Familial Cancer

, Volume 4, Issue 4, pp 323–333 | Cite as

Syndrome of Early Onset Colon Cancers, Hematologic Malignancies & Features of Neurofibromatosis in HNPCC Families with Homozygous Mismatch Repair Gene Mutations

  • Prathap Bandipalliam
Review

Abstract

Hereditary nonpolyposis colon cancer (HNPCC) is the most common hereditary colon cancer syndrome. It is characterized by multiple colon as well as extracolonic cancers such as endometrial, ovarian and urinary tract cancers. In addition, it is well known that some cases of HNPCC can present with unique tumor spectrums such as sebaceous tumors, which is often referred to as the ‘Muir–Torre’ syndrome. In recent years there have been a few reports of families presenting with early onset of colon tumors along with café-au-lait spots and/or hematologic malignancies often associated with homozygous mutations involving one of the mismatch repair genes. In this article we have performed a comprehensive review of the entire medical literature to identify all cases with similar presentations reported in the literature and have summarized the clinical features and genetic test results of the same. The available data clearly highlight such presentations as a distinct clinical entity characterized by early onset of gastrointestinal tumors, hematologic malignancies as well as features of neurofibromatosis (easily remembered by the acronym `CoLoN'; Colon tumors or/and Leukemia/Lymphoma or/and Neurofibromatosis features). Furthermore, there has also been some evidence that the neurofibromatosis type-1 gene is a mutational target of the mismatch repair deficiency that is seen in families with HNPCC, and that mlh1 deficiency can accelerate the development of leukemia in neurofibromatosis (Nf1) heterozygous mice. Recognition of this syndrome has significant importance in terms of earlier detection of cancers, cancer screening recommendations as well as genetic counseling offered to such families.

Keywords:

hematologic malignancies hereditary nonpolyposis colon cancer mismatch repair gene mutations neurofibromatosis 

Abbreviations

HNPCC

hereditary nonpolyposis colon cancer

MSI

microsatellite instability

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References

  1. 1.
    Lynch, HT, Kimberling, W, Albano, WA,  et al. 1985Hereditary nonpolyposis colorectal cancer (Lynch syndrome I and II). I. Clinical description of resourceCancer5693438PubMedGoogle Scholar
  2. 2.
    Marra, G, Boland, CR 1995Hereditary nonpolyposis colorectal cancer: The syndrome, the genes, and historical perspectivesJ Natl Cancer Inst87111425PubMedGoogle Scholar
  3. 3.
    Vasen, HF 2000Clinical diagnosis and management of hereditary colorectal cancer syndromesJ Clin Oncol1881S92SPubMedGoogle Scholar
  4. 4.
    Giardiello, F, Brensinger, JD, Petersen, GM 2001AGA Technical review␣on hereditary colorectal cancer and genetic testingGastroenterology121198213PubMedGoogle Scholar
  5. 5.
    Rodriguez-Bigas, M, Boland, CR, Hamilton, SR,  et al. 1997A National Cancer Institute workshop on Hereditary Nonpolyposis Colorectal Cancer Syndrome: Meeting highlights and BethesdaguidelinesJ Natl Cancer Inst89175862CrossRefPubMedGoogle Scholar
  6. 6.
    Umar, A, Boland, CR, Terdiman, JP,  et al. 2004Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instabilityJ Natl Cancer Inst962618PubMedGoogle Scholar
  7. 7.
    Terdiman, JP, Gum, JR,Jr., Conrad, PG,  et al. 2001Efficient detection of hereditary nonpolyposis colorectal cancer gene carriers by screening for tumor microsatellite instability before germline genetic testingGastroenterology1202130CrossRefPubMedGoogle Scholar
  8. 8.
    Lynch, HT, Fusaro, RM 1999The Muir-Torre syndrome in kindreds with hereditary nonpolyposis colorectal cancer (Lynch syndrome): A classic obligation in preventive medicineJ Am Acad Dermatol417979PubMedGoogle Scholar
  9. 9.
    Suspiro, A, Fidalgo, P, Cravo, M,  et al. 1998The Muir-Torre syndrome: A rare variant of hereditary nonpolyposis colorectal cancer associated with hMSH2 mutationAm J Gastroenterol9315724CrossRefPubMedGoogle Scholar
  10. 10.
    Menko, FH, Kaspers, GL, Meijer, GA,  et al. 2004A homozygous MSH6 mutation in a child with café-au-lait spots, oligodendroglioma and rectal cancerFam Cancer31237PubMedGoogle Scholar
  11. 11.
    Hegde, MR, Blazo, MA, Chin, LH,  et al. 2003A novel homozygous mutation in the MSH6 gene in a Turcot syndrome family characterized by pediatric glioblastoma multiforme, lymphoma, colorectal cancer and neurofibromatosisAm J Hum Genet73237Google Scholar
  12. 12.
    De Vos, M, Hayward, BE, Picton, S,  et al. 2004Novel PMS2 pseudogenes can conceal recessive mutations causing a distinctive childhood cancer syndromeAm J Hum Genet7495464CrossRefPubMedGoogle Scholar
  13. 13.
    Miyaki, M, Nishio, J, Konishi, M,  et al. 1997Drastic genetic instability of tumors and normal tissues in Turcot syndromeOncogene15287781CrossRefPubMedGoogle Scholar
  14. 14.
    Gallinger, S, Aronson, M, Shayan, K,  et al. 2004Gastrointestinal cancers and neurofibromatosis type 1 features in children with a germline homozygous MLH1 mutationGastroenterology12657685CrossRefPubMedGoogle Scholar
  15. 15.
    Ricciardone, MD, Ozcelik, T, Cevher, B,  et al. 1999Human MLH1 deficiency predisposes to hematological malignancy and neurofibromatosis type 1Cancer Res592903PubMedGoogle Scholar
  16. 16.
    Whiteside, D, McLeod, R, Graham, G,  et al. 2002A homozygous germ-line mutation in the human MSH2 gene predisposes to hematological malignancy and multiple café-au-lait spotsCancer Res6235962PubMedGoogle Scholar
  17. 17.
    Wang, Q, Lasset, C, Desseigne, F,  et al. 1999Neurofibromatosis and early onset of cancers in hMLH1-deficient childrenCancer Res592947PubMedGoogle Scholar
  18. 18.
    Raevaara, TE, Gerdes, AM, Lonnqvist, KE,  et al. 2004HNPCC mutation MLH1 P648S makes the functional protein unstable, and homozygosity predisposes to mild neurofibromatosis type 1Genes Chromosomes Cancer402615CrossRefPubMedGoogle Scholar
  19. 19.
    Vilkki, S, Tsao, JL, Loukola, A,  et al. 2001Extensive somatic microsatellite mutations in normal human tissueCancer Res6145414PubMedGoogle Scholar
  20. 20.
    Trimbath, JD, Petersen, GM, Erdman, SH,  et al. 2001Café-au-lait spots and early onset colorectal neoplasia: A variant of HNPCC?Fam Cancer11015CrossRefPubMedGoogle Scholar
  21. 21.
    Hamilton, SR, Liu, B, Parsons, RE,  et al. 1995The molecular basis of Turcot’s syndromeN Engl J Med33283947CrossRefPubMedGoogle Scholar
  22. 22.
    Taylor, MD, Perry, J, Zlatescu, MC,  et al. 1999The hPMS2 exon 5 mutation and malignant glioma. Case reportJ Neurosurg9094650PubMedGoogle Scholar
  23. 23.
    De Rosa, M, Fasano, C, Panariello, L,  et al. 2000Evidence for a recessive inheritance of Turcot’s syndrome caused by compound heterozygous mutations within the PMS2 geneOncogene19171923CrossRefPubMedGoogle Scholar
  24. 24.
    Bougeard, G, Charbonnier, F, Moerman, A,  et al. 2003Early onset brain tumor and lymphoma in MSH2-deficient childrenAm J Hum Genet722136CrossRefPubMedGoogle Scholar
  25. 25.
    Syngal, S 2000Hereditary nonpolyposis colorectal cancer: A call for attentionJ Clin Oncol18218992PubMedGoogle Scholar
  26. 26.
    Korf, BR 2002Clinical features and pathobiology of neurofibromatosis 1J Child Neurol175737discussion 602–4, 646–51PubMedGoogle Scholar
  27. 27.
    Qin, X, Zhou, H, Liu, L, Gerson, SL 1999Transgenic expression of human MGMT blocks the hypersensitivity of PMS2-deficient mice to low dose MNU thymic lymphomagenesisCarcinogenesis20166773CrossRefPubMedGoogle Scholar
  28. 28.
    Qin, X, Liu, L, Gerson, SL 1999Mice defective in the DNA mismatch gene PMS2 are hypersensitive to MNU induced thymic lymphoma and are partially protected by transgenic expression of human MGMTOncogene184394400CrossRefPubMedGoogle Scholar
  29. 29.
    Reitmair, AH, Redston, M, Cai, JC,  et al. 1996Spontaneous intestinal carcinomas and skin neoplasms in Msh2-deficient miceCancer Res5638429PubMedGoogle Scholar
  30. 30.
    Baker, SM, Bronner, CE, Zhang, L,  et al. 1995Male mice defective in the DNA mismatch repair gene PMS2 exhibit abnormal chromosome synapsis in meiosisCell8230919CrossRefPubMedGoogle Scholar
  31. 31.
    de Wind, N, Dekker, M, Berns, A,  et al. 1995Inactivation of the mouse Msh2 gene results in mismatch repair deficiency, methylation tolerance, hyperrecombination, and predisposition to cancerCell8232130PubMedGoogle Scholar
  32. 32.
    Edelmann, W, Yang, K, Umar, A,  et al. 1997Mutation in the mismatch repair gene Msh6 causes cancer susceptibilityCell9146777CrossRefPubMedGoogle Scholar
  33. 33.
    Prolla, TA, Baker, SM, Harris, AC,  et al. 1998Tumour susceptibility and spontaneous mutation in mice deficient in Mlh1, Pms1 and Pms2 DNA mismatch repairNat Genet182769CrossRefPubMedGoogle Scholar
  34. 34.
    Wang, Q, Montmain, G, Ruano, E,  et al. 2003Neurofibromatosis type 1 gene as a mutational target in a mismatch repair-deficient cell typeHum Genet11211723PubMedGoogle Scholar
  35. 35.
    Gutmann, DH, Winkeler, E, Kabbarah, O,  et al. 2003Mlh1 deficiency accelerates myeloid leukemogenesis in neurofibromatosis 1 (Nf1) heterozygous miceOncogene2245815CrossRefPubMedGoogle Scholar

Copyright information

© Springer 2005

Authors and Affiliations

  • Prathap Bandipalliam
    • 1
  1. 1.Department of Adult Oncology, Division of Population SciencesDana-Farber Cancer InstituteBostonUSA

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