Skip to main content
SpringerLink
Log in

From families to chromosomes: genetic linkage, and other methods for finding cancer-predisposition genes

  • Chapter
Genetic Predisposition to Cancer

Abstract

The past decade has seen rapid progress towards the mapping and identification of genes involved in inherited predisposition to cancer. Before 1987 no genes conferring a high inherited risk of cancer had been identified or even localized; at that time the only genetic loci known to be involved in cancer predisposition were the HLA system, where certain HLA haplotypes were known to predispose to Hodgkin’s disease [1] and to nasopharyngeal cancer [2], and the ABO blood group, where stomach cancer had been shown to be slightly more common in individuals with group A [3]. All of these associations are, however, quite weak. This situation was transformed in the 1980s by the development of techniques for typing DNA polymorphisms which could be used for linkage analysis [4]. In 1987 the genes for familial adenomatous polyposis [5] and multiple endocrine neoplasia [6, 7] were first localized, and since then genes for all the major ‘inherited cancer syndromes’ (that is, those rare syndromes where evidence for Mendelian inheritance was apparent from clinical studies) have now been either identified or at least mapped precisely within the human genome (see Chapter 1). Genetic linkage analysis has been the major technique by which these genes have been initially localized, although in some cases there were cytogenetic clues as to the location.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 39.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 54.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Dausset, J., Colombani, J. and Hors, J. (1982) Major histocompatibility complex and cancer. Cancer Sum., 1, 120–47.

    Google Scholar 

  2. Simons, M.J., Wee, G.B., Chan, S.H., Shanmugaratnam, K., Day, N.E. and de Thé, G. (1975) Probable identification of an HLA second locus antigen associated with a high risk of nasopharyngeal carcinoma. Lancet, i, 142–3.

    Article  Google Scholar 

  3. Hoskins, L.C., Loux, H.A., Britten, A. and Zamcheck, N. (1965) Distribution of ABO blood groups in patients with pernicious anemia, gastric carcinoma and gastric carcinoma associated with blood group A. N. Engl. J. Med., 273, 633–7.

    Article  PubMed  CAS  Google Scholar 

  4. Botstein, D., White, R., Skolnick, M.H. and Davis, R. (1980) Construction of a genetic linkage map in map using restriction fragment length polymorphisms. Am. J. Hum. Genet., 32, 314–31.

    PubMed  CAS  Google Scholar 

  5. Bodmer, W.F., Bailey, C.J., Bodmer, J. et al. (1987) Localisation of the gene for familial adenomatous polyposis on chromosome 5. Nature, 328, 614–16.

    Article  PubMed  CAS  Google Scholar 

  6. Mathew, C.G.P., Chin, K.S., Easton, D.F. et al. (1987) A linked genetic marker for multiple endocrine neoplasia type 2A on chromosome 10. Nature, 328, 527–8.

    Article  PubMed  CAS  Google Scholar 

  7. Simpson, N.E., Kidd, K.K., Goodfellow, P.J. et al. (1987) Assignment of multiple endocrine neoplasia type 2A to chromosome 10 by linkage. Nature, 328, 528–30.

    Article  PubMed  CAS  Google Scholar 

  8. Peltomaki, L., Aaltonen, L.A., Sistonen, P. et al. (1993) Genetic mapping of a locus predisposing to human colorectal cancer. Science, 260, 810–12.

    Article  PubMed  CAS  Google Scholar 

  9. Lindblöm, A., Tannergard, P., Werelius, B. and Nordenskjord, M. (1993) Genetic mapping of a second locus predisposing to hereditary non-polyposis colon cancer. Nature Genet., 5, 279–82.

    Article  PubMed  Google Scholar 

  10. Cannon-Albright, L.A., Goldgar, D.E., Meyer, L.J. et al. (1992) Assignment of a locus for familial melanoma, MLM, to chromosome 9p13-p22. Science, 258, 1148–52.

    Article  PubMed  CAS  Google Scholar 

  11. Hall, J.M., Lee, M.K., Morrow, J. et al. (1990) Linkage analysis of early onset familial breast cancer to chromosome 17q21. Science, 250, 1684–9.

    Article  PubMed  CAS  Google Scholar 

  12. Wooster, R., Neuhausen, S., Mangion, J. et al. (1994) Localization of a breast cancer susceptibility gene to chromosome 13q12-q13. Science, 265, 2088–90.

    Article  PubMed  CAS  Google Scholar 

  13. Easton, D.F., Bishop, D.T., Ford, D., Crockford, G.P. and the Breast Cancer Linkage Consortium (1993) Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. Am. J. Hum. Genet., 52, 678–701.

    PubMed  CAS  Google Scholar 

  14. Narod, S.A., Ford, D., Devilee, P. et al. (1995) An evaluation of genetic heterogeneity in 145 breast-ovarian cancer families. Am. J. Hum. Genet., 56, 254–64.

    PubMed  CAS  Google Scholar 

  15. Stratton, M.R., Ford, D., Neuhausen, S. et al. (1994) Familial male breast cancer is not linked to the BRCA1 locus on chromosome 17q. Nature Genet, 7, 103–7.

    Article  PubMed  CAS  Google Scholar 

  16. Terwillinger, J.D. and Ott, J. (1994) Handbook of Human Genetic Linkage. Johns Hopkins University Press, Baltimore.

    Google Scholar 

  17. Morton, N.E. (1955) Sequential tests for the detection of linkage. Am. J. Hum. Genet., 7, 277–318.

    PubMed  CAS  Google Scholar 

  18. Lander, E.S. and Schork, N.J. (1994) Genetic dissection of complex traits. Science, 265, 2037–48.

    Article  PubMed  CAS  Google Scholar 

  19. Skolnick, M.H., Thompson, E.A., Bishop, D.T. and Cannon, L. A. (1984) Possible linkage of a breast cancer susceptibility locus to the ABO locus: sensitivity of LOD scores to a single new recombinant observation. Genet. Epidemiol, 1, 363–73.

    Article  PubMed  CAS  Google Scholar 

  20. Weeks, D.E., Lehner, T., Squires-Wheeler, E. et al. (1990) Measuring the inflation in the lod score due to its maximisation over model parameter values in human linkage analysis. Genet. Epidemiol, 7, 237–43.

    Article  PubMed  CAS  Google Scholar 

  21. Lathrop, G.M., Lalouel, J.M., Julier, C. and Ott, J. (1984) Strategies for multilocus linkage analysis in humans. Proc. Natl Acad. Sci. USA, 81, 3443–6.

    Article  PubMed  CAS  Google Scholar 

  22. Lange, K., Weeks, D. and Boehnke, M. (1988) Programs for pedigree analysis: MENDEL, FISHER and dGENE. Genet. Epidemiol, 5, 471–2.

    Article  PubMed  CAS  Google Scholar 

  23. Cohen, B.B., Porter, D.E., Wallace, M.R., Carothers, A. and Steel, C.M. (1993) Linkage of a major breast cancer gene to chromosome 17q12-21: results from 15 Edinburgh families. Am. J. Hum. Genet., 52, 723–9.

    PubMed  CAS  Google Scholar 

  24. Southern, E.M. (1975) Detection of specific sequences among DNA fragments separated by gel electrophoresis. J. Mol. Biol., 98, 503–17.

    Article  PubMed  CAS  Google Scholar 

  25. Jeffreys, A.J., Wilson, V. and Thein, S.L. (1985) Hypervariable ‘minisatellite’ regions in human DNA. Nature, 314, 67–73.

    Article  PubMed  CAS  Google Scholar 

  26. Weber, J.L. and May, P.E. (1989) Abundant class of human DNA polymorphisms which can be typed using the polymerase chain reaction. Am. J. Hum. Genet., 44, 388–96.

    PubMed  CAS  Google Scholar 

  27. Eeles, R.A. and Stamps, A.C. (1993) Polymerase Chain Reaction (PCR):the Technique and its Applications. R.G. Landes, Austin, Texas.

    Google Scholar 

  28. Lisitsyn, N., Lisitsyn, N. and Wigler, M. (1993) Cloning the differences between two complex genomes. Science, 259, 946–51.

    Article  PubMed  CAS  Google Scholar 

  29. Nelson, S.F., McCusker, J.H., Sander, M.A. et al. (1993) Genomic mismatch scanning: a new approach to genetic linkage mapping. Nature Genet., 4, 11–18.

    Article  PubMed  CAS  Google Scholar 

  30. Ott, J. (1978) A simple scheme for the analysis of HLA linkages in pedigrees. Ann. Hum. Genet., 42, 255–7.

    Article  PubMed  CAS  Google Scholar 

  31. Kong, A., Cox, N., Frigge, M. and Irwin, M. (1993) Sequential imputation and multipoint linkage analysis. Genet. Epidemiol., 10, 483–8.

    Article  PubMed  CAS  Google Scholar 

  32. Guo, S.W. and Thompson, E.A. (1992) A monte carlo method for combined segregation and linkage analysis. Am. J. Hum. Genet., 51, 1111–26.

    PubMed  CAS  Google Scholar 

  33. Claus, E.B., Risch, N.J. and Thompson, W.D. (1990) Age at onset as an indicator of familial risk of breast cancer. Am. J. Epidemiol., 131, 961–72.

    PubMed  CAS  Google Scholar 

  34. Hastbacka, J., de la Chapelle, A., Mahtani, M.M. et al. (1994) The diastrophic dysplasia gene encodes a novel sulfate transporter — positional cloning by fine structure linkage disequilibrium mapping. Cell, 78, 1073–87.

    Article  PubMed  CAS  Google Scholar 

  35. Murray, J.C., Buetow, K.H., Weber, J.L. et al. (1994) A comprehensive human linkage map with centimorgan density. Science, 265, 2049–54.

    Article  PubMed  CAS  Google Scholar 

  36. Smith, C.A.B. (1961) Homogeneity test for linkage data. Proc. Sec. Int. Congr. Hum. Genet., 1, 212–13.

    Google Scholar 

  37. Nyström-Lahti, M., Parsons, R., Sistonen, P. et al. (1994) Mismatch repair genes on chromosomes 2p and 3p account for a major share of hereditary nonpolyposis colorectal cancer families évaluable by linkage. Am. J. Hum. Genet, 55, 659–65.

    PubMed  Google Scholar 

  38. Leach, F.S., Nicolaides, N.C., Papadopoulos, N. et al. (1993) Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell, 75, 1215–25.

    Article  PubMed  CAS  Google Scholar 

  39. Lander, E.S. and Botstein, D. (1986) Strategies for studying heterogeneous genetic traits in humans by using a linkage map of restriction fragment length polymorphisms. Proc. Natl Acad. Sci. USA, 83, 7353–7.

    Article  PubMed  CAS  Google Scholar 

  40. Holmans, P. (1993) Asymptotic properties of affected-sib-pair linkage analysis. Am. J. Hum. Genet., 52, 362–74.

    PubMed  CAS  Google Scholar 

  41. Risch, N. (1990) Linkage strategies for genetically complex traits. II. The power of affected relative pairs. Am. J. Hum. Genet. 46, 226–41.

    Google Scholar 

  42. Bishop, D.T. and Williamson, J.A. (1990) The power of identity-by-state methods for linkage analysis. Am. J. Hum. Genet. 46, 254–65.

    PubMed  CAS  Google Scholar 

  43. Weeks, D.E. and Lange, K. (1988) The affected-pedigree-member method of linkage analysis. Am. J. Hum. Genet., 42, 315–26.

    PubMed  CAS  Google Scholar 

  44. Clerget-Darpoux, F., Bonaiti-Pellie, C. and Hochez, J. (1986) Effects of misspecifying genetic parameters in lod score analysis. Biometrics 42, 393–9.

    Article  PubMed  CAS  Google Scholar 

  45. Risch, N. and Giuffra, L. (1992) Model misspecification and multipoint linkage analysis. Human Hered, 42, 77–92.

    Article  CAS  Google Scholar 

  46. Green, P. (1990) Genetic linkage and complex diseases: a comment. Genet. Epidemiol., 7, 25–7.

    Article  Google Scholar 

  47. MacClean, C.J., Bishop, D.T., Sherman, S.L. and Diehl, S.R. (1993) Distribution of lod scores under uncertain mode of inheritance. Am. J. Hum. Genet., 52, 54–61.

    Google Scholar 

  48. Weeks, D.E., Ott, J. and Lathrop, G.M. (1990) SLINK: a general simulation program for linkage analysis. Am. J. Hum. Genet. 47, A204.

    Google Scholar 

  49. Ploughman, L.M. and Boehnke, M. (1989) Estimating the power of a proposed linkage study for a complex genetic trait. Am. J. Hum. Genet. 44, 543–51.

    PubMed  CAS  Google Scholar 

  50. Goldgar, D.E., Easton, D.F., Cannon-Albright, L. A. and Skolnick, M.H. (1994) A systematic population based assessment of cancer risk in first-degree relatives of cancer probands. J. Natl Cancer Inst., 86, 1600–8.

    Article  PubMed  CAS  Google Scholar 

  51. Easton, D.F. and Goldgar, D.E. (1994) Optimal sampling strategies for detecting linkage of a complex trait with known genetic heterogeneity. Am. J. Hum. Genet. 55, A128.

    Google Scholar 

  52. Risch, N. (1984) Segregation analysis incorporating linkage markers. I. Single-locus models with an application to type 1 diabetes. Am. J. Hum. Genet., 36, 363–86.

    PubMed  CAS  Google Scholar 

  53. Greenberg, D.A. (1989) Inferring mode of inheritance by comparison of lod scores. Am. J. Med. Genet., 35, 480–6.

    Article  Google Scholar 

  54. Knudson, A. G. (1971) Mutation and cancer: a statistical study of retinoblastoma. Proc. Natl Acad. Sei. USA, 68, 820–3.

    Article  Google Scholar 

  55. Cavenee, W.K., Dryja, T.P., Phillips, R. A. et al. (1983) Expression of recessive alleles by chromosomal mechanisms in retinoblastoma. Nature, 305, 779–89.

    Article  PubMed  CAS  Google Scholar 

  56. Smith, S.A., Easton, D.F., Evans, D.G.R. and Ponder, B.A.J. (1992) Allele losses in the region 17q12-q21 in familial breast and ovarian cancer involve the wild type chromosome. Nature Genet., 2, 128–31.

    Article  PubMed  CAS  Google Scholar 

  57. Rebbeck, T.R., Lustbader, E.D., and Buetow, K.H. (1994) Somatic allele loss in genetic linkage analysis of cancer. Genet. Epidemiol., 11, 419–29.

    Article  PubMed  CAS  Google Scholar 

  58. Easton, D.F. and Bishop, D.T. The power of linkage analysis to detect cancer susceptibility genes using affected relative pairs and loss of heterozygosity data in tumours. In preparation.

    Google Scholar 

  59. Burt, R.W., Cannon-Albright, L.A., Bishop, D.T. et al. (1993) Familial factors in sporadic adenomas and colorectal cancer. Problems in General Surgery, 10, 688–94.

    Google Scholar 

  60. Green, A. and Swerdlow, A.J. (1989) Epidemiology of melanocytic naevi. Epidemiol. Rev., 11, 204–21.

    PubMed  CAS  Google Scholar 

  61. Scott, D., Jones, L.A., Elyan, S.A.G. et al. (1992) Identification of A-T hétérozygotes, in Ataxia-Telangiectasia, (eds R.A. Gatti and R.B. Painter), Springer-Verlag, pp. 101-16.

    Google Scholar 

  62. Barnes, D.M., Hanby, A.M., Gillett, C.E. et al. (1992) Abnormal expression of wild type p53 protein in normal cells of a cancer family patient. Lancet, 340, 259–63.

    Article  PubMed  CAS  Google Scholar 

  63. Goldgar, D.E., Cannon-Albright, L.A., Meyer, L.J. et al. (1992) Inheritance of nevus number and size in melanoma/DNS kindreds. Cytogenet. Cell Genet, 59, 200–2.

    Article  PubMed  CAS  Google Scholar 

  64. Risch, N. and Sherman, S. (1992) Genetic Analysis Workshop 7: summary of the melanoma workshop. Cytogenet. Cell Genet., 59, 148–58.

    Article  PubMed  CAS  Google Scholar 

  65. Krontiris, T.G., Devlin, B., Karp, D.D., Robert, N.J. and Risch, N. (1993) An association between the risk of cancer and mutations in the Hrasl minisatellite locus. N. Engl. J. Med., 329, 517–23.

    Article  PubMed  CAS  Google Scholar 

  66. Weir, B.S. (1990) Genetic Data Analysis: Methods for Discrete Population Genetic Data. Sinauer, Sunderland, MA.

    Google Scholar 

  67. Stephens, J.C., Briscoe, D. and O’Brien, S.J. (1994) Mapping by admixture linkage disequilibrium in human populations: limits and guidelines. Am. J. Hum. Genet., 55, 603–860.

    Google Scholar 

  68. Peterson, A., Slatkin, M., DiRienzo, A., Lehesjoki, A., de la Chapelle, A. and Freimer, N. (1994) A genomic survey of linkage disequilibrium. Am. J. Hum. Genet., 55, A124.

    Google Scholar 

  69. Spielman, R.S., McGinnis, R.E. and Ewens, W.J. (1993) Transmission disequilibrium test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am. J. Hum. Genet., 52, 506–16.

    PubMed  CAS  Google Scholar 

  70. Self, S., Longton, G., Kopecky, K. and Liang, K.-Y. (1991) On estimating HLA/ disease association with application to a study of aplastic anaemia. Biometrics, 47, 53–61.

    Article  PubMed  CAS  Google Scholar 

Download references

Authors
  1. Douglas F. Easton
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Cancer Genetics and Clinical Oncology, Institute of Cancer Research and Royal Marsden Hospital, Surrey, UK

    Rosalind A. Eeles (Senior Lecturer and Honorary Consultant) (Senior Lecturer and Honorary Consultant)

  2. CRC Human Cancer Genetics Research Group, University of Cambridge, UK

    Bruce A. J. Ponder (Director) (Director)

  3. CRC Genetic Epidemiology Unit, University of Cambridge, UK

    Douglas F. Easton (Director) (Director)

  4. Academic Unit of Radiotherapy and Oncology, Institute of Cancer Research and Royal Marsden Hospital, Surrey, UK

    Alan Horwich (Director of Clinical Research) (Director of Clinical Research)

Rights and permissions

Reprints and permissions

Copyright information

© 1996 Springer Science+Business Media Dordrecht

About this chapter

Cite this chapter

Easton, D.F. (1996). From families to chromosomes: genetic linkage, and other methods for finding cancer-predisposition genes. In: Eeles, R.A., Ponder, B.A.J., Easton, D.F., Horwich, A. (eds) Genetic Predisposition to Cancer. Springer, Boston, MA. https://doi.org/10.1007/978-1-4899-4501-3_2

Download citation

  • DOI: https://doi.org/10.1007/978-1-4899-4501-3_2

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-0-412-56580-9

  • Online ISBN: 978-1-4899-4501-3

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation