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. 1998 Jun;106(Suppl 3):801–806. doi: 10.1289/ehp.98106801

Genetic predispositions and childhood cancer.

K Shannon 1
PMCID: PMC1533076  PMID: 9646040

Abstract

This article provides an overview of the problem of genetic susceptibility to childhood cancer with a particular emphasis on problems with ascertaining inherited cancer risk and the role of tumor-suppressor gene mutations in cancer predispositions. The association between neurofibromatosis type 1 and childhood leukemia is used to illustrate some of the issues faced by molecular biologists and genetic epidemiologists in identifying and analyzing at-risk individuals. The problem of incomplete penetrance in cancer susceptibility is presented and potential models are discussed. The article concludes with a number of tentative conclusions from existing data and speculations for future studies.

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Selected References

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  1. Boguski M. S., McCormick F. Proteins regulating Ras and its relatives. Nature. 1993 Dec 16;366(6456):643–654. doi: 10.1038/366643a0. [DOI] [PubMed] [Google Scholar]
  2. Bollag G., Clapp D. W., Shih S., Adler F., Zhang Y. Y., Thompson P., Lange B. J., Freedman M. H., McCormick F., Jacks T. Loss of NF1 results in activation of the Ras signaling pathway and leads to aberrant growth in haematopoietic cells. Nat Genet. 1996 Feb;12(2):144–148. doi: 10.1038/ng0296-144. [DOI] [PubMed] [Google Scholar]
  3. Bos J. L. ras oncogenes in human cancer: a review. Cancer Res. 1989 Sep 1;49(17):4682–4689. [PubMed] [Google Scholar]
  4. Brannan C. I., Perkins A. S., Vogel K. S., Ratner N., Nordlund M. L., Reid S. W., Buchberg A. M., Jenkins N. A., Parada L. F., Copeland N. G. Targeted disruption of the neurofibromatosis type-1 gene leads to developmental abnormalities in heart and various neural crest-derived tissues. Genes Dev. 1994 May 1;8(9):1019–1029. doi: 10.1101/gad.8.9.1019. [DOI] [PubMed] [Google Scholar]
  5. Capecchi M. R. Altering the genome by homologous recombination. Science. 1989 Jun 16;244(4910):1288–1292. doi: 10.1126/science.2660260. [DOI] [PubMed] [Google Scholar]
  6. Castro-Malaspina H., Schaison G., Passe S., Pasquier A., Berger R., Bayle-Weisgerber C., Miller D., Seligmann M., Bernard J. Subacute and chronic myelomonocytic leukemia in children (juvenile CML). Clinical and hematologic observations, and identification of prognostic factors. Cancer. 1984 Aug 15;54(4):675–686. doi: 10.1002/1097-0142(1984)54:4<675::aid-cncr2820540415>3.0.co;2-q. [DOI] [PubMed] [Google Scholar]
  7. Cawthon R. M., Weiss R., Xu G. F., Viskochil D., Culver M., Stevens J., Robertson M., Dunn D., Gesteland R., O'Connell P. A major segment of the neurofibromatosis type 1 gene: cDNA sequence, genomic structure, and point mutations. Cell. 1990 Jul 13;62(1):193–201. doi: 10.1016/0092-8674(90)90253-b. [DOI] [PubMed] [Google Scholar]
  8. Colman S. D., Williams C. A., Wallace M. R. Benign neurofibromas in type 1 neurofibromatosis (NF1) show somatic deletions of the NF1 gene. Nat Genet. 1995 Sep;11(1):90–92. doi: 10.1038/ng0995-90. [DOI] [PubMed] [Google Scholar]
  9. Dietrich W. F., Lander E. S., Smith J. S., Moser A. R., Gould K. A., Luongo C., Borenstein N., Dove W. Genetic identification of Mom-1, a major modifier locus affecting Min-induced intestinal neoplasia in the mouse. Cell. 1993 Nov 19;75(4):631–639. doi: 10.1016/0092-8674(93)90484-8. [DOI] [PubMed] [Google Scholar]
  10. Diller L., Sexsmith E., Gottlieb A., Li F. P., Malkin D. Germline p53 mutations are frequently detected in young children with rhabdomyosarcoma. J Clin Invest. 1995 Apr;95(4):1606–1611. doi: 10.1172/JCI117834. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Draper G. J., Sanders B. M., Kingston J. E. Second primary neoplasms in patients with retinoblastoma. Br J Cancer. 1986 May;53(5):661–671. doi: 10.1038/bjc.1986.110. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Easton D. F., Ponder M. A., Huson S. M., Ponder B. A. An analysis of variation in expression of neurofibromatosis (NF) type 1 (NF1): evidence for modifying genes. Am J Hum Genet. 1993 Aug;53(2):305–313. [PMC free article] [PubMed] [Google Scholar]
  13. Easton D., Peto J. The contribution of inherited predisposition to cancer incidence. Cancer Surv. 1990;9(3):395–416. [PubMed] [Google Scholar]
  14. Eng C. Seminars in medicine of the Beth Israel Hospital, Boston. The RET proto-oncogene in multiple endocrine neoplasia type 2 and Hirschsprung's disease. N Engl J Med. 1996 Sep 26;335(13):943–951. doi: 10.1056/NEJM199609263351307. [DOI] [PubMed] [Google Scholar]
  15. Fearon E. R., Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990 Jun 1;61(5):759–767. doi: 10.1016/0092-8674(90)90186-i. [DOI] [PubMed] [Google Scholar]
  16. Friend S. H., Dryja T. P., Weinberg R. A. Oncogenes and tumor-suppressing genes. N Engl J Med. 1988 Mar 10;318(10):618–622. doi: 10.1056/NEJM198803103181007. [DOI] [PubMed] [Google Scholar]
  17. Glover T. W., Stein C. K., Legius E., Andersen L. B., Brereton A., Johnson S. Molecular and cytogenetic analysis of tumors in von Recklinghausen neurofibromatosis. Genes Chromosomes Cancer. 1991 Jan;3(1):62–70. doi: 10.1002/gcc.2870030111. [DOI] [PubMed] [Google Scholar]
  18. Gurney J. G., Severson R. K., Davis S., Robison L. L. Incidence of cancer in children in the United States. Sex-, race-, and 1-year age-specific rates by histologic type. Cancer. 1995 Apr 15;75(8):2186–2195. doi: 10.1002/1097-0142(19950415)75:8<2186::aid-cncr2820750825>3.0.co;2-f. [DOI] [PubMed] [Google Scholar]
  19. Jacks T., Shih T. S., Schmitt E. M., Bronson R. T., Bernards A., Weinberg R. A. Tumour predisposition in mice heterozygous for a targeted mutation in Nf1. Nat Genet. 1994 Jul;7(3):353–361. doi: 10.1038/ng0794-353. [DOI] [PubMed] [Google Scholar]
  20. Kalra R., Paderanga D. C., Olson K., Shannon K. M. Genetic analysis is consistent with the hypothesis that NF1 limits myeloid cell growth through p21ras. Blood. 1994 Nov 15;84(10):3435–3439. [PubMed] [Google Scholar]
  21. Kaneko Y., Maseki N., Sakurai M., Shibuya A., Shinohara T., Fujimoto T., Kanno H., Nishikawa A. Chromosome pattern in juvenile chronic myelogenous leukemia, myelodysplastic syndrome, and acute leukemia associated with neurofibromatosis. Leukemia. 1989 Jan;3(1):36–41. [PubMed] [Google Scholar]
  22. King M. C. Leaving Kansas ... finding genes in 1997. Nat Genet. 1997 Jan;15(1):8–10. doi: 10.1038/ng0197-8. [DOI] [PubMed] [Google Scholar]
  23. Knudson A. G. All in the (cancer) family. Nat Genet. 1993 Oct;5(2):103–104. doi: 10.1038/ng1093-103. [DOI] [PubMed] [Google Scholar]
  24. Laird P. W., Jackson-Grusby L., Fazeli A., Dickinson S. L., Jung W. E., Li E., Weinberg R. A., Jaenisch R. Suppression of intestinal neoplasia by DNA hypomethylation. Cell. 1995 Apr 21;81(2):197–205. doi: 10.1016/0092-8674(95)90329-1. [DOI] [PubMed] [Google Scholar]
  25. Largaespada D. A., Brannan C. I., Jenkins N. A., Copeland N. G. Nf1 deficiency causes Ras-mediated granulocyte/macrophage colony stimulating factor hypersensitivity and chronic myeloid leukaemia. Nat Genet. 1996 Feb;12(2):137–143. doi: 10.1038/ng0296-137. [DOI] [PubMed] [Google Scholar]
  26. Levine E. G., Bloomfield C. D. Leukemias and myelodysplastic syndromes secondary to drug, radiation, and environmental exposure. Semin Oncol. 1992 Feb;19(1):47–84. [PubMed] [Google Scholar]
  27. MacPhee M., Chepenik K. P., Liddell R. A., Nelson K. K., Siracusa L. D., Buchberg A. M. The secretory phospholipase A2 gene is a candidate for the Mom1 locus, a major modifier of ApcMin-induced intestinal neoplasia. Cell. 1995 Jun 16;81(6):957–966. doi: 10.1016/0092-8674(95)90015-2. [DOI] [PubMed] [Google Scholar]
  28. Maris J. M., Wiersma S. R., Mahgoub N., Thompson P., Geyer R. J., Hurwitz C. G., Lange B. J., Shannon K. M. Monosomy 7 myelodysplastic syndrome and other second malignant neoplasms in children with neurofibromatosis type 1. Cancer. 1997 Apr 1;79(7):1438–1446. [PubMed] [Google Scholar]
  29. Matsui I., Tanimura M., Kobayashi N., Sawada T., Nagahara N., Akatsuka J. Neurofibromatosis type 1 and childhood cancer. Cancer. 1993 Nov 1;72(9):2746–2754. doi: 10.1002/1097-0142(19931101)72:9<2746::aid-cncr2820720936>3.0.co;2-w. [DOI] [PubMed] [Google Scholar]
  30. McIntyre J. F., Smith-Sorensen B., Friend S. H., Kassell J., Borresen A. L., Yan Y. X., Russo C., Sato J., Barbier N., Miser J. Germline mutations of the p53 tumor suppressor gene in children with osteosarcoma. J Clin Oncol. 1994 May;12(5):925–930. doi: 10.1200/JCO.1994.12.5.925. [DOI] [PubMed] [Google Scholar]
  31. Menon A. G., Anderson K. M., Riccardi V. M., Chung R. Y., Whaley J. M., Yandell D. W., Farmer G. E., Freiman R. N., Lee J. K., Li F. P. Chromosome 17p deletions and p53 gene mutations associated with the formation of malignant neurofibrosarcomas in von Recklinghausen neurofibromatosis. Proc Natl Acad Sci U S A. 1990 Jul;87(14):5435–5439. doi: 10.1073/pnas.87.14.5435. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Miles D. K., Freedman M. H., Stephens K., Pallavicini M., Sievers E. L., Weaver M., Grunberger T., Thompson P., Shannon K. M. Patterns of hematopoietic lineage involvement in children with neurofibromatosis type 1 and malignant myeloid disorders. Blood. 1996 Dec 1;88(11):4314–4320. [PubMed] [Google Scholar]
  33. Narod S. A., Stiller C., Lenoir G. M. An estimate of the heritable fraction of childhood cancer. Br J Cancer. 1991 Jun;63(6):993–999. doi: 10.1038/bjc.1991.216. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Neubauer A., Shannon K., Liu E. Mutations of the ras proto-oncogenes in childhood monosomy 7. Blood. 1991 Feb 1;77(3):594–598. [PubMed] [Google Scholar]
  35. Nowak R. Genetic testing set for takeoff. Science. 1994 Jul 22;265(5171):464–467. doi: 10.1126/science.8036486. [DOI] [PubMed] [Google Scholar]
  36. Oshima M., Dinchuk J. E., Kargman S. L., Oshima H., Hancock B., Kwong E., Trzaskos J. M., Evans J. F., Taketo M. M. Suppression of intestinal polyposis in Apc delta716 knockout mice by inhibition of cyclooxygenase 2 (COX-2). Cell. 1996 Nov 29;87(5):803–809. doi: 10.1016/s0092-8674(00)81988-1. [DOI] [PubMed] [Google Scholar]
  37. Rodenhuis S. ras and human tumors. Semin Cancer Biol. 1992 Aug;3(4):241–247. [PubMed] [Google Scholar]
  38. Sakai T., Ohtani N., McGee T. L., Robbins P. D., Dryja T. P. Oncogenic germ-line mutations in Sp1 and ATF sites in the human retinoblastoma gene. Nature. 1991 Sep 5;353(6339):83–86. doi: 10.1038/353083a0. [DOI] [PubMed] [Google Scholar]
  39. Shannon K. M., O'Connell P., Martin G. A., Paderanga D., Olson K., Dinndorf P., McCormick F. Loss of the normal NF1 allele from the bone marrow of children with type 1 neurofibromatosis and malignant myeloid disorders. N Engl J Med. 1994 Mar 3;330(9):597–601. doi: 10.1056/NEJM199403033300903. [DOI] [PubMed] [Google Scholar]
  40. Shannon K. M., Watterson J., Johnson P., O'Connell P., Lange B., Shah N., Steinherz P., Kan Y. W., Priest J. R. Monosomy 7 myeloproliferative disease in children with neurofibromatosis, type 1: epidemiology and molecular analysis. Blood. 1992 Mar 1;79(5):1311–1318. [PubMed] [Google Scholar]
  41. Side L., Taylor B., Cayouette M., Conner E., Thompson P., Luce M., Shannon K. Homozygous inactivation of the NF1 gene in bone marrow cells from children with neurofibromatosis type 1 and malignant myeloid disorders. N Engl J Med. 1997 Jun 12;336(24):1713–1720. doi: 10.1056/NEJM199706123362404. [DOI] [PubMed] [Google Scholar]
  42. Skuse G. R., Kosciolek B. A., Rowley P. T. Molecular genetic analysis of tumors in von Recklinghausen neurofibromatosis: loss of heterozygosity for chromosome 17. Genes Chromosomes Cancer. 1989 Sep;1(1):36–41. doi: 10.1002/gcc.2870010107. [DOI] [PubMed] [Google Scholar]
  43. Stiller C. A., Chessells J. M., Fitchett M. Neurofibromatosis and childhood leukaemia/lymphoma: a population-based UKCCSG study. Br J Cancer. 1994 Nov;70(5):969–972. doi: 10.1038/bjc.1994.431. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Sørensen S. A., Mulvihill J. J., Nielsen A. Long-term follow-up of von Recklinghausen neurofibromatosis. Survival and malignant neoplasms. N Engl J Med. 1986 Apr 17;314(16):1010–1015. doi: 10.1056/NEJM198604173141603. [DOI] [PubMed] [Google Scholar]
  45. Toguchida J., Yamaguchi T., Dayton S. H., Beauchamp R. L., Herrera G. E., Ishizaki K., Yamamuro T., Meyers P. A., Little J. B., Sasaki M. S. Prevalence and spectrum of germline mutations of the p53 gene among patients with sarcoma. N Engl J Med. 1992 May 14;326(20):1301–1308. doi: 10.1056/NEJM199205143262001. [DOI] [PubMed] [Google Scholar]
  46. Viskochil D., Buchberg A. M., Xu G., Cawthon R. M., Stevens J., Wolff R. K., Culver M., Carey J. C., Copeland N. G., Jenkins N. A. Deletions and a translocation interrupt a cloned gene at the neurofibromatosis type 1 locus. Cell. 1990 Jul 13;62(1):187–192. doi: 10.1016/0092-8674(90)90252-a. [DOI] [PubMed] [Google Scholar]
  47. Wallace M. R., Marchuk D. A., Andersen L. B., Letcher R., Odeh H. M., Saulino A. M., Fountain J. W., Brereton A., Nicholson J., Mitchell A. L. Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients. Science. 1990 Jul 13;249(4965):181–186. doi: 10.1126/science.2134734. [DOI] [PubMed] [Google Scholar]
  48. Weinberg R. A. Tumor suppressor genes. Science. 1991 Nov 22;254(5035):1138–1146. doi: 10.1126/science.1659741. [DOI] [PubMed] [Google Scholar]
  49. Xu G. F., O'Connell P., Viskochil D., Cawthon R., Robertson M., Culver M., Dunn D., Stevens J., Gesteland R., White R. The neurofibromatosis type 1 gene encodes a protein related to GAP. Cell. 1990 Aug 10;62(3):599–608. doi: 10.1016/0092-8674(90)90024-9. [DOI] [PubMed] [Google Scholar]
  50. Xu W., Mulligan L. M., Ponder M. A., Liu L., Smith B. A., Mathew C. G., Ponder B. A. Loss of NF1 alleles in phaeochromocytomas from patients with type I neurofibromatosis. Genes Chromosomes Cancer. 1992 Jun;4(4):337–342. doi: 10.1002/gcc.2870040411. [DOI] [PubMed] [Google Scholar]

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