Abstract
Neuroblastoma occasionally occurs in diseases associated with abnormal neurocrest differentiation, e.g. Hirschsprung disease. Expression studies in developing mice suggest that the proto-oncogeneRET plays a role in neurocrest differentiation. In humans expression ofRET is limited to certain tumor types, including neuroblastoma, that derive from migrating neural crest cells. Mutations ofRET are found associated with Hirschsprung disease. These data prompted us to investigate expression ofRET and to search for gene mutations in neuroblastoma. Out of 16 neuroblastoma cell lines analyzed, 9 show clear expression ofRET in a Northern blot analysis. In a single-strand conformation polymorphism (SSCP) analysis of all exons, no mutations were detected other than neutral polymorphisms. In a patient with neuroblastoma, from a family in which different neurocrestopathies, including neuroblastoma and Hirschsprung disease, had occurred, we also failed to detect RET mutations. Possibly, expression ofRET in neuroblastoma merely reflects the differentiation status of the tumor cells. The absence of mutations suggests thatRET does not play a crucial role in the tumorigenesis of neuroblastoma.
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Biedler JL, Helson L, Spenler BA (1973) Morphology and growth, tumorigenicity, and cytogenetics of human neuroblastoma cells in continuous culture. Cancer Res 33:2643–2652
Brodeur GM, Sekhon GS, Goldstein MN (1977) Chromosomal abberations in human neuroblastomas Cancer40:2256–2263
Carlson KM, Don S, ChiD, ScavardaN, Toshima K, Jackson CE, Wells SA, Goodfellow PJ, Donis-Keller H (1994) Single missense mutation in the tyrosine kinase catalytic domain of the RET proto-oncogene is associated with multiple endocrine neoplasia type 2B. Proc Natl Acad Sci USA 91:1579–1583
Caron HN, van Sluis P, van Hoeve M, de Kraker J, Bras JH, Slater RS, Mannens M, Voute PA, Westerveld A, Versteeg R (1993) Allelic loss of chromosome 1p36 in neuroblastoma is of preferential maternal origin and correlates with N-myc amplification. Nature Genet 4:187–190
Caron HN, van Sluis P, van Roy N, de Kraker J, Speleman F, Voute PA, Westerveld A, Slater R, Versteeg R (1994) Recurrent 1;17 translocation in human neuroblastoma reveal nonhomologous mitotic recombination during the S/G2 phase as a novel mechanism for loss of heterozygosity. Am J Hum Genet 55:341–347
Ceccherini I, Hofstra RMW, Yin L, Stulp RP, Barone V, Stelwagen T, Bocciardi R, Nijveen H, Bolino A, Seri M, Ronchetto P, Pasini B, Bozzano B, Buys CHCM, Romeo G (1994) DNA polymorphisms and conditions for SSCP analysis of the 20 exons of theRET proto-oncogene. Oncogene 9: 3025–3029
Cheng NC, van Roy N, Chan A, Beitsma M, Westerveld A, Speleman F, Versteeg R (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
Clausen N, Andersson P, Tommerup N (1989) Familial occurrence of neuroblastoma, von Recklinghausen's neurofibromatosis, Hirschsprung's aganglionosis, and jaw-winking syndrome. Acta Paediatr Scan 78:736–741
Van Dommeleln MW, Peters van der Sanden MJH, Molenaar JC, Meijers C. Pattern of malformations and dysmorphisms associated with Hirschsprung disease: an evaluation of 214 patients. Am J Med Genet: in press
Donis-Keller H, Dou S, Chi D, Carlson K, Toshima K, Lairmore TC, Howe JR, Moley JF, Goodfellow P, Wells SA (1993) Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. Hum Mol Genet 7:851–856
Edery P, Lyonnet S, Mulligan LM, Pelet A, Dow E, Abel L, Holder S, Nihoul-Fékéte C, Ponder BAJ, Munnich A (1994) Mutations of theRET proto-oncogene in Hirschsprung's disease. Nature 367:378–380
Eng C, Smith DP, Mulligan LM, Nagai MA, Healey CS, Ponder MA, Gardner E, Scheumann FW, Jackson CE, Tunnacliffe A, Ponder BAJ (1994) Point mutations within the tyrosine kinase domain of theRET proto-oncogene in multiple endocrine neoplasia type 2B and related sporadic tumors. Hum Mol Genet 3: 237–241
Fong CT, Dracopoli NC, White PS, Merrill PT, Griffith RC, Housman DE, Brodeur GM (1989) Loss of heterozygosity for the short arm of chromosome 1 in human neuroblastoma: correlation with N-myc amplification. Proc Natl Acad Sci USA 86: 3753–3757
Hofstra RMW, Landsvater RM, Ceccherini I, Stulp RP, StelwagenT, Yin L, Pasini B, Höppener JWM, Ploos van Amstel HK, Romeo G, Lips CJM, Buys CHCM (1994) A mutation in theRET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature 367:375–376
Ikeda I, Ishizaka Y, Tahira T, Suzuki T, Onda M, Sugimura T, Nagao M (1990) Specific expression of theRET proto-oncogene in human neuroblastoma cell lines. Oncogene 5:1291–1296
Itoh F, Ishizaka Y, Tahira T, Yamamoto M, Miya A, Imai K, Yachi A, Shinichiro T, Sugimura T, Nagao M (1992) Identification and analysis of theRET proto-oncogene promoter region in neuroblastoma cell lines and medullary thyroid carcinomas from MEN 2A patients. Oncogene 7:1201–1206
Iwamoto T, Taniguchi M, Wajjwalku W, Nakashima I, Takahashi M (1993) Neuroblastoma in a transgenic mouse carrying a metallothionein/RET fusion gene. Br J Cancer 67:504–507
Miya A, Yamamoto M, Morimoto H, Tanaka N, Shin E, Karakawa K, Toyoshima K, Ishizaka Y, Mori T, Takai SI (1992) Expression of theRET proto-oncogene in human medullary thyroid carcinoma and pheochromocytomas of MEN 2A. Henry Ford Hosp Med J 40:215–218
Mulligan LM, Kwok JBJ, Healey CS, Elsdon MJ, Eng C, Gardner E, Love DR, Mole SE, Moore J, Papi L, Ponder MA, Telenius H, Tunnacliffe A, Ponder BAJ (1993) Germline mutations of theRET proto-oncogene in multiple endocrine neoplasia type 2A. Nature 363:458–460
Nagao M, Ishizaka Y, Nakagawara A, Kohno K, Kuwano M, Tahira T, Itoh F, Ikeda I, Sugimura T (1990) Expression ofRET proto-oncogene in human neuroblastomas. Jpn J Cancer Res 81:309–312
Pachnis V, Mankoo B, Constantini F (1993) Expression of the CRET proto-oncogene during mouse embryogenesis. Development 119:1005–1017
Romeo G, Ronchetto P, Yin L, Barone V, Seri M, Ceccherini I, Pasini B, Bocciardi R, Lerone M, Kääriäinen H, Martucciello G (1994) Point mutations affecting the tyrosine kinase domain of the RET proto-oncogene in Hirschsprung's disease. Nature 367:377–378
Santoro M, Rosati R, Grieco M, Berlingieri MT, d'Amato GLC, de Franciscis V, Fusco A (1990) TheRET proto-oncogene is consistently expressed in human pheochromocytomas and thyroid medullary carcinomas. Oncogene 5: 1595–1598
Sarkar G, Yoon HS, Sommer SS (1992) Screening for mutations by RNA single-strand conformation polymorphism (rSSCP): comparison with DNA-SSCP. Nucleic Acids Res 20:871–878
Savelyeva L, Corvi R, Schwab M (1994) Translocation involving lp and 17q is a recurrent genetic alteration of human neuroblastoma cells. Am J Hum Genet 55:334–340
Seeger RC, Brodeur GM, Sather H, Dalton A,Siegel SE, Wong KY, Hammond MD (1985) Association of multiple copies of the N-myc oncogene with rapid progression of neuroblastomas. N Engl J Med 313:1111–1117
Tahira T, Ishizaka Y, Itoh F, Nakayasu M,Sugimura T, Nagao M (1991) Expression of theRET proto-oncogene in human neuroblastoma cell lines and its increase during neuronal differentiation induced by retinoic acid. Oncogene 6:2333–2338
Takahashi M, Cooper GM (1987)RET transforming gene encodes a fusion protein homologous to tyrosine kinases. Mol Cell Biol 7:1378–1385
Takahashi M, Buma Y, Taniguchi M (1991) Identification of the RET proto-oncogene in neuroblastoma and leukemia cells. Oncogene 6:297–301
Verloes A, Elmer C, Lacombe D, Heinrichs C, Rebuffat E, Demarquez JL, Moncla A, Adam E (1993) Ondine-Hirschsprung syndrome (Haddad syndrome). Eur J Pediatr 152:75–77
Weith A, Martinsson T, Cziepluch C, Bruderlein S, Amler LC, Berthold F, Schwab M (1989) Neuroblastoma consensus deletion maps to lp361-2. Genes Chromosomes Cancer 1: 159–166
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Hofstra, R.M.W., Stulp, R.P., Stelwagen, T. et al. No mutations found byRET mutation scanning in sporadic and hereditary neuroblastoma. Hum Genet 97, 362–364 (1996). https://doi.org/10.1007/BF02185773
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DOI: https://doi.org/10.1007/BF02185773