H2ax

DNA repair

Celeste et al.(2003)

Nbn

DNA repair

Dumon-Jones et al. (2003)

Anx7

DNA repair

Srivastava et al.(2003)

Figure 4.4

Genetic heterogeneity of LOH regions (depicted by black capped bars) may explain the failure to find the "neuroblastoma suppressor gene." In case of genetic heterogeneity, there could actually be at least two (B, C), if not more genes involved, and these might be separated many megabases from each other. Combining these LOH regions into a single consensus region (A) would inevitably initiate a gene search in a region that is unlikely to harbor the long-sought NSG

According to this hypothesis, there would actually be two SROs, each harboring a different gene that is damaged only in tumors of the corresponding group. As mentioned above, previous studies have indicated that two, or even more, "neuroblastoma genes" may reside in chromosome 1p (Caron et al. 2001). The existence of two separate 1p regions with relevance to neuroblastoma is also supported by an independent study that indicated two regions of loss, at 1p36 and 1p22 (Mora et al. 2000). Another study concluded that there were three regions of loss at 1p36.1-2,1p36.3, and 1p32-34, and each was associated with different neuroblastoma groups (Hiyama et al. 2001).

4.5 Comparative Genomic Hybridization

In CGH, differentially labeled tumor DNA and normal DNA are competitively hybridized to normal human metaphase chromosomes (Kallioniemi et al. 1992). This methodology detects quantitative chromosomal changes, such as deletions, duplications or amplifications on the basis of the ratio of the hybridization of the two differently labeled DNAs. The advantage of this approach is that the complete set of quantitative genomic changes can be determined in a single experiment. Limitations are the low level of resolution (several Mb) and the fact that absolute quantitation of the changes is not precise. More recently, array CGH has been performed in an effort to increase the resolution of this technique. This strategy utilizes an array of DNA targets, and both cDNA and BAC arrays have been used (Beheshti et al. 2003; Cowel and Nowak 2003).

Both CGH and array CGH (Cunsolo et al. 2000; Plantaz et al. 2001; Schleiermacher et al. 2003; Stallings et al. 2003; Vettenranta et al. 2001) have largely confirmed previous cytogenetic and LOH studies revealing a high-frequency of 1p loss, 11p loss, 2p gain, and 17q gain (Schleiermacher et al. 2004; Brinkschmidt et al. 1997; Lastowska et al. 1997b, 2002; Plantaz et al. 1997; Vandesompele et al. 1998). The CGH studies have also revealed that about 50% of neuroblastomas have an additional segment of 17q, indicating that gain of 17q is the most frequent genetic alteration in neuroblastoma. Gain of 17q ap pears more common in advanced-stage tumors, in tumors from children aged over 1 year, and in tumors showing 1p loss, amplified MYCN, and diploidy or tetraploidy. In contrast,triploidy with whole chromosome 17 gain is associated more often with neuroblastomas showing favorable clinical and genetic features (Bown et al. 1999). Amplified MYCN rarely, if ever, occurs without either 1p deletion or 17q gain or both, implying that MYCN amplification is a later event in the sequence of genetic aberrations underlying neuroblastoma progression (Bown et al. 1999). Although several studies appear to suggest 17q gain as a powerful prognostic factor (Abel et al. 1999; Bown et al. 1999,2001; Caron 1995; Caron et al. 1996; Lastowska et al. 1997a), a recent study could not confirm this association (Spitz et al. 2003).

4.6 Tumor Cell Ploidy

Many neuroblastomas have higher than normal DNA content or hyperploidy. Kaneko and Knudson have suggested that in neuroblastoma, aneuploidy may be a consequence of tetraploidization with subsequent bipolar, tripolar, or tetrapolar divisions (Kaneko and Knudson 2000). Supernumerary centrosomes leading to multipolar divisions have been implicated in both chromosome missegregation and the generation of aneuploid cells in various cancer types, including neuroblastoma (Brinkley 2001). A defect of spindle formation may cause incomplete segregation during mitosis; thus, such a defect in a tetraploid cell undergoing a tripolar division could lead to one near-triploid and one near-pentaploid cell. In fact, in neu-roblastoma tumors with more than one tumor cell clone,near-pentaploid tumor cells are often observed together with near-triploid tumor cells.

Recently, Kaneko and Knudson have developed an attractive hypothesis explaining the association between ploidy and neuroblastoma phenotype (Kaneko and Knudson 2000). This hypothesis is based on the assumption that both clinically "favorable" triploid tumors and clinically "unfavorable" diploid tumors arise through the same genetic event, as suggested from observations in familial cases (Knudson and Strong 1972; Kushner et al. 1986). The initiating tumorigenic event may be a mutation in a classical tumor suppressor gene with recessive effect at cellular level (Comings 1973; Knudson and Strong 1972). Tetraploidization and subsequent multipolar division of a diploid cell heterozygous for a mutation in such a gene would give rise to diploid and tetraploid daughter cells with no normal allele and highly malignant phenotype, or triploid daughter cells with at least one normal allele and less malignant phenotype.

4.7 Conclusion

Despite many advances in understanding the genetics and developmental molecular pathways,they have not yet translated into more effective therapy for high-risk neuroblastoma Nevertheless, the fascinating multiplicity of its clinical and biological pheno-types has attracted a growing number of clinical and basic scientists. Their combined efforts will inevitably resolve the intricate pathways that govern both progression and spontaneous regression of this disease. This knowledge should provide the platform for the development of new diagnostic tools and novel therapeutic strategies. Until then, we should be careful and avoid offering simplified suggestions for a rapid clinical translation.

Acknowledgements. Work in the author's laboratory was supported by grants from the Deutsche Krebshilfe, Sander Stiftung, Bundesministerium für Forschung und Technology, and by DKFZ-MOS (Israel) cooperation.

References

Abel F, Ejeskar K, Kogner P et al. (1999) Gain of chromosome arm 17q is associated with unfavourable prognosis in neuroblastoma, but does not involve mutations in the somatostatin receptor 2(SSTR2) gene at 17q24. Br J Cancer 81:1402-1409 Alaminos M, Mora J, Cheung NK et al. (2003) Genome-wide analysis of gene expression associated with MYCN in human neuroblastoma. Cancer Res 63:4538-4546 Alt FW, Kellems RE, Bertino JR et al. (1978) Selective multiplication of dihydrofolate reductase genes in methotrexate-resistant variants of cultured murine cells. J Biol Chem

253:1357-1370

Amler LC, Corvi R, Praml C et al. (1995) A reciprocal translocation (i;i5) (36.2;q24) in a neuroblastoma cell line is accompanied by DNA duplication and may signal the site of a putative tumor suppressor-gene. Oncogene 10:1095-1101 Amler LC, Bauer A, Corvi R et al. (2000) Identification and characterization of novel genes located at the t(1;15) (p36.2;q24) translocation breakpoint in the neuroblastoma cell line NGP. Genomics 64:195-202 Balaban-Malenbaum G, Gilbert F (1977) Double minute chromosomes and the homogeneously staining regions in chromosomes of a human neuroblastoma cell line. Science 198:739-741 Barton K, Nucifora G (2000) AML1 haploinsufficiency, gene dosage, and the predisposition to acute leukemia. Bioessays 22:214-218

Bauer A, Savelyeva L, Claas A et al (2001) Smallest region of overlapping deletion in 1p36 in human neuroblastoma: a 1 Mbp cosmid and PAC contig. Genes Chromosomes Cancer 31:228-239

Beheshti B, Braude I, Marrano P et al. (2003) Chromosomal localization of DNA amplifications in neuroblastoma tumors using cDNA microarray comparative genomic hybridization. Neoplasia 5:53-62 Berwanger B, Hartmann O, Bergmann E et al. (2002) Loss of a FYN-regulated differentiation and growth arrest pathway in advanced stage neuroblastoma. Cancer Cell 2:377-386 Biedler JL, Spengler BA (1976) A novel chromosome abnormality in human neuroblastoma and antifolate-resistant Chinese hamster cell lives in culture. J Natl Cancer Inst 57:683-695

Biegel JA, White PS, Marshall HN et al. (1993) Constitutional 1p36 deletion in a child with neuroblastoma. Am J Hum Genet 52:176-182 Bishop JM (1981) Enemies within: the genesis of retrovirus oncogenes. Cell 23:5-6 Bishop JM (1982) Retroviruses and cancer genes. Adv Cancer Res 37:1-32

Bishop JM (1987) The molecular genetics of cancer. Science

235:305-311

Bown N, Pearson AD, Reid MM (1993) High incidence of constitutional balanced translocations in neuroblastoma. Cancer Genet Cytogenet 69:166-167 Bown N, Cotterill S, Lastowska M et al. (1999) Gain of chromosome arm 17q and adverse outcome in patients with neu-roblastoma. N Engl J Med 340:1954-1961 Bown N, Lastowska M, Cotterill S et al. (2001) 17q gain in neu-roblastoma predicts adverse clinical outcome. U.K. Cancer Cytogenetics Group and the U.K. Children's Cancer Study Group. Med Pediatr Oncol 36:14-19 Brinkley BR (2001) Managing the centrosome numbers game: from chaos to stability in cancer cell division. Trends Cell Biol 11:18-21

Brinkschmidt C, Christiansen H, Terpe HJ et al. (1997) Comparative genomic hybridization (CGH) analysis of neuro-blastomas: an important methodological approach in paediatric tumour pathology. J Pathol 181:394-400

Brodeur GM, Sekhon G, Goldstein MN (1977) Chromosomal aberrations in human neuroblastomas. Cancer 40:22562263

Brodeur GM, Green AA, Hayes FA et al. (1981) Cytogenetic features of human neuroblastomas and cell lines. Cancer Res 41:4678-4686

Caron H (1995) Allelic loss of chromosome 1 and additional chromosome 17 material are both unfavourable prognostic markers in neuroblastoma. Med Pediatr Oncol 24:215-221 Caron H, van Sluis P, van Hoeve M et al. (1993) Allelic loss of chromosome 1p36 in neuroblastoma is of preferential maternal origin and correlates with N-myc amplification. Nat Genet 4:187-190 Caron H, van Sluis P, van Roy N et al. (1994) Recurrent 1;17 translocations in human neuroblastoma reveal nonhomol-ogous mitotic recombination during the S/G2 phase as a novel mechanism for loss of heterozygosity. Am J Hum Genet 55:341-347 Caron H, Peter M,van Sluis P et al (1995) Evidence for two tumour suppressor loci on chromosomal bands 1p35-36 involved in neuroblastoma: one probably imprinted, another associated with N-myc amplification. Hum Mol Genet 4:535-539 Caron H, van Sluis P, de Kraker J et al. (1996) Allelic loss of chromosome 1p as a predictor of unfavorable outcome in patients with neuroblastoma. N Engl J Med 334:225-230 Caron H, Spieker N, Godfried M et al. (2001) Chromosome bands 1p35-36 contain two distinct neuroblastoma tumor suppressor loci, one of which is imprinted. Genes Chromosomes Cancer 30:168-174 Caspersson T, Farber S, Foley GE et al. (1968) Chemical differentiation along metaphase chromosomes. Exp Cell Res 49:219-222

Cavenee WK, Dryja TP, Phillips RA et al. (1983) Expression of recessive alleles by chromosomal mechanisms in retino-blastoma. Nature 305:779-784 Cavenee WK, Hansen MF, Nordenskjold M et al (1985) Genetic origin of mutations predisposing to retinoblastoma. Science 228:501-503 Celeste A, Difilippantonio S, Difilippantonio MJ et al. (2003) H2AX haploinsufficiency modifies genomic stability and tumor susceptibility. Cell 114:371-383 Chatten J,Voorhess ML (1967) Familial neuroblastoma. Report of a kindred with multiple disorders, including neuroblas-tomas in four siblings. N Engl J Med 277:1230-1236 Cheng NC, van Roy N, Chan A, Beitsma M et al. (1995) Deletion mapping in neuroblastoma cell lines suggests two distinct tumor suppressor genes in the 1p35-36 region, only one of which is associated with N-myc amplification. Oncogene

10:291-297

Comings DE (1973) A general theory of carcinogenesis. Proc

Natl Acad Sci USA 70:3324-3328 Corvi R, Savelyeva L, Schwab M (1995) Duplication of N-MYC at its resident site 2p24 may be a mechanism of activation alternative to amplification in human neuroblastoma cells. Cancer Res 55:3471-3474

Cowel JK, Nowak NJ (2003) High-resolution analysis of genetic events in cancer cells using bacterial artificial chromosome arrays and comparative genome hybridization. Adv Cancer Res 90:91-125 Cox D, Yuncken C, Spriggs AI (1965) Minute chromatin bodies in malignant tumours of childhood. Lancet 62:55-58 Cunsolo CL, Bicocchi MP, Petti AR, Tonini GP (2000) Numerical and structural aberrations in advanced neuroblastoma tumours by CGH analysis; survival correlates with chromosome 17 status. Br J Cancer 83:1295-1300 Dalla-Favera R, Bregni M, Erikson J et al. (1982) Human c-myc onc gene is located on the region of chromosome 8 that is translocated in Burkitt lymphoma cells. Proc Natl Acad Sci USA 79:7824-7827 Der CJ, Krontiris TG, Cooper GM (1982) Transforming genes of human bladder and lung carcinoma cell lines are homologous to the ras genes of Harvey and Kirsten sarcoma viruses. Proc Natl Acad Sci USA 79:3637-3640 Dryja TP, Cavenee W, White R et al (1984) Homozygosity of chromosome 13 in retinoblastoma. N Engl J Med 310:550553

Dumon-Jones V, Frappart PO, Tong WM et al. (2003) Nbn het-erozygosity renders mice susceptible to tumor formation and ionizing radiation-induced tumorigenesis. Cancer Res 63:7263-7269

Ejeskar K, Sjoberg RM, Abel F et al. (2001) Fine mapping of a tumour suppressor candidate gene region in 1p36.2-3, commonly deleted in neuroblastomas and germ cell tumours. Med Pediatr Oncol 36:61-66 Fan J, Tam P, Woude GV et al (2004) Normalization and analysis of cDNA microarrays using within-array replications applied to neuroblastoma cell response to a cytokine. Proc Natl Acad Sci USA 101:1135-1140 Fero ML, Randel E, Gurley KE et al. (1998) The murine gene p27Kip1 is haplo-insufficient for tumour suppression. Nature 396:177-180 Fong CT, Dracopoli NC,White PS et al. (1989) Loss of heterozy-gosity for the short arm of chromosome 1 in human neu-roblastomas: correlation with N-myc amplification. Proc Natl Acad Sci USA 86:3753-3757 Fong CT, White PS, Peterson K et al. (1992) Loss of heterozy-gosity for chromosomes 1 or 14 defines subsets of advanced neuroblastomas. Cancer Res 52:1780-1785 Friend SH, Bernards R, Rogelj S et al. (1986) A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature 323:643-646 Fung YK, Murphree AL, T'Ang A et al. (1987) Structural evidence for the authenticity of the human retinoblastoma gene. Science 236:1657-1661 Gehring M, Berthold F, Edler L et al. (1995) The 1p deletion is not a reliable marker for the prognosis of patients with neu-roblastoma. Cancer Res 55:5366-5369 Gennett IN, Cavenee WK (1990) Molecular genetics in the pathology and diagnosis of retinoblastoma. Brain Pathol 1:25-32

Gilbert F, Balaban G,Moorhead P et al. (1982) Abnormalities of chromosome 1p in human neuroblastoma tumors and cell lines. Cancer Genet Cytogenet 7:33-42 Goss KH, Risinger MA, Kordich JJ et al. (2002) Enhanced tumor formation in mice heterozygous for Blm mutation. Science 297:2051-2053 Gratacos M,Nadal M,Martin-Santos R et al. (2001) A polymorphic genomic duplication on human chromosome 15 is a susceptibility factor for panic and phobic disorders. Cell

106:367-379

Groffen J, Stephenson JR, Heisterkamp N et al. (1984) Philadelphia chromosomal breakpoints are clustered within a limited region, bcr, on chromosome 22. Cell 36:93-99 Gruber SB, Ellis NA, Scott KK et al. (2002) BLM heterozygosity and the risk of colorectal cancer. Science 297:2013 Guo C,White PS,Weiss MJ et al. (1999) Allelic deletion at 11q23 is common in MYCN single copy neuroblastomas. Onco-gene 18:4948-4957 Guo C,White PS, Hogarty MD et al. (2000) Deletion of 11q23 is a frequent event in the evolution of MYCN single-copy high-risk neuroblastomas. Med Pediatr Oncol 35:544-546 Hecht F, Hecht BK,Northrup JC et al. (1982) Genetics of familial neuroblastoma: long-range studies. Cancer Genet Cyto-genet 7:227-230 Heisterkamp N, Stephenson JR, Groffen J et al. (1983) Localization of the c-ab1 oncogene adjacent to a translocation break point in chronic myelocytic leukaemia. Nature 306:239-242 Hiyama E, Hiyama K, Ohtsu K et al. (2001) Biological characteristics of neuroblastoma with partial deletion in the short arm of chromosome 1. Med Pediatr Oncol 36:67-74 Hogarty MD, Liu X, Guo C et al. (2000) Identificaiton of a 1-megabase consensus region of deletion at 1p36.3 in primary neuroblastomas. Med Pediatr Oncol 35:512-515 Hoshi M, Otagiri N, Shiwaku HO et al. (2000) Detailed deletion mapping of chromosome band 14q32 in human neuroblas-toma defines a 1.1-Mb region of common allelic loss. Br J Cancer 82:1801-1807 Ide F, Kitada M, Sakashita H et al. (2003) p53 haploinsufficien-cy profoundly accelerates the onset of tongue tumors in mice lacking the xeroderma pigmentosum group A gene. Am J Pathol 163:1729-1733 Inoue K, Zindy F, Randle DH et al. (2001) Dmp1 is haplo-insuf-ficient for tumor suppression and modifies the frequencies of Arf and p53 mutations in Myc-induced lymphomas. Genes Dev 15:2934-2939 Kallioniemi A, Kallioniemi OP, Sudar D et al. (1992) Comparative genomic hybridization for molecular cytogenetic analysis of solid tumors. Science 258:818-821 Kaneko Y, Knudson AG (2000) Mechanism and relevance of ploidy in neuroblastoma. Genes Chromosomes Cancer

29:89-95

Khan J, Wei JS, Ringner M et al. (2001) Classification and diagnostic prediction of cancers using gene expression profiling and artificial neural networks. Nat Med 7:673-679

Knudson AG Jr (1971) Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 68:820-823 Knudson AG Jr, Strong LC (1972) Mutation and cancer: neuroblastoma and pheochromocytoma. Am J Hum Genet 24:514-532

Koiffmann CP, Gonzalez CH,Vianna-Morgante AM et al. (1995) Neuroblastoma in a boy with MCA/MR syndrome, deletion nq, and duplication 12q. Am J Med Genet 58:46-49 Kucherlapati M,Yang K, Kuraguchi M et al. (2002) Haploinsuf-ficiency of Flap endonuclease (Fern) leads to rapid tumor progression. Proc Natl Acad Sci USA 99:9924-9929 Kushner BH, Gilbert F, Helson L (1986) Familial neuroblastoma. Case reports, literature review, and etiologic considerations. Cancer 57:1887-1893 Kwabi-Addo B, Giri D, Schmidt K et al. (2001) Haploinsufficien-cy of the Pten tumor suppressor gene promotes prostate cancer progression. Proc Natl Acad Sci USA 98:11563-11568 Lastowska M, Cotterill S, Pearson AD et al. (1997a) Gain of chromosome arm 17q predicts unfavourable outcome in neurob-lastoma patients.U.K.Children's Cancer Study Group and the U.K. Cancer Cytogenetics Group. Eur J Cancer 33:1627-1633 Lastowska M, Nacheva E, McGuckin A et al. (1997b) Comparative genomic hybridization study of primary neuroblas-toma tumors. United Kingdom Children's Cancer Study Group. Genes Chromosomes Cancer 18:162-169 Lastowska M, Roberts P, Pearson AD et al. (1997c) Promiscuous translocations of chromosome arm 17q in human neuro-blastomas. Genes Chromosomes Cancer 19:143-149 Lastowska M, Cotterill S, Bown N et al. (2002) Breakpoint position on 17q identifies the most aggressive neuroblastoma tumors. Genes Chromosomes Cancer 34:428-436 Laureys G, Speleman F, Opdenakker G et al. (1990) Constitutional translocation t(1;17)(p36;q12-21) in a patient with neuroblastoma. Genes Chromosomes Cancer 2:252-254 Lee WH, Bookstein R, Hong F et al. (1987) Human retinoblastoma susceptibility gene: cloning, identification, and sequence. Science 235:1394-1399 Maris JM, Kyemba SM, Rebbeck TR et al. (1996) Familial predisposition to neuroblastoma does not map to chromosome band 1p36. Cancer Res 56:3421-3425 Maris JM,Weiss MJ, Guo C et al. (2000) Loss of heterozygosity at 1p36 independently predicts for disease progression but not decreased overall survival probability in neuroblas-toma patients: a Children's Cancer Group study. J Clin Oncol 18:1888-1899 Maris JM, Guo C, White PS et al. (2001a) Allelic deletion at chromosome bands 11q14-23 is common in neuroblastoma. Med Pediatr Oncol 36:24-27 Maris JM, Guo C, Blake D et al. (2001b) Comprehensive analysis of chromosome 1p deletions in neuroblastoma. Med Pe-diatr Oncol 36:32-36 Marshall B, Isidro G, Martins AG et al. (1997) Loss of hetero-zygosity at chromosome 9p21 in primary neuroblastomas: evidence for two deleted regions. Cancer Genet Cytogenet

96:134-139

Martinsson T, Sjoberg RM, Hedborg F et al. (1995) Deletion of chromosome ip loci and microsatellite instability in neuroblastomas analyzed with short-tandem repeat polymorphisms. Cancer Res 55:5681-5686 Martinsson T, Sjoberg RM, Hallstensson K et al. (1997) Delimitation of a critical tumour suppressor region at distal 1p in neuroblasoma tumours. Eur J Cancer 33:1997-2001 Meddeb M, Danglot G, Chudoba I et al. (1996) Additional copies of a 25 Mb chromosomal region originating from 17q23.1-17qter are present in 90% of high-grade neuroblas-tomas. Genes Chromosomes Cancer 17:156-165 Mertens F, Johansson B, Hoglund M et al. (1997) Chromosomal imbalance maps of malignant solid tumors: a cytogenetic survey of 3185 neoplasms. Cancer Res 57:2765-2780 Miller RW, Fraumeni JF Jr, Hill JA (1968) Neuroblastoma: epidemiologic approach to its origin. Am J Dis Child 115: 253-261

Miyoshi H,Nakau M, Ishikawa TO et al. (2002) Gastrointestinal hamartomatous polyposis in Lkb1 heterozygous knockout mice. Cancer Res 62:2261-2266 Mora J, Cheung NK, Kushner BH et al. (2000) Clinical categories of neuroblastoma are associated with different patterns of loss of heterozygosity on chromosome arm 1p. J Mol Diagn 2:37-46 Mora J, Gerald WL, Cheung NK (2003) Evolving significance of prognostic markers associated with new treatment strategies in neuroblastoma. Cancer Lett 197:119-124 Mosse Y, Greshock J, King A et al. (2003) Identification and high-resolution mapping of a constitutional nq deletion in an infant with multifocal neuroblastoma. Lancet Oncol

4:769-771

Neel BG, Jhanwar SC, Chaganti RS et al. (1982) Two human c-onc genes are located on the long arm of chromosome 8. Proc Natl Acad Sci USA 79:7842-7846 Nowell PC, Hungerford DA (1960a) Chromosome studies on normal and leukemic human leukocytes. J Natl Cancer Inst 25:85-109

Nowell PC, Hungerford DA (1960b) A minute chromosome in human granulocytic leukemia. Science 132:1497-1499 Ohira M, Kageyama H, Mihara M et al. (2000) Identification and characterization of a 500-kb homozygously deleted region at 1p36.2-p36.3 in a neuroblastoma cell line. Oncogene

19:4302-4307

Parada LF, Tabin CJ, Shih C et al. (1982) Human EJ bladder carcinoma oncogene is homologue of Harvey sarcoma virus ras gene. Nature 297:474-478 Perri P, Longo L, Cusano R et al. (2002) Weak linkage at 4p16 to predisposition for human neuroblastoma. Oncogene 21:8356-8360

Plantaz D, Mohapatra G, Matthay KK et al. (1997) Gain of chromosome 17 is the most frequent abnormality detected in neuroblastoma by comparative genomic hybridization. Am J Pathol 150:81-89

Plantaz D,Vandesompele J,van Roy N et al. (2001) Comparative genomic hybridization (CGH) analysis of stage 4 neuroblastoma reveals high frequency of iiq deletion in tumors lacking MYCN amplification. Int J Cancer 91:680-686 Sandberg AA, Sakurai M, Holdsworth RN (1972) Chromosomes and causation of human cancer and leukemia. 8. DMS chromosomes in a neuroblastoma. Cancer 29:16711679

Santos E, Tronick SR, Aaronson SA et al. (1982) T24 human bladder carcinoma oncogene is an activated form of the normal human homologue of BALB- and Harvey-MSV transforming genes. Nature 298:343-347 Satge D, Moore SW, Stiller CA et al. (2003) Abnormal constitutional karyotypes in patients with neuroblastoma: a report of four new cases and review of 47 others in the literature. Cancer Genet Cytogenet 147:89-98 Savelyeva L, Claas A, Matzner I et al. (2001) Constitutional ge-nomic instability with inversions, duplications, and amplifications in 9p23-24 in BRCA2 mutation carriers. Cancer Res 61:5179-5185 Savelyeva L, Corvi R, Schwab M (1994) Translocation involving 1p and 17q is a recurrent genetic alteration of human neu-roblastoma cells. Am J Hum Genet 55:334-340 Schleiermacher G, Peter M, Michon J et al. (1994) Two distinct deleted regions on the short arm of chromosome 1 in neu-roblastoma. Genes Chromosomes Cancer 10:275-281 Schleiermacher G, Delattre O, Peter M et al. (1996) Clinical relevance of loss heterozygosity of the short arm of chromosome 1 in neuroblastoma: a single-institution study. Int J Cancer 69:73-78 Schleiermacher G, Janoueix-Lerosey I, Combaret V et al. (2003) Combined 24-color karyotyping and comparative genomic hybridization analysis indicates predominant rearrangements of early replicating chromosome regions in neuro-blastoma. Cancer Genet Cytogenet 141:32-42 Schleiermacher G, Raynal V, Janoueix-Lerosey I et al. (2004) Variety and complexity of chromosome 17 translocations in neuroblastoma. Genes Chromosomes Cancer 39:143-150 Schwab M (1998) Amplification of oncogenes in human cancer cells. Bioessays 20:473-479 Schwab M, Alitalo K, Klempnauer KH et al. (1983a) Amplified DNA with limited homology to myc cellular oncogene is shared by human neuroblastoma cell lines and a neuroblas-toma tumour. Nature 305:245-248 Schwab M, Alitalo K,Varmus HE et al. (1983b) A cellular oncogene (c-Ki-ras) is amplified, overexpressed, and located within karyotypic abnormalities in mouse adrenocortical tumour cells. Nature 303:497-501 Schwab M, Varmus HE, Bishop JM et al. (1984) Chromosome localization in normal human cells and neuroblastomas of a gene related to c-myc. Nature 308:288-291 Schwab M, Varmus HE, Bishop JM (1985) Human N-myc gene contributes to neoplastic transformation of mammalian cells in culture. Nature 316:160-162

Schwab M, Praml C, Amler LC et al. (1996) Genomic instability in ip and human malignancies. Genes Chromosomes Cancer 16:211-229

Schwab M,Westermann F, Hero B et al. (2003) Neuroblastoma: biology and molecular and chromosomal pathology. Lancet Oncol 4:472-480 Shaffer LG, Heilstedt HA (2001) Terminal deletion of 1p36.

Lancet 358 (Suppl):S9 Shapira SK,McCaskill C,Northrup H et al. (1997) Chromosome 1p36 deletions: the clinical phenotype and molecular characterization of a common newly delineated syndrome. Am J Hum Genet 61:642-650 Smits R, Ruiz P, Diaz-Cano S et al. (2000) E-cadherin and ade-nomatous polyposis coli mutations are synergistic in intestinal tumor initiation in mice. Gastroenterology 119:

10 Ways To Fight Off Cancer

10 Ways To Fight Off Cancer

Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.

Get My Free Ebook


Post a comment