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3. Metalloenzymes

Author

Pollard, J. W., Danilkovitch-Miagkova, A., Minaguchi, T., Waite, K. A., Buys, T. P. H., Lam, W. L., Müller-Hermelink, H. K., Ott, G., Robb, V. A., Henske, E. P., Lynge, E., Boyd, N., Geisler, C., Seger, R., De Wolf-Peeters, C., Sagaert, X., Sheng, S., Ribatti, D., Verstovsek, S., Akin, C., Stack, M. S., Kitada, S., Gartenhaus, R., Moretti, F., Frühwald, Michael C., Mooi, W. J., Krausz, T., Kefford, R., Peikert, T., Specks, U., Tueting, T., Pföhler, C., Blask, D. E., Stevens, R. G., Nies, A. T., Gotoh, N., Tsuchida, N., Escriba, P., Singh, V., Hickey, M., Saunders, C., Xiao, G.-H., Testa, J. R., Furtwängler, R., Scholler, N., Carbone, M., Furge, K., Woude, G. F. V., Roland, W. C., Muschel, R., Hunter, K., Welch, D. R., Vaidya, K. S., Hurst, D. R., Silveira, A. C., Zang, X. A., Bari, R., Silveira, A., Szmulewitz, R., Taylor, J., Rinker-Schaffer, C., Shim, H., Plass, C., Lindsey, J. C., Clifford, S. C., Holdenrieder, S., Steinle, A., Salih, H., Brown, D. A., Breit, S. N., Bauskin, A. R., Mousses, S., Lung, M. L., Alix-Panabieres, C., Pantel, K., Djuzenova, C. S., Dalmay, T., Ahlquist, T., Lothe, R. A., Bhat, K., Setaluri, V., Rutka, J. T., Salhia, B., Cockell, K. A., Radich, J. P., Yamagishi, S.-I., Bignami, M., Verma, M., Kumar, D., Brenner, C., Zhang, Y.-W., Jamieson, D., Chi, Y.-H., Jeang, K.-T., Roninson, I., Dragani, T., Sobolev, A. S., Powers, M. V., Workmann, P., Evans, M. F., Cooper, K., Kausch, I., Doehn, C., Janz, S., Huang, C.-L., Toland, A. E., Osinaga, E., Kaye, F., Lemos, M. C., Thakker, R. V., Teh, B. T., Ponder, B. A. J., Mulligan, L. M., Gullo, C., Klein, G., Wu, X., Araten, D. J., Loeb, L. A., Cheadle, J. P., Lipsick, J., Albihn, A., Henriksson, M., Kremens, B., Germing, U., Zangemeister-Wittke, U., Simon, H.-U., Yu, Y. P., Luo, J., and Aman, P.

Published
2020

4. Metallothionein enzymes

Author

Pollard, J. W., Danilkovitch-Miagkova, A., Minaguchi, T., Waite, K. A., Buys, T. P. H., Lam, W. L., Müller-Hermelink, H. K., Ott, G., Robb, V. A., Henske, E. P., Lynge, E., Boyd, N., Geisler, C., Seger, R., De Wolf-Peeters, C., Sagaert, X., Sheng, S., Ribatti, D., Verstovsek, S., Akin, C., Stack, M. S., Kitada, S., Gartenhaus, R., Moretti, F., Frühwald, Michael C., Mooi, W. J., Krausz, T., Kefford, R., Peikert, T., Specks, U., Tueting, T., Pföhler, C., Blask, D. E., Stevens, R. G., Nies, A. T., Gotoh, N., Tsuchida, N., Escriba, P., Singh, V., Hickey, M., Saunders, C., Xiao, G.-H., Testa, J. R., Furtwängler, R., Scholler, N., Carbone, M., Furge, K., Woude, G. F. V., Roland, W. C., Muschel, R., Hunter, K., Welch, D. R., Vaidya, K. S., Hurst, D. R., Silveira, A. C., Zang, X. A., Bari, R., Silveira, A., Szmulewitz, R., Taylor, J., Rinker-Schaffer, C., Shim, H., Plass, C., Lindsey, J. C., Clifford, S. C., Holdenrieder, S., Steinle, A., Salih, H., Brown, D. A., Breit, S. N., Bauskin, A. R., Mousses, S., Lung, M. L., Alix-Panabieres, C., Pantel, K., Djuzenova, C. S., Dalmay, T., Ahlquist, T., Lothe, R. A., Bhat, K., Setaluri, V., Rutka, J. T., Salhia, B., Cockell, K. A., Radich, J. P., Yamagishi, S.-I., Bignami, M., Verma, M., Kumar, D., Brenner, C., Zhang, Y.-W., Jamieson, D., Chi, Y.-H., Jeang, K.-T., Roninson, I., Dragani, T., Sobolev, A. S., Powers, M. V., Workmann, P., Evans, M. F., Cooper, K., Kausch, I., Doehn, C., Janz, S., Huang, C.-L., Toland, A. E., Osinaga, E., Kaye, F., Lemos, M. C., Thakker, R. V., Teh, B. T., Ponder, B. A. J., Mulligan, L. M., Gullo, C., Klein, G., Wu, X., Araten, D. J., Loeb, L. A., Cheadle, J. P., Lipsick, J., Albihn, A., Henriksson, M., Kremens, B., Germing, U., Zangemeister-Wittke, U., Simon, H.-U., Yu, Y. P., Luo, J., and Aman, P.

Published
2020

11. SO-35 Tumor infiltrating CD3 lymphocytes and CD68 macrophages are associated with long-time survival in metastatic colorectal cancer patients treated with chemotherapy

Author

Aasebø, K., primary, Bruun, J., additional, Bergsland, C., additional, Eide, G., additional, Dragomir, A., additional, Ponten, F., additional, Guren, M., additional, Svindland, A., additional, Pfeiffer, P., additional, Glimelius, B., additional, Sveen, A., additional, Nesbakken, A., additional, Lothe, R., additional, and Sorbye, H., additional

Published
2020
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12. Tumour-infiltrating CD8+ lymphocytes and colorectal cancer recurrence by tumour and nodal stage

Author

Glaire, MA, Domingo, E, Sveen, A, Bruun, J, Nesbakken, A, Nicholson, G, Novelli, M, Lawson, K, Oukrif, D, Kidal, W, Danielsen, HE, Kerr, R, Kerr, D, Tomlinson, I, Lothe, R, and Church, D

Subjects
Tumour biomarkers, Tumour immunology, Colorectal cancer, Article
Abstract

Background Intratumoural T-cell infiltrate intensity cortes wrelaith clinical outcome in stage II/III colorectal cancer (CRC). We aimed to determine whether this association varies across this heterogeneous group. Methods We performed a pooled analysis of 1804 CRCs from the QUASAR2 and VICTOR trials. Intratumoural CD8+ and CD3+ densities were quantified by immunohistochemistry in tissue microarray (TMA) cores, and their association with clinical outcome analysed by Cox regression. We validated our results using publicly available gene expression data in a pooled analysis of 1375 CRCs from seven independent series. Results In QUASAR2, intratumoural CD8+ was a stronger predictor of CRC recurrence than CD3+ and showed similar discriminative ability to both markers in combination. Pooled multivariable analysis of both trials showed increasing CD8+ density was associated with reduced recurrence risk independent of confounders including DNA mismatch repair deficiency, POLE mutation and chromosomal instability (multivariable hazard ratio [HR] for each two-fold increase = 0.92, 95%CI = 0.87–0.97, P = 3.6 × 10−3). This association was not uniform across risk strata defined by tumour and nodal stage: absent in low-risk (pT3,N0) cases (HR = 1.03, 95%CI = 0.87–1.21, P = 0.75), modest in intermediate-risk (pT4,N0 or pT1-3,N1-2) cases (HR = 0.92, 95%CI = 0.86–1.0, P = 0.046) and strong in high-risk (pT4,N1-2) cases (HR = 0.87, 95%CI = 0.79–0.97, P = 9.4 × 10−3); PINTERACTION = 0.090. Analysis of tumour CD8A expression in the independent validation cohort revealed similar variation in prognostic value across risk strata (PINTERACTION = 0.048). Conclusions The prognostic value of intratumoural CD8+ cell infiltration in stage II/III CRC varies across tumour and nodal risk strata.

Published
2019

15. Functional categories of TP53 mutation in colorectal cancer: results of an International Collaborative Study

Author

Iacopetta, B., Russo, A., Bazan, V., Dardanoni, G., Gebbia, N., Soussi, T., Kerr, D., Elsaleh, H., Soong, R., Kandioler, D., Janschek, E., Kappel, S., Lung, M., Leung, C.-S. S., Ko, J. M., Yuen, S., Ho, J., Leung, S. Y., Crapez, E., Duffour, J., Ychou, M., Leahy, D. T., OʼDonoghue, D. P., Agnese, V., Cascio, S., Di Fede, G., Chieco-Bianchi, L., Bertorelle, R., Belluco, C., Giaretti, W., Castagnola, P., Ricevuto, E., Ficorella, C., Bosari, S., Arizzi, C. D., Miyaki, M., Onda, M., Kampman, E., Diergaarde, B., Royds, J., Lothe, R. A., Diep, C. B., Meling, G. I., Ostrowski, J., Trzeciak, L., Guzińska-Ustymowicz, K., Zalewski, B., Capellá, G. M., Moreno, V., Peinado, M. A., Lönnroth, C., Lundholm, K., Sun, X. F., Jansson, A., Bouzourene, H., Hsieh, L.-L., Tang, R., Smith, D. R., Allen-Mersh, T. G., Khan, Z. A. J., Shorthouse, A. J., Silverman, M. L., Kato, S., and Ishioka, C.

Published
2006

16. Characterization of early recurrences following liver resection by ALPPS and two stage hepatectomy in patients with colorectal liver-metastases and small future liver remnants; a translational substudy of the LIGRO-RCT

Author

Rosok, B. I, Host-Brunsell, T., Brudvik, K. W., Carling, U., Dorenberg, E., Björnsson, Bergthor, Lothe, R. A., Bjombeth, B. A., Sandström, Per, Rosok, B. I, Host-Brunsell, T., Brudvik, K. W., Carling, U., Dorenberg, E., Björnsson, Bergthor, Lothe, R. A., Bjombeth, B. A., and Sandström, Per

Abstract

Background: Associated liver partition and portal vein ligation in staged hepatectomy (ALPPS) is an alternative resection method to portal vein embolization (PVE) in patients with small future liver remnants (FLR) but has been associated with early tumor recurrences. Methods: Twenty-four patients with colorectal liver metastases (CRLM) patients from the randomized multicenter LIGRO trial comparing outcome of ALPPS (n = 13) vs PVE (n = 11) were included in the study. Mutational analyses of the KRAS, NRAS, BRAF, PIC3CA and TP53 genes of the metastases were performed in 21 patients and correlated to early tumor recurrence. Results: Within 12 months, 13 patients experienced recurrences (6 in TSH group and 7 in ALPPS group). Nine of 13 patients with recurrences had mutations in the TP53 gene, while 3 of 8 patients without recurrence carried the same mutation. Only sporadic cases of the other mutations studied were identified. Conclusions: ALPPS did not appear to be associated with higher rate of rapid recurrences than PVE following radical resection of colorectal liver metastases. Mutations in genes associated with negative oncologic outcome after surgical resection most likely play a role for tumor recurrences in these patients., Funding Agencies|Norwegian Cancer Society [182759-2016]; South-East Regional Health Trust, Norway; Norwegian Research Council [250993]

Published
2019
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20. Characterization of early recurrences following liver resection by ALPPS and two stage hepatectomy (TSH) in patients with colorectal liver-metastases and small future liver remnants (FLR)

Author

Røsok, B.I., primary, Brunsell, T.H., additional, Carling, U., additional, Dorenberg, E., additional, Brudvik, K., additional, Bjørnbeth, B.A., additional, Nesbakken, A., additional, Björnsson, B., additional, Lothe, R., additional, and Sandstrøm, P., additional

Published
2018
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26. Novel genomic aberrations in testicular germ cell tumors by array-CGH, and associated gene expression changes

Author

Skotheim, R. I., Reija Autio, Lind, G. E., Kraggerud, S. M., Andrews, P. W., Monni, O., Kallioniemi, O., and Lothe, R. A.

Abstract

Introduction: Testicular germ cell tumors of adolescent and young adult men (TGCTs) generally have near triploid and complex karyotypes. The actual genes driving the tumorigenesis remain essentially to be identified. Materials and Methods: To determine the detailed DNA copy number changes, and investigate their impact on gene expression levels, we performed an integrated microarray profiling of TGCT genomes and transcriptomes. We analyzed 17 TGCTs, three precursor lesions, and the embryonal carcinoma cell lines, NTERA2 and 2102Ep, by comparative genomic hybridization microarrays (array-CGH), and integrated the data with transcriptome profiles of the same samples. Results: The gain of chromosome arm 12p was, as expected, the most common aberration, and we found CCND2, CD9, GAPD, GDF3, NANOG, and TEAD4 to be the therein most highly over-expressed genes. Additional frequent genomic aberrations revealed some shorter chromosomal segments, which are novel to TGCT, as well as known aberrations for which we here refined boundaries. These include gains from 7p15.2 and 21q22.2, and losses of 4p16.3 and 22q13.3. Integration of DNA copy number information to gene expression profiles identified that BRCC3, FOS, MLLT11, NES, and RAC1 may act as novel oncogenes in TGCT. Similarly, DDX26, ERCC5, FZD4, NME4, OPTN, and RB1 were both lost and under-expressed genes, and are thus putative TGCT suppressor genes. Conclusion: This first genome-wide integrated array-CGH and gene expression profiling of TGCT provides novel insights into the genome biology underlying testicular tumorigenesis.

Published
2006

27. Prognostic impact of genomic instability in colorectal cancer

Author

Hveem, T S, primary, Merok, M A, additional, Pretorius, M E, additional, Novelli, M, additional, Bævre, M S, additional, Sjo, O H, additional, Clinch, N, additional, Liestøl, K, additional, Svindland, A, additional, Lothe, R A, additional, Nesbakken, A, additional, and Danielsen, H E, additional

Published
2014
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30. Testicular germ cell tumor susceptibility associated with the UCK2 locus on chromosome 1q23

Author

Schumacher, F. R., primary, Wang, Z., additional, Skotheim, R. I., additional, Koster, R., additional, Chung, C. C., additional, Hildebrandt, M. A. T., additional, Kratz, C. P., additional, Bakken, A. C., additional, Timothy Bishop, D., additional, Cook, M. B., additional, Erickson, R. L., additional, Fossa, S. D., additional, Greene, M. H., additional, Jacobs, K. B., additional, Kanetsky, P. A., additional, Kolonel, L. N., additional, Loud, J. T., additional, Korde, L. A., additional, Le Marchand, L., additional, Pablo Lewinger, J., additional, Lothe, R. A., additional, Pike, M. C., additional, Rahman, N., additional, Rubertone, M. V., additional, Schwartz, S. M., additional, Siegmund, K. D., additional, Skinner, E. C., additional, Turnbull, C., additional, Van Den Berg, D. J., additional, Wu, X., additional, Yeager, M., additional, Nathanson, K. L., additional, Chanock, S. J., additional, Cortessis, V. K., additional, and McGlynn, K. A., additional

Published
2013
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39. A germline E-cadherin mutation in a family with gastric and colon cancer

Author

Salahshor, S., primary, Hou, H., additional, Diep, C., additional, Loukola, A., additional, Zhang, H., additional, Liu, T., additional, Chen, J., additional, Iselius, L., additional, Rubio, C., additional, Lothe, R., additional, Aaltonen, L., additional, Sun, X.-F., additional, Lindmark, G., additional, and Lindblom, A., additional

Published
2001
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41. CHAPTER 11: Nerve sheath tumours.

Author

Antonescu, C. R., Perry, A., Woodruff, J. M., Stratakis, C. A., Brems, H., Legius, E., Hornick, J. L., Fletcher, C. D. M., Fletcher, J. A., Lazar, A., Fetsch, J. F., Dry, S. M., Kutzner, H., Thompson, L. D. R., Michal, M., Nielsen, G. P., Lothe, R. A., Fanburg-Smith, J. C., and Coffin, C. M.

Published
2013

47. Genetic and Protein Markers Related to in situ Growth and Multiplicity in Small Sporadic Colorectal Adenomas.

Author

T., Løvig, L., Thorstensen, B., Hofstad, S., Norheim Andersen, P., Fraas Clausen O., M., Vatn, A., Lothe R., and O., Rognum T.

Subjects
STOMACH cancer, AUTOIMMUNE diseases, LYMPHOMAS, HELICOBACTER pylori
Abstract

Background: Some early genetic events in the development of colorectal adenomas are known, but their relationship to in vivo growth characteristics is uncertain. This study compared in situ size changes and other clinicopathological variables with selected genetic and protein markers. Methods: 56 adenomas (≤10 mm) from 39 patients were analysed for APC, CTNNB1 and K- ras mutations, allelic imbalance on 1p and 18q, microsatellite instability and immunohistochemical expression of HLA-DR, BAX, BCL-2 and Ki-67. For 42 of the adenomas, in situ growth was measured over 3 years. The total number of polyps in each patient was recorded. Results: K- ras was mutated in 8/56 adenomas. None of the regressing adenomas revealed such mutations, compared to 20% in those that maintained or increased their size. Multivariate linear regression analysis showed that tumour growth was higher in females compared to males, and was even higher in the presence of a K- ras mutation. APC mutations were found in 37/56 adenomas. CTNNB1 mutations were found in 2/19 adenomas without APC mutation. Deletions of 1p were found in 12/56 adenomas and, seemingly, most frequent in patients with few tumours. The most frequently expressed protein was BAX (33/41), but neither this nor the other proteins showed associations with an in situ growth pattern. Conclusion: The multivariate linear regression model showed that patient gender and the presence of K- ras mutation had significant effects on tumour growth. The lack of the proliferative stimulus resulting from a K- ras mutation may contribute to the process of adenoma regression. [ABSTRACT FROM AUTHOR]

Published
2003

48. Identification of Two Potential Suppressor Gene Regions on Chromosome Arm 14q That Are Commonly Lost in Advanced Colorectal Carcinomas.

Author

Thorstensen, L., Qvist, H., Nesland, J. M., Giercksky, K.-E., and Lothe, R. A.

Subjects
COLON cancer, LIVER metastasis, CHROMOSOMES
Abstract

Background: Remarkably little is known about the molecular alterations contributing to the establishment of a distant metastasis from a primary colorectal carcinoma. Previous studies on primary colorectal carcinomas have suggested an association between loss of chromosome 14 sequences and cancer progression. Methods: In the present study, we analyzed 20 distant metastases and peripheral blood samples from 18 patients using 24 microsatellite markers spanning chromosome arm 14q. In addition, DNA from microdissected corresponding primary tumors (formalin-fixed and paraffinembedded) was analyzed at selected 14q loci. Results: Sixty-five percent (13/20) of the metastases, from 11/18 patients, showed loss of one or more markers at 14q, and the majority (94%) of the primary carcinomas showed identical 14q genotypes to those found in the metastasis. Two minimal common deleted regions were delineated in the metastases, one between markers D14S288-D14S52 at 14q13-21 and the other between D14S284-D14S81 at 14q24-31, pinpointing two previously unrecognized map positions for potential target genes. The genotype pattern of five tumors was consistent with monosomy or large chromosomal deletions spanning both potential suppressor regions. The reasons for monosomy in cancer remain unknown, but our data support the hypothesis that deletions of several tumor suppressor genes are more readily obtained by one chromosome loss than by several molecular events, and through this unison loss a growth advantage may be provided. Conclusion: Our data suggest that 14q loss is not a rate-limiting event in colorectal metastasis formation, but the high frequency of this alteration in primary tumors with metastatic ability, as well as in the metastases themselves, suggests it is part of the tumor clone with selective growth capacity. [ABSTRACT FROM AUTHOR]

Published
2001
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