E., Loudon, William, Couldwell, William T., Jiang, Jack B., Burns, David, Couldwell, William T., Weiss, Martin H., Apuzzo, Michael L. J., Desbaillets I., Tada M., de Tribolet N., Van Meir, E., Davis, R. L., Onda, K., Prados, M. D., Dolan, M. Eileen, Fleig, Matthew J., Friedman, Henry S., Ekstrand, A. Jonas, Longo, Nicola, James, C. David, Chou, D., Wijnhoven, B., Bellinzona, M., Nakagawa, M., Feuerstein B. G., Basu H. S., Dolan M. E., Bergeron C., Pellarm M., Deen D. F., Marton L. J., Finlay, Jonathan, Fulton D. S., Urtasun R. C., Giese, Alf, Scheck, Adrienne C., Geddes, J., Vowles, G. M., Ashmore, S. M., Gillespie, G. Y., Goldman, C. K., Tucker, M. T., Lyon, E., Tsai, J. -C., Gobbel, G. T., Chan, P. H., Greenberg, Hairy S., Chandler, W. F., Ensminger, W. D., Junck, L., Sandler, H., Bromberg, J., McKeever, P., Gonzalez G. G., Sarkar A., Basu H., Feuerstein B. G., Deen D. F., Haugland, Kr., Tysnes, Ole-Bjørn, Hiraga, Shoju, Arita, Norio, Ohnishi, Takanori, Taki, Takuyu, Yamamoto, Hiroshi, Higuchi, Masahide, Hayakawa, Toru, Isern, Erik, Unsgaard, Geirmund, Marthinsen, Anne Beate Langeland, Strickert, Trond, Helseth, Eirik, Hochberg F., Cosgrove R., Valenzuela R., Pardo F., Zervas N., Jenkins, Robert B., Ritland, Steven R., Hailing, Kevin C., Thibodeau, Stephen N., Juillerat L., Darekar P., Janzer R. C., Hamou M. F., Kato, Tsutomu, Sawamura, Yutaka, Tada, Mitsuhiro, Sakuma, Shirou, Sudo, Masako, Abe, Hiroshi, Kallio M., Leppää J., Nikula T., Nikkinen P., Gylling H., Färkkilä M., Hiltunen J., Jääskeläinen J., Liewendahl K., Keles, G. Evren, Berger, Mitchel S., Deliganis, Anna, Kellie S. J., De Graaf S. S. N., Bloemhof H., Johnston I., Uges D. D. R., Besser M., Chaseling R. W., Ouvrier R. A., Kitchen, N. D., Hughes, S., Beaney, R., Thomas, D. G. T., Kim D. H., Maeda T., Mohapatra G., Park S., Waldman F. W., Gray J. W., Koala, D., Silber, J., Berger, M., Krauseneck P., Müller B., Strik H., Warmuth-Metz M., Kuratsu, Jun-ichi, Takeshima, Hideo, Ushio, Yukitaka, Kretschmar, C., Grodman, H., Linggood, R., Kyritsis, A. P., Bondy, M., Cunningham, J., Xiao, M., Levin, V., Leeds, N., Bruner, J., Yung, W. K. A., Saya, H., Lampson, L. A., Nichols, M. R., Lampson, M. A., Dunne, A. D., Li, Hong, Hamou, Marie-France, Jaufeerally, Rehana, Diserens, Annie-Claire, Van Meir, Erwin, de Tribolet, Nicolas, Levin, V. A., Maor, M., Sawaya, R., Leavens, M., Woo, S., Thall, P., Gleason, M. J., Liang, Bertrand C., Ross, D. A., Meltzer, P. S., Trent, J. M., Greenberg, H. S., Lillehei K. O., Kong Q., DeMasters B. K., Withrow S. J., Macdonald D. R., Cairncross J. G., Ludwin S., Lee D., Cascino T., Buckner J., Dropcho E., Fulton D., Stewart D., Schold C., Wainman N., Eisenhauer E., Kirby S., Fisher B. J., Magrassi, L., Butti, G., Pezzotta, S., Milanesi∘, G., Matsutani, Masao, Marienhagen, Kirsten, Laerum, Ole Didrik, Baldwin, N. G., Merzak, Abderrahim, Koocheckpour, Shahriar, Roxanis, Yannis, Pilktngton, Geoffrey J., Nagai, Masakatsu, Watanabe, Kunihiko, Narita, Jun-ichi, Hagiwara, Hideaki, Noble, Mark, Nomura, K., Oyama, H., Motoo, M., Shibui, S., Tokuue, K., Akine, Y., Ohnishi, T., Arita, N., Hiraga, S., Hayakawa, T., Nygaard, Svein J. Tjoflaat, Tysnes, Ole-Bjørn, Pardo, F. S., Hsu, D. W., Hedley-Whyte, E. T., Efird, J., Schmidt, E. V., Marienhagen, Paal-Henning Pedersenl Kirsten, Pilkington, Geoffrey J., Clarke, Tracey M., Yu, Hui Tian, Rogers, Joan P., Stern, Robert, Phuphanich, Surasak, Greenberg, Harvey, Murtagh, R., Viloria, Jesus, Ransohoff, Joseph, Martin, Kimberly, Hatva, V. Erika, Rao, Jasti S., Mohanam, S., Rempel, Sandra A., Schwechheimer, Karl, Davis, Richard L., Cavenee, Webster K., Rosenblum, Mark L., Reifenberger, Guido, Liu, Lu, Ichimura, Koichi, Schmidt, Esther E., Collins, V. Peter, Revesz T., Scaravilli F., Cockburn H., Thomas D. G. T., Rice, C. D., Biron, R. T., Merchant, R. E., McKerrow, James, Sloane, Bonnie, Mikkelsen, Tom, Roosen, Norbert, Coopersmith, Peter, Smith, Robert, Rooprai, Harcharan Kaur, Maidment, Steven, Rucklidge, Garry, Volovsek, Anton, Rutka J. T., Smith S. L., Matsuzawa K., Sankar, A. A., Darling, J. L., Williams, S. R., Fukuyama K., Marton L. J., Ikeda, Jun, Selker, R. G., Vertosick, F. T., Goldenberg, M. T., Bindal, R., Diez B., Taratuto A., Picco P., Monges J., Martinez M., Pacheco G., Gamboni M., Schultz M., Silber J. R., Mueller B. A., Ewers T. G., Berger M. S., Shiraishi, T., Tabuchi, K., Nakagawa, S., Kihara, S., Stewart, D. J., Eapen, L., Agboola, O., Popovic, P., Goel, R., Raaphorst, P., Wong, P. T. T., Shimokawa, S., Oh-uchida, M., Hori, K., Markert C., Pflughaupt K. -W., Tada M., Diserens A. -C., Jauferrally R., Desbaillets I., Hamou M. -F., de Tribolet N., Takeshima H., Mochizuki H., Clifford J. L., Nishi T., Levin V. A., Lotan R., Saya H., Terzis, A. J. A., Arnold, H., Laerum, O. D., Bjerkvig, R., Taratuto A. L., Sevlever G., Diaz D., Di Tella M., Cuccia V., Pomata H., Gallo G., Dietze, A., Knopp, U., Thomas, R., Brada, M., Carnochan, P., Flux, G., Kitchen, N., Thomas, D., Zalutsky, M., Bigner, D., Tofilon, Philip, Borchardt, Paul, Torp, Sverre H., Dalen, Are, Tohyama, Takashi, Kubo, Osami, Takakura, Kintomo, Lee, Virginia M. -Y., Trojanowski, John Q., Nygaard, Svein, Urtasun, R. C., Parliament, M. B., McEwan, A. J., Mannan, R. H., Weibe, L. I., Unsgårp, G., Sonnewald, U., Gribbestad, I., Isern, E., Petersen, S. B., Wang J., Delgado D. A., Warr, Tracy J., Sheer, Denise, Gorman, Pat, Yamaguchi, F., Westphal, M., Anker, L., Hamel, W., Lücke, M., Shepard, M., Kleihues, P., Herrmann, H. D., Yung, W. K. Alfred, Taylor, Scott, and Steck, Peter A.

Published
1993
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12. Patterns of epidermal growth factor receptor amplification in malignant gliomas

Author

Sauter, G., Maeda, T., Waldman, F. M., Davis, R. L., and Feuerstein, B. G.

Subjects
ErbB Receptors, Brain Neoplasms, Gene Amplification, Humans, Glioma, Glioblastoma, Chromosomes, Human, Pair 7, In Situ Hybridization, Fluorescence, Research Article
Abstract

Amplification of the gene for epidermal growth factor receptor (EGFR) is a common finding in malignant gliomas. We found that 18 of 29 grade 3 and grade 4 gliomas had EGFR amplification when assayed using fluorescence in situ hybridization. The amplification pattern suggests that the amplicon is contained within double minute chromosomes in most cases. EGFR copy number can differ by 20-fold in amplified cells within a single case. Polysomy 7 occurs frequently in both EGFR-amplified and -unamplified cells. More than one-third of the cases had < or = 10 percent of cells with amplified EGFR, and it is likely that these cases would not have been identified by methods that do not examine DNA on a cell by cell basis.

Published
1996

13. Genomic copy number alterations in clear cell renal carcinoma: associations with case characteristics and mechanisms of VHL gene inactivation

Author

Moore, L E, primary, Jaeger, E, additional, Nickerson, M L, additional, Brennan, P, additional, De Vries, S, additional, Roy, R, additional, Toro, J, additional, Li, H, additional, Karami, S, additional, Lenz, P, additional, Zaridze, D, additional, Janout, V, additional, Bencko, V, additional, Navratilova, M, additional, Szeszenia-Dabrowska, N, additional, Mates, D, additional, Linehan, W M, additional, Merino, M, additional, Simko, J, additional, Pfeiffer, R, additional, Boffetta, P, additional, Hewitt, S, additional, Rothman, N, additional, Chow, W-H, additional, and Waldman, F M, additional

Published
2012
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14. Analysis of changes in DNA sequence copy number by comparative genomic hybridization in archival paraffin-embedded tumor samples

Author

Isola, J., DeVries, S., Chu, L., Ghazvini, S., and Waldman, F.

Subjects
Genome, Neoplasms, Chromosome Mapping, Humans, DNA, Neoplasm, Prognosis, Molecular Biology, Research Article
Abstract

Analysis of previously unknown genetic aberrations in solid tumors has become possible through the use of comparative genomic hybridization (CGH), which is based on competitive binding of tumor and control DNA to normal metaphase chromosomes. CGH allows detection of DNA sequence copy number changes (deletions, gains, and amplifications) on a genome-wide scale in a single hybridization. We describe here an improved CGH technique, which enables reliable detection of copy number changes in archival formalin-fixed paraffin-embedded tumor samples. The technique includes a modified DNA extraction protocol, which produces high molecular weight DNA which is necessary for high quality CGH. The DNA extraction includes a 3-day digestion with proteinase K, which remarkably improves the yield of high molecular weight DNA. Labeling of the test DNA with a directly fluorescein-conjugated nucleotide (instead of biotin labeling) improved significantly the quality of hybridization. Using the paraffin-block technique, we could analyze 70 to 90% of paraffin blocks, including very old samples as well as samples taken at autopsy. CGH from paraffin blocks was highly concordant (95%) with analyses done from matched freshly frozen tumor samples (n = 5 sample pairs; kappa coefficient = 0.83). The method described here has wide applicability in tumor pathology, allowing large retrospective prognostic studies of genetic aberrations as well as studies on genetic pathogenesis of solid tumors, inasmuch as premalignant lesions and primary and metastatic tumors can be analyzed by using archival paraffin-embedded samples.

Published
1994

17. Use of Von-Hippel Lindau (VHL) mutation status to predict objective response to vascular endothelial growth factor (VEGF) -targeted therapy in metastatic renal cell carcinoma (RCC)

Author

Choueiri, T. K., primary, Vaziri, S. A., additional, Rini, B. I., additional, Elson, P., additional, Bhalla, I., additional, Jaeger, E., additional, Weinberg, V., additional, Waldman, F. M., additional, Zhou, M., additional, Bukowski, R. M., additional, and Ganapathi, R., additional

Published
2007
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19. Genomic and transcriptional events associated with poor clinical responses to conventional therapies

Author

Chin, K, primary, Devries, S, additional, Fridlyand, J, additional, Spellman, P, additional, Kuo, W-L, additional, Lapuk, A, additional, Neve, R, additional, Tokuyasu, T, additional, Kingsley, C, additional, Dairkee, S, additional, Chew, K, additional, Jain, A, additional, Ljung, BM, additional, Esserman, L, additional, Waldman, F, additional, and Gray, JW, additional

Published
2005
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29. Molecular Cytogenetics of Human Breast Cancer

Author

Gray, J.W., primary, Collins, C., additional, Henderson, I.C., additional, Isola, J., additional, Kallioniemi, A., additional, Kallioniemi, O.-P., additional, Nakamura, H., additional, Pinkel, D., additional, Stokke, T., additional, Tanner, M., additional, and Waldman, F., additional

Published
1994
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32. GENETIC PROGRESSION OF CANCER BY COMPARATIVE GENOMIC HYBRIDIZATION.

Author

Kallioniemi, O.-P., Waldman, F., Visakorpi, T., Kuukasjarvi, T., Tanner, M., Nishizaki, T., Tirkonen, M., Kallioniemi, A., and Isola, J.

Abstract

Describes the application of the comparative genomic hybridization technique for defining DNA sequence copy number aberrations in solid tumors. Analysis of archival, paraffin-embedded tissues; Investigation of new cancer genes; Evaluation of differences in the genetic composition of clonally related specimens such as tumors and metastases.

Published
1999

33. Academia-pharma intersect: gastrointestinal cancer. Prognostic and predictive biomarkers in resected colon cancer: current status and future perspectives for integrating genomics into biomarker discovery.

Author

Tejpar S, Bertagnolli M, Bosman F, Lenz H, Garraway L, Waldman F, Warren R, Bild A, Collins-Brennan D, Hahn H, Harkin DP, Kennedy R, Ilyas M, Morreau H, Proutski V, Swanton C, Tomlinson I, DeLorenzi M, Fiocca R, and Van Cutsem E

Abstract

The number of agents that are potentially effective in the adjuvant treatment of locally advanced resectable colon cancer is increasing. Consequently, it is important to ascertain which subgroups of patients will benefit from a specific treatment. Despite more than two decades of research into the molecular genetics of colon cancer, there is a lack of prognostic and predictive molecular biomarkers with proven utility in this setting. A secondary objective of the Pan European Trials in Adjuvant Colon Cancer-3 trial, which compared irinotecan in combination with 5-fluorouracil and leucovorin in the postoperative treatment of stage III and stage II colon cancer patients, was to undertake a translational research study to assess a panel of putative prognostic and predictive markers in a large colon cancer patient cohort. The Cancer and Leukemia Group B 89803 trial, in a similar design, also investigated the use of prognostic and predictive biomarkers in this setting. In this article, the authors, who are coinvestigators from these trials and performed similar investigations of biomarker discovery in the adjuvant treatment of colon cancer, review the current status of biomarker research in this field, drawing on their experiences and considering future strategies for biomarker discovery in the postgenomic era. [ABSTRACT FROM AUTHOR]

Published
2010
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37. Violence or discipline? Working with multicultural court-ordered clients.

Author

Waldman, Fanny and Waldman, F

Subjects
*COUNSELING, *MULTICULTURALISM, *COUNSELOR-client relationship, *APPLIED psychology, *HELPING behavior, *FAMILY psychotherapy laws, *CULTURE, *MEDICAL protocols, *PARENT-child relationships, *CULTURAL pluralism
Abstract

Therapists working with court-ordered clients from cultures differing from the mainstream face challenging issues of compulsory therapy in the context of cultural diversity. This article reviews the literature on court-ordered and multicultural counseling, highlighting central elements of both. It then suggests guidelines that blend these elements. The author illustrates how using these guidelines can enable therapists to engage these clients in the therapeutic process and focus on culture as the context for change. [ABSTRACT FROM AUTHOR]

Published
1999
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38. p53 and erbB-2 protein overexpression are associated with early invasion and metastasis in bladder cancer.

Author

Moch, H., Sauter, G., Moore, D., Mihatsch, M., Gudat, F., and Waldman, F.

Abstract

Overexpression of p53 and erbB-2 was studied by immunohistochemistry in formalin-fixed tissue samples of 179 patients with transitional cell carcinoma of the urinary bladder. p53 immunostaining was strongly correlated with tumour stage ( P<0.0001). This was driven by a marked difference in p53 expression between pTa (37% positive) and pT1 (71%) tumours, while there was no difference between pT1 and pT2-4 tumours. Similarly, a strong overall association between p53 expression and grade ( P<0.0001) was driven by a marked difference between grade 1 (28%) and grade 2 tumours (71%), and there was no significant difference between grade 2 and grade 3 tumours. Surprisingly, the frequency of erbB-2 overexpression was higher in pT1 tumours (74%) than in either pTa (49%; P=0.0265) or pT2-T4 (56%; P=0.0645) tumours. Both p53 and erbB-2 expression was also associated with metastasis. Metastases were found in 77% of patients with p53 positive primary tumours, but in only 50% of the patients with p53 negative primary tumours ( P=0.022). Metastases were found in 66% of patients with erbB-2 positive primaries, but in only 37% of the erbB-2 negative primaries ( P=0.020). Of 32 patients with positivity for both p53 and erbB-2, 84% developed metastases, as compared to 49% of patients with positivity for either one or neither positive ( P=0.002). We conclude that both p53 and erbB-2 over-expression are associated with early invasion in bladder cancer. Furthermore, p53 and erbB-2 may be important predictors for metastasis. [ABSTRACT FROM AUTHOR]

Published
1993
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40. HER2 protein expression and gene amplification in androgen-independent prostate cancer.

Author

Reese, D M, Small, E J, Magrane, G, Waldman, F M, Chew, K, and Sudilovsky, D

Abstract

The role of the HER2 receptor remains uncertain in the pathogenesis and progression of human prostate cancer. Previous studies have reported widely divergent rates for HER2 expression in primary prostate tumors, probably owing to significant methodologic differences in the studies. Few data exist about the frequency of HER2 protein overexpression and gene amplification in androgen-independent prostate cancer (AIPC), although recent xenograft models suggest HER2 expression may be up-regulated in the transition from androgen-dependent to androgen-independent disease. We studied the role of HER2 protein in AIPC by immunohistochemical and fluorescence in situ hybridization (FISH) analyses on AIPC specimens using well-characterized and validated reagents. Fourteen (36%) of 39 specimens expressed HER2; however, only 2 (5%) had moderate (2+) expression, and 2 (5%) had high-level (3+) expression. Two (6%) of 36 specimens had gene amplification by FISH. These data suggest that HER2 protein overexpression and gene amplification are relatively uncommon in AIPC.

Published
2001
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41. Comparison of genetic changes in schistosome-related transitional and squamous bladder cancers using comparative genomic hybridization.

Author

Muscheck, M, Abol-Enein, H, Chew, K, Moore, D, Bhargava, V, Ghoneim, M A, Carroll, P R, and Waldman, F M

Abstract

The development of bladder tumors has been associated with a number of causative agents, including schistosomiasis. Schistosome-related cancers show different clinical and pathological features compared with non-schistosome-related bladder cancers, occurring in younger patients, and being predominantly of squamous cell type. This study addresses the difference between squamous and transitional tumor types in the presence of schistosome infection as a measure of the relationship between tumor genotype and phenotype. We have used comparative genomic hybridization to analyze primary muscleinvasive schistosome-related bladder tumors in 54 patients. Twenty-six of these tumors were squamous cell carcinomas; the remaining 28 were of transitional cell type. On average, transitional cell tumors showed 1.8 times the number of chromosomal aberrations as squamous cell tumors (14.4 versus 8.2, P: < 0.001). For both groups combined, the most prevalent genetic alterations were losses of 8p and 18q, and gains of 8q. Transitional cell cancers also showed frequent losses involving 5q, 9p, 10q, 11p and 11q, and gains at 1q and 17q. Loss of 11p was significantly more frequent in TCC than in SCC tumors (50 versus 4%, P: = 0.01). Squamous cell cancers showed more frequent losses of 17p and 18p than transitional tumors, which was clearly significant given the overall reduced frequency of changes in squamous cancers (P: = 0.001 and P: = 0.03, respectively). These data show that different histologic subgroups of bladder tumors are characterized by distinct patterns of chromosomal alterations. The genetic changes found in the transitional cell group are similar to those reported in non-schistosome-related transitional cell tumors, but differ from tumors exhibiting squamous differentiation.

Published
2000
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42. Cell Cycle Analysis Using Flow Cytometry

Author

Gray, J. W., Dolbeare, F., Pallavicini, M. G., Beisker, W., and Waldman, F.

Abstract

This manuscript reviews the utility of flow cytometry for the study of cell proliferation. The applications of univariate DNA distribution analysis to cytokinetic studies of asynchronous and perturbed cell populations are discussed briefly. The newly developed technique for simultaneous flow cytometric measurement of cellular DNA content and amount of incorporated bromodeoxyuridine is discussed in more detail. The cytochemistry required for this analysis is reviewed as are its applications to: (a) determination of the fractions of cells in the G1-, S- and G2 + M phases of the cell cycle; (b) determination of the G1-, S- and G2 + M phase durations and dispersions and growth fraction for asynchronous cells; (c) detection of ara-C resistant cells present at low frequency in an otherwise sensitive population; and (d) analysis of the cytokinetic response of a solid murine tumour to treatment in vivo with a cell cycle specific agent.

Published
1986
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44. Overcoming cellular senescence in human cancer pathogenesis.

Author

Yeager, T R, DeVries, S, Jarrard, D F, Kao, C, Nakada, S Y, Moon, T D, Bruskewitz, R, Stadler, W M, Meisner, L F, Gilchrist, K W, Newton, M A, Waldman, F M, and Reznikoff, C A

Abstract

Elevation of p16, the CDKN2/p16 tumor suppressor gene (TSG) product, occurs at senescence in normal human uroepithelial cells (HUC). Immortal HUCs and bladder cancer cell lines show either alteration of p16 or pRb, the product of the retinoblastoma (RB) TSG. In addition, many human cancers show p16 or pRb alteration along with other genetic alterations that we associated with immortalization, including +20q and -3p. These observations led us to hypothesize that p16 elevation plays a critical role in senescence cell cycle arrest and that overcoming this block is an important step in tumorigenesis in vivo, as well as immortalization in vitro. Using a novel approach, we tested these hypotheses in the present study by examining p16 and pRb status in primary culture (P0) and after passage in vitro of transitional cell carcinoma (TCC) biopsies that represented both superficial bladder tumors and invasive bladder cancers. We demonstrated that all superficial TCCs showed elevated p16 after limited passage in vitro and then senesced, like normal HUCs. In contrast, all muscle invasive TCCs contained either a p16 or a pRb alteration at P0 and all spontaneously bypassed senescence (P = 0.001). Comparative genomic hybridization (CGH) was used to identify regions of chromosome loss or gain in all TCC samples. The application of a statistical model to the CGH data showed a high probability of elevated alteration rates of +20q11-q12 (0.99) and +8p22-pter (0.94) in the immortal muscle invasive TCCs, and of -9q (0.99) in the superficial TCCs. Three myoinvasive TCCs lost 3p13-p14. In this study, four of six myoinvasive TCCs also showed TP53 mutation that associated well with genome instability (P = 0.001), as previously hypothesized. Notably, TP53 mutation, which has been used as a marker of tumor progression in many human cancers, was less significant in associating with progression in this study (P = 0.04) than was p16 or pRb alteration (P = 0.001). Thus, these data support a new model in which overcoming senescence plays a critical role in human cancer pathogenesis and requires at least two genetic changes that occur in several combinations that can include either p16 or pRb loss and at least one additional alteration, such as +20q11-q12, -3p13-p14, or -8p21-pter.

Published
1998

46. c-myc Copy number gains in bladder cancer detected by fluorescence in situ hybridization

Author

Sauter, G., Carroll, P., Moch, H., Anne Kallioniemi, Kerschmann, R., Narayan, P., Mihatsch, M. J., and Waldman, F. M.

Subjects
Proto-Oncogene Proteins c-myc, Ki-67 Antigen, Urinary Bladder Neoplasms, Gene Amplification, Genes, myc, Humans, Nuclear Proteins, Tumor Suppressor Protein p53, In Situ Hybridization, Fluorescence, Research Article, Chromosomes, Human, Pair 8, Neoplasm Proteins, Neoplasm Staging
Abstract

Amplification and overexpression of c-myc have been suggested as prognostic markers in human cancer. To assess the role of c-myc gene copy number alterations in bladder cancer, 87 bladder tumors were examined for c-myc aberrations by fluorescence in situ hybridization. Dual labeling hybridization with a repetitive pericentromeric probe specific for chromosome 8 and a probe for the c-myc locus (at 8q24) was performed to analyze c-myc copy number in relation to chromosome 8 copy number on a cell by cell basis. A clear-cut c-myc amplification (up to 40 to 150 copies per cell) was found in 3 tumors. There was a low level c-myc copy number increase in 32 of the remaining 84 tumors. There was no association of low level c-myc copy number increase with c-myc protein overexpression. This suggests that a c-myc gene copy number gain as detected by fluorescence in situ hybridization does not necessarily reflect a disturbed c-myc gene function but may indicate a structural chromosome 8 abnormality including gain of distal 8q. The strong association of low level c-myc (8q) gains with tumor grade (P < 0.0001), stage (P < 0.0001), chromosome polysomy (P < 0.0001), p53 protein expression (P = 0.0019), p53 deletion (P = 0.0403), and tumor cell proliferation (Ki67 labeling index; P = 0.0021) is consistent with a role of chromosome 8 alterations in bladder cancer progression.

47. Comparative genomic hybridization: a rapid new method for detecting and mapping DNA amplification in tumors

Author

Kallioniemi, O. -P, Kallioniemi, A., Damir Sudar, Rutovitz, D., Gray, J. W., Waldman, F., and Pinkel, D.

Subjects
Neoplasms, Gene Amplification, Image Processing, Computer-Assisted, Chromosome Mapping, Humans, Oncogenes, In Situ Hybridization
Abstract

Recent evidence indicates that many more genes than the currently known oncogenes may undergo amplification in tumors. We have developed a new technique, Comparative Genomic Hybridization (CGH), which allows rapid detection of DNA amplification anywhere in the tumor genome and maps the amplified sequences on normal chromosomes. CGH is based on a competitive in situ hybridization of differentially labeled tumor DNA and normal DNA to a normal human metaphase spread. Regions of gain of DNA sequences are seen as an increased color ratio of two fluorochromes used to detect the labeled DNAs. Over 20 different regions of amplification have been identified using CGH.

50. Pathologic and biologic response to preoperative endocrine therapy in patients with ER-positive ductal carcinoma in situ

Author

Shim Veronica, Chin Koei, Swain Rebecca, Lessing Juan, Anderson Joseph, DeVries Sandy, Chen Yunn-Yi, Esserman Laura J, Waldman Frederic M, and Hwang E Shelley

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Endocrine therapy is commonly recommended in the adjuvant setting for patients as treatment for ductal carcinoma in situ (DCIS). However, it is unknown whether a neoadjuvant (preoperative) anti-estrogen approach to DCIS results in any biological change. This study was undertaken to investigate the pathologic and biomarker changes in DCIS following neoadjuvant endocrine therapy compared to a group of patients who did not undergo preoperative anti-estrogenic treatment to determine whether such treatment results in detectable histologic alterations. Methods Patients (n = 23) diagnosed with ER-positive pure DCIS by stereotactic core biopsy were enrolled in a trial of neoadjuvant anti-estrogen therapy followed by definitive excision. Patients on hormone replacement therapy, with palpable masses, or with histologic or clinical suspicion of invasion were excluded. Premenopausal women were treated with tamoxifen and postmenopausal women were treated with letrozole. Pathologic markers of proliferation, inflammation, and apoptosis were evaluated at baseline and at three months. Biomarker changes were compared to a cohort of patients who had not received preoperative treatment. Results Median age of the cohort was 53 years (range 38–78); 14 were premenopausal. Following treatment, predominant morphologic changes included increased multinucleated histiocytes and degenerated cells, decreased duct extension, and prominent periductal fibrosis. Two postmenopausal patients had ADH only with no residual DCIS at excision. Postmenopausal women on letrozole had significant reduction of PR, and Ki67 as well as increase in CD68-positive cells. For premenopausal women on tamoxifen treatment, the only significant change was increase in CD68. No change in cleaved caspase 3 was found. Two patients had invasive cancer at surgery. Conclusion Preoperative therapy for DCIS is associated with significant pathologic alterations. These changes may be clinically significant. Further work is needed to identify which women may be the best candidates for such treatment for DCIS, and whether best responders may safely avoid surgical intervention. Trial Registration ClinicalTrials.gov NCT00290745

Published
2009
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