Skip to main content
SpringerLink
Log in

Genetics of Colorectal Cancer

An Updated Review

  • Chapter
Cancer Genetics for the Clinician

  • 83 Accesses

Abstract

The annual incidence of colorectal cancer (CRC) in the United States is approximately 131,600.1A positive family history is the most common risk factor for hereditary colon cancer (CRC).2 If one accepts the most conservative estimate that 10% of CRC is hereditary, more than 13,000 of these CRC cases will have a hereditary etiology. The majority of hereditary CRC cases will be hereditary nonpolyposis colorectal cancer (HNPCC), although the exact frequency is not known. Estimates range from a low of about 2% to a high of 10–15% of the total CRC burden. The rare hereditary CRC disorders, such as familial adenomatous polyposis (FAP) and Peutz-Jeghers syndrome (PJS), account for less than 1% of all cases. Table 1 describes hereditary disorders that predispose to CRC.Advancing knowledge may aid in additional molecular genetic diagnoses for hereditary forms of cancer.

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

Access this chapter

Log in via an institution
eBook
USD 16.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 16.99
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. Landis SH, Murray T, Bolden S, et al: Cancer statistics, 1998. CA: a Cancer Journal for Clinicians 48:6–29, 1998

    Google Scholar 

  2. Zwick A, Munir M, Ryan CK, et al: Gastric adenocarcinoma and dysplasia in fundic gland polyps of a patient with attenuated adenomatous polyposis coli. Gastroenterology 113:659–663, 1997

    Article  PubMed  CAS  Google Scholar 

  3. Fuchs C, Giovannucci E, Colditz G, et al: A prospective study of family history and the risk of colorectal cancer. N Engl J Med 331:1669–1674, 1994

    Article  PubMed  CAS  Google Scholar 

  4. St. John JB, McDermott FT, Hopper JL, et al: Cancer risk in relatives of patients with common colorectal cancer. Ann Intern Med 118:785–790, 1993

    PubMed  CAS  Google Scholar 

  5. Bulow S: Familial polyposis coli. Dan Med Bull 34:1–15, 1987

    PubMed  CAS  Google Scholar 

  6. Luschka H: Ueber polypose Vegetationen der gesammten Dickdarmschleimhaut. Arch Path Anat Phys Klin Med 20:133–142, 1861

    Google Scholar 

  7. Sklifasowski NW: Polyadenoma tractus intestinalis. Vrac 4:55–57, 1881

    Google Scholar 

  8. Cripps WH: Two cases of disseminated polyps of the rectum. Trans Path Soc London 165–168, 1882

    Google Scholar 

  9. Smith T: Three cases of multiple polypi of the lower bowel occurring in one family. St Bartholomew’s Hosp Rep 23:225–229, 1887

    Google Scholar 

  10. Handford H: Disseminated polypi of the large intestine becoming malignant: strictures (malignant adenoma) of the rectum and of the splenic flexure of the colon; secondary growths in the liver. Trans Path Soc London 41:133–137, 1890

    Google Scholar 

  11. Lockhart-Mummery P: Cancer and heredity. Lancet i:427–429, 1925

    Article  Google Scholar 

  12. Lynch HT, Fitzgibbons R, Jr, Chong S, et al: Use of doxorubicin and dacarbazine for the management of unresectable intra-abdominal desmoid tumors in Gardner’s syndrome. Dis Colon Rectum 37:260–267, 1994

    Article  PubMed  CAS  Google Scholar 

  13. Lynch HT, Fitzgibbons R, Jr: Surgery, desmoid tumors and familial adenomatous polyposis: case report and literature review. Am J Gastroenterol 91:2598–2601, 1996

    PubMed  CAS  Google Scholar 

  14. Groden J, Thliveris A, Samowitz W, et al: Identification and characterization of the familial adenomatous polyposis coli gene. Cell 66:589–600, 1991

    Article  PubMed  CAS  Google Scholar 

  15. Kinzler KW, Nilbert MC, Su L-K, et al: Identification of FAP locus genes from chromosome 5q21. Science 253:661–665, 1991

    Article  PubMed  CAS  Google Scholar 

  16. Lynch HT, Smyrk T, McGinn T, et al: Attenuated familial adenomatous polyposis (AFAP): a pheno-typically and genotypically distinctive variant of FAP. Cancer 76:2427–2433, 1995

    Article  PubMed  CAS  Google Scholar 

  17. Spirio L, Olschwang S, Groden J, et al: Alleles of the APC gene: an attenuated form of familial polyposis. Cell 75:951–957, 1993

    Article  PubMed  CAS  Google Scholar 

  18. Lynch HT, Smyrk T, Lynch J: Wanebo HJ, editors. Surgery for Gastrointestinal Cancer: A Multidisci-plinary Approach. Philadelphia: Lippincott-Raven Publishers, 1997, 59–86

    Google Scholar 

  19. Burt RW, Bishop DT, Cannon LA, et al: Dominant inheritance of adenomatous colonic polyps and colorectal cancer. N Engl J Med 312:1540–1544, 1985

    Article  PubMed  CAS  Google Scholar 

  20. Giardiello FM, Welsh SB, Hamilton SR, et al: Increased risk of cancer in the Peutz-Jeghers syndrome. N Engl J Med 316:1511–1514, 1987

    Article  PubMed  CAS  Google Scholar 

  21. Jenne DE, Reimann H, Nezu J, et al: Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase. Nat Genet 18:38–44, 1998

    Article  PubMed  CAS  Google Scholar 

  22. Hemminki A, Tomlinson I, Markie D, et al: Localization of a susceptibility locus for Peutz-Jeghers syndrome to 19p using comparative genomic hybridization and targeted linkage analysis. Nature Genet 15:87–90, 1997

    Article  PubMed  CAS  Google Scholar 

  23. Olschwang S, Markie D, Seal S, et al: Peutz-Jeghers disease: most, but not all, families are compatible with linkage to 19pl3.3. J Med Genet 35:42–44, 1998

    Article  PubMed  CAS  Google Scholar 

  24. Mehenni H, Blouin J-L, Radhakrishna U, et al: Peutz-Jeghers syndrome: confirmation of linkage to chromosome 19pl3.3 and identification of a potential second locus, on 19ql3.4. Am J Hum Genet 61:1327–1334, 1997

    Article  PubMed  CAS  Google Scholar 

  25. Lynch HT, Smyrk T, Lynch J, et al: Genetic counseling in an extended attenuated familial adenomatous polyposis kindred. Am J Gastroenterol 91:455–459, 1996

    PubMed  CAS  Google Scholar 

  26. Lynch ED, Ostermeyer EA, Lee MK, et al: Inherited mutations in PTEN that are associated with breast cancer, Cowden disease, and juvenile polyposis. Am J Hum Genet 61:1254–1260, 1997

    Article  PubMed  CAS  Google Scholar 

  27. Warthin AS: Heredity with reference to carcinoma. Arch Intern Med 12:546–555, 1913

    Article  Google Scholar 

  28. Warthin AS: The further study of a cancer family. J Cancer Res 9:279–286, 1925

    Google Scholar 

  29. Warthin AS: Heredity of carcinoma in man. Ann Int Med 4:681–696, 1931

    Google Scholar 

  30. Lynch HT, Krush AJ: Cancer family “G” revisited: 1895–1970. Cancer 27:1505–1511, 1971

    Article  PubMed  CAS  Google Scholar 

  31. Lynch HT, Shaw MW, Magnuson CW, et al: Hereditary factors in cancer: study of two large midwestern kindreds. Arch Intern Med 117:206–212, 1966

    Article  PubMed  CAS  Google Scholar 

  32. Itoh H, Houlston RS, Harocopos C, et al: Risk of cancer death in first-degree relatives of patients with hereditary nonpolyposis cancer syndrome (Lynch Type II): a study of 130 kindreds in the United Kingdom. Br J Surg 77:1367–1370, 1990

    Article  PubMed  CAS  Google Scholar 

  33. Jass JR, Stewart SM, Schroeder D, et al: Screening for hereditary nonpolyposis colorectal cancer in New Zealand. Eur J Gastroenterol Hepatol 4:523–527, 1992

    Google Scholar 

  34. Vasen HF, Hartog Jager FCA, Menko FH, et al: Screening for hereditary nonpolyposis colorectal cancer: a study of 22 kindreds in the Netherlands. Am J Med 86:278–281, 1989

    Article  PubMed  CAS  Google Scholar 

  35. Ponz de Leon M, Sassatelli R, Sacchetti C, et al: Familial aggregation of tumors in the three year experience of a population-based colorectal cancer registry. Cancer Res 49:4344–4348, 1989

    PubMed  CAS  Google Scholar 

  36. Cristofaro G, Lynch HT, Caruso ML, et al: New phenotypic aspects in a family with Lynch syndrome II. Cancer 60:51–58, 1987

    Article  PubMed  CAS  Google Scholar 

  37. Abusamra H, Maximova S, Bar-Meir S, et al: Cancer family syndrome of Lynch. Am J Med 83:981–981, 1987

    Article  PubMed  CAS  Google Scholar 

  38. Mecklin J-P, Jarvinen HJ, Peltokallio P: Cancer family syndrome: genetic analysis of 22 Finnish kindreds. Gastroenterology 30:328–333, 1986

    Google Scholar 

  39. Mecklin JP: Frequency of hereditary colorectal carcinoma. Gastroenterology 93:1021–1025, 1987

    PubMed  CAS  Google Scholar 

  40. Boland CR, Troncale FJ: Familial colonic cancer without antecedent polyposis. Ann Intern Med 100:700–701, 1984

    PubMed  CAS  Google Scholar 

  41. Lynch HT, Smyrk T: Hereditary nonpolyposis colorectal cancer (Lynch syndrome): an updated review. Cancer 78:1149–1167, 1996

    Article  PubMed  CAS  Google Scholar 

  42. Lynch HT, Smyrk T, Lynch J: An update of HNPCC (Lynch syndrome). Cancer Genet Cytogenet 93:84–99, 1997

    Article  PubMed  CAS  Google Scholar 

  43. Watson P, Lin K, Rodriguez-Bigas MA, et al: Colorectal carcinoma survival in hereditary nonpolyposis colorectal cancer family members. Cancer 83:259–266, 1998

    Article  PubMed  CAS  Google Scholar 

  44. Sankila R, Aaltonen LA, Jarvinen HJ, et al: Better survival rates in patients with MLHl-associated hereditary colorectal cancer. Gastroenterology 110:682–687,1996

    Article  PubMed  CAS  Google Scholar 

  45. Lynch HT, Albano W, Recabaren J, et al: Prolonged survival as a component of hereditary breast and nonpolyposis colon cancer. Med Hypoth 7:1201–1209, 1981

    Article  CAS  Google Scholar 

  46. Albano WA, Recabaren JA, Lynch HT, et al: Natural history of hereditary cancer of the breast and colon. Cancer 50:360–363, 1982

    Article  PubMed  CAS  Google Scholar 

  47. Watson P, Lynch HT: Extracolonic cancer in hereditary nonpolyposis colorectal cancer. Cancer 71:677–685, 1993

    Article  PubMed  CAS  Google Scholar 

  48. Lynch HT, Fusaro RM, Roberts L, et al: Muir-Torre syndrome in several members of a family with a variant of the cancer family syndrome. Br J Dermatol 113:295–301, 1985

    Article  PubMed  CAS  Google Scholar 

  49. Lynch HT, Lynch PM, Pester JA, et al: Lynch HT, Fusaro RM, editors. Cancer-associated Genoder-matoses. New York: Van Nostrand Reinhold, 1982, 366–393

    Google Scholar 

  50. Lynch HT, Fusaro RM: Muir-Torre Syndrome: heterogeneity, natural history, diagnosis, and management. Problems in General Surgery 10:1–14, 1993

    Google Scholar 

  51. Hamilton SR, Liu B, Parsons RE, et al: The molecular basis of Turcot’s syndrome. N Engl J Med 332:839–847, 1995

    Article  PubMed  CAS  Google Scholar 

  52. Fishel R, Lescoe MK, Rao MRS, et al: The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 75:1027–1038, 1993

    Article  PubMed  CAS  Google Scholar 

  53. Leach FS, Nicolaides NC, Papadopoulos N, et al: Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell 75:1215–1225, 1993

    Article  PubMed  CAS  Google Scholar 

  54. Nicolaides NC, Papadopoulos N, Liu B, et al: Mutations of two PMS homologues in hereditary nonpolyposis colon cancer. Nature 371:75–80, 1994

    Article  PubMed  CAS  Google Scholar 

  55. Palombo F, Gillinari P, Iaccarino I, et al: GTBP, a 160-kilodalton protein essential for mismatch-binding activity in human cells. Science 268:1912–1914, 1995

    Article  PubMed  CAS  Google Scholar 

  56. Peltomaki P, Aaltonen L, Sistonen P, et al: Genetic mapping of a locus predisposing to human colorectal cancer. Science 260:810–812, 1993

    Article  PubMed  CAS  Google Scholar 

  57. Lindblom A, Tannergard P, Werelius B, et al: Genetic mapping of a second locus predisposing to hereditary nonpolyposis colorectal cancer. Nature Genet 5:279–282, 1993

    Article  PubMed  CAS  Google Scholar 

  58. Ionov YM, Peinado MA, Malkhosyan S, et al: Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature 363:558–561, 1993

    Article  PubMed  CAS  Google Scholar 

  59. Thibodeau SN, Bren G, Schaid D: Microsatellite instability in cancer of the proximal colon. Science 260:816–819, 1993

    Article  PubMed  CAS  Google Scholar 

  60. Tomlinson IPM, Beck NE, Homfray T, et al: Germline HNPCC gene variants have little influence on the risk for sporadic colorectal cancer. J Med Genet 34:39–42, 1997

    Article  PubMed  CAS  Google Scholar 

  61. Peltomaki P, Lothe RA, Aaltonen LA, et al: Microsatellite instability is associated with tumors that characterize the hereditary nonpolyposis colorectal carcinoma syndrome. Cancer Res 53:5853–5855, 1993

    PubMed  CAS  Google Scholar 

  62. Aaltonen LA, Peltomaki P, Leach FS, et al: Clues to the pathogenesis of familial colorectal cancer. Science 260:812–816, 1993

    Article  PubMed  CAS  Google Scholar 

  63. Strand M, Prolla TA, Liskay RM, et al: Destabilization of tracts of simple repetitive DNA in yeast by mutations affecting DNA mismatch repair. Nature 365:274–276, 1993

    Article  PubMed  CAS  Google Scholar 

  64. Bronner CE, Baker SM, Morrison PT, et al: Mutation in the DNA mismatch repair gene homologue hMLHl is associated with hereditary nonpolyposis colon cancer. Nature 368:258–261, 1994

    Article  PubMed  CAS  Google Scholar 

  65. Papadopoulos N, Nicolaides NC, Wei Y-F, et al: Mutation of a mutL homolog in hereditary colon cancer. Science 263:1625–1629, 1994

    Article  PubMed  CAS  Google Scholar 

  66. Viel A, Genuardi M, Capozzi E, et al: Characterization of MSH2 and MLH1 mutations in Italian families with hereditary nonpolyposis colorectal cancer. Genes Chromosomes Cancer 18:8–18, 1997

    Article  PubMed  CAS  Google Scholar 

  67. Liu B, Farrington SM, Petersen GM, et al: Genetic instability occurs in the majority of young patients with colorectal cancer. Nature Med 1:348–352, 1995

    Article  PubMed  CAS  Google Scholar 

  68. Liu B, Nicolaides NC, Markowitz S, et al: Mismatch repair gene defects in sporadic colorectal cancers with microsatellite instability. Nature Genet 9:48–55, 1995

    Article  PubMed  CAS  Google Scholar 

  69. Miyaki M, Konishi M, Tanaka K, et al: Germline mutation of MSH6 as the cause of hereditary nonpolyposis colorectal cancer. Nat Genet 17:271–272, 1997

    Article  PubMed  CAS  Google Scholar 

  70. Fujii H, Shimada T: Isolation and characterization of cDNA clones derived from the divergently transcribed gene in the region upstream from the human dihydrofolate reductase gene. J Biol Chem 264:10057–10064, 1989

    PubMed  CAS  Google Scholar 

  71. Akiyama Y, Sato H, Yamada T, et al: Germ-line mutation of the hMSH6/GTBP gene in an atypical hereditary nonpolyposis colorectal cancer kindred. Cancer Res 57:3920–3923, 1997

    PubMed  CAS  Google Scholar 

  72. Peltomäki P, Vasen HFA, International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer: Mutations predisposing to hereditary nonpolyposis colorectal cancer: database and results of a collaborative study. Gastroenterology 113:1146–1158, 1997

    Article  PubMed  Google Scholar 

  73. Wijnen J, Khan PM, Vasen H, et al: Hereditary nonpolyposis colorectal cancer families not complying with the Amsterdam criteria show extremely low frequency of mismatch-repair-gene mutations. Am J Hum Genet 61:329–335, 1997

    Article  PubMed  CAS  Google Scholar 

  74. Vasen HFA, Wijnen JT, Menko FH, et al: Cancer risk in families with hereditary nonpolyposis colorectal cancer diagnosed by mutation analysis. Gastroenterology 110:1020–1027, 1996

    Article  PubMed  CAS  Google Scholar 

  75. Lin KM, Shashidharan M, Ternent CA, et al: Colorectal and extracolonic cancer variations in MLH1/MSH2 hereditary nonpolyposis colorectal cancer kindreds and the general population. Dis Colon Rectum 41:428–433, 1998

    Article  PubMed  CAS  Google Scholar 

  76. Beck NE, Tomlinson IPM, Homfray T, et al: Genetic testing is important in families with a history suggestive of hereditary non-polyposis colorectal cancer even if the Amsterdam criteria are not fulfilled. Br J Surg 84:233–237, 1997

    Article  PubMed  CAS  Google Scholar 

  77. Muir EG, Bell AJ, Barlow KA: Multiple primary carcinomata of the colon, duodenum, and larynx associated with keratoacanthomata of the face. Br J Surg 54:191–195, 1966

    Article  Google Scholar 

  78. Torre D: Multiple sebaceous tumors. Arch Dermatol 98:549–551, 1968

    Article  PubMed  CAS  Google Scholar 

  79. Lynch HT, Lynch PM, Pester J, et al: The cancer family syndrome: rare cutaneous phenotypic linkage of Torre’s syndrome. Arch Intern Med 141:607–611, 1981

    Article  PubMed  CAS  Google Scholar 

  80. Hall NR, Murday VA, Chapman P, et al: Genetic linkage in Muir-Torre syndrome to the same chromosomal region as cancer family syndrome. Eur J Cancer 30A:180–182, 1994

    Article  Google Scholar 

  81. Rodriguez-Bigas MA, Boland CR, Hamilton SR, et al: A National Cancer Institute workshop on hereditary nonpolyposis colorectal cancer syndrome: meeting highlights and Bethesda Guidelines. J Natl Cancer Inst 89:1758–1762, 1997

    Article  PubMed  CAS  Google Scholar 

  82. Liu B, Parsons R, Papadopoulos N, et al: Analysis of mismatch repair genes in hereditary nonpolyposis colorectal cancer patients. Nat Med 2:169–174, 1996

    Article  PubMed  CAS  Google Scholar 

  83. International Workshop on Microsatellite Instability and RER Phenotypes in Cancer Detection and Familial Predisposition Meeting. National Cancer Institute; 1997; Bethesda, MD. 1997

    Google Scholar 

  84. Jass JR: Colorectal adenoma progression and genetic change: is there a link? Ann Med 27:301–306, 1995

    Article  PubMed  CAS  Google Scholar 

  85. Winawer SJ, Fletcher RH, Miller L, et al: Colorectal cancer screening: clinical guidelines and rationale. Gastroenterology 112:594–642, 1997

    Article  PubMed  CAS  Google Scholar 

  86. Jass JR, Cottier DS, Pokos V, et al: Mixed epithelial polyps in association with hereditary nonpolyposis colorectal cancer providing an alternative pathway of cancer histogenesis. Pathology 29:28–33, 1997

    Article  PubMed  CAS  Google Scholar 

  87. Jass JR: Familial cancer: histopathological perspectives. J Clin Pathol 50:892–895, 1997

    Article  PubMed  CAS  Google Scholar 

  88. Sheng GG, Shao J, Sheng H, et al: A selective cyclooxygenase 2 inhibitor suppresses the growth of H-ras-transformed rat intestinal epithelial cells. Gastroenterology 113:1883–1891, 1997

    Article  PubMed  CAS  Google Scholar 

  89. Elder DJE, Paraskeva C: NSAIDs to prevent colorectal cancer: a question of sensitivity. Gastroenterology 113:1999–2003, 1997

    PubMed  CAS  Google Scholar 

  90. Rodriguez-Bigas MA, Vasen HFA, Pekka-Mecklin J, et al: Rectal cancer risk in hereditary nonpoly-posis colorectal cancer after abdominal colectomy. Ann Surg 225:202–207, 1997

    Article  PubMed  CAS  Google Scholar 

  91. Lynch HT: Is there a role for prophylactic subtotal colectomy among hereditary nonpolyposis colorectal cancer germline mutation carriers? Dis Colon Rectum 39:109–110, 1996

    Article  PubMed  CAS  Google Scholar 

  92. Church JM: Prophylactic colectomy in patients with hereditary nonpolyposis colorectal cancer. Ann Med 28:479–482, 1996

    Article  PubMed  CAS  Google Scholar 

  93. Lynch HT, Cavalieri RJ, Lynch JF, et al: Gynecologic cancer clues to Lynch syndrome II diagnosis: a family report. Gynecologic Oncol 44:198–203, 1992

    Article  CAS  Google Scholar 

  94. Lynch HT, Fusaro RM, Lemon SJ, et al: Survey of cancer genetics: genetic testing implications. Cancer 80(suppl):523–532, 1997

    Article  Google Scholar 

  95. Myrhoj T, Bisgaard ML, Bernstein I, et al: Hereditary non-polyposis colorectal cancer: clinical features and survival: results from the Danish HNPCC Register. Scand J Gastroenterol 32:572–576, 1997

    Article  PubMed  CAS  Google Scholar 

  96. Fink D, Aebi S, Howell SB: The role of DNA mismatch repair in drug resistance. Clin Cancer Res 4:1–6, 1998

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Preventive Medicine, Creighton University School of Medicine, 2500 California Plaza, Omaha, Nebraska, 68178, USA

    Henry T. Lynch, Jane F. Lynch & Trudy G. Shaw

  2. Department of Pathology, University of Nebraska Medical Center, 4350 Dewey Avenue, Omaha, Nebraska, 68105, USA

    Thomas C. Smyrk

Authors
  1. Henry T. Lynch
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jane F. Lynch
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Trudy G. Shaw
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Thomas C. Smyrk
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. H. Lee Moffitt Cancer Center and Research Institute, University of South Florida College of Medicine, Tampa, Florida, USA

    Gail L. Shaw

Rights and permissions

Reprints and permissions

Copyright information

© 1999 Springer Science+Business Media New York

About this chapter

Cite this chapter

Lynch, H.T., Lynch, J.F., Shaw, T.G., Smyrk, T.C. (1999). Genetics of Colorectal Cancer. In: Shaw, G.L. (eds) Cancer Genetics for the Clinician. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-4699-3_10

Download citation

  • DOI: https://doi.org/10.1007/978-1-4615-4699-3_10

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4613-7128-1

  • Online ISBN: 978-1-4615-4699-3

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation