Human Genetics

, Volume 124, Issue 2, pp 105–122

Constitutional mismatch repair-deficiency syndrome: have we so far seen only the tip of an iceberg?

Review Article

Abstract

Heterozygous mutations in one of the mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2 cause the dominant adult cancer syndrome termed Lynch syndrome or hereditary non-polyposis colorectal cancer. During the past 10 years, some 35 reports have delineated the phenotype of patients with biallelic inheritance of mutations in one of these MMR genes. The patients suffer from a condition that is characterised by the development of childhood cancers, mainly haematological malignancies and/or brain tumours, as well as early-onset colorectal cancers. Almost all patients also show signs reminiscent of neurofibromatosis type 1, mainly café au lait spots. Alluding to the underlying mechanism, this condition may be termed as “constitutional mismatch repair-deficiency (CMMR-D) syndrome”. To give an overview of the current knowledge and its implications of this recessively inherited cancer syndrome we summarise here the genetic, clinical and pathological findings of the so far 78 reported patients of 46 families suffering from this syndrome.

References

  1. Aaltonen LA, Peltomaki P, Leach FS, Sistonen P, Pylkkanen L, Mecklin JP, Jarvinen H, Powell SM, Jen J, Hamilton SR et al (1993) Clues to the pathogenesis of familial colorectal cancer. Science 260:812–816PubMedCrossRefGoogle Scholar
  2. Agostini M, Tibiletti MG, Lucci-Cordisco E, Chiaravalli A, Morreau H, Furlan D, Boccuto L, Pucciarelli S, Capella C, Boiocchi M, Viel A (2005) Two PMS2 mutations in a Turcot syndrome family with small bowel cancers. Am J Gastroenterol 100:1886–1891PubMedCrossRefGoogle Scholar
  3. Alonso M, Hamelin R, Kim M, Porwancher K, Sung T, Parhar P, Miller DC, Newcomb EW (2001) Microsatellite instability occurs in distinct subtypes of pediatric but not adult central nervous system tumors. Cancer Res 61:2124–2128PubMedGoogle Scholar
  4. Auclair J, Leroux D, Desseigne F, Lasset C, Saurin JC, Joly MO, Pinson S, Xu XL, Montmain G, Ruano E, Navarro C, Puisieux A, Wang Q (2007) Novel biallelic mutations in MSH6 and PMS2 genes: gene conversion as a likely cause of PMS2 gene inactivation. Hum Mutat 28(11):1084–1090PubMedCrossRefGoogle Scholar
  5. Bandipalliam P (2005) Syndrome of early onset colon cancers, hematologic malignancies & features of neurofibromatosis in HNPCC families with homozygous mismatch repair gene mutations. Fam Cancer 4:323–333PubMedCrossRefGoogle Scholar
  6. Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, Burt RW, Meltzer SJ, Rodriguez-Bigas MA, Fodde R, Ranzani GN, Srivastava S (1998) A national cancer institute workshop on microsatellite instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res 58:5248–5257PubMedGoogle Scholar
  7. Bougeard G, Charbonnier F, Moerman A, Martin C, Ruchoux MM, Drouot N, Frebourg T (2003) Early onset brain tumor and lymphoma in MSH2-deficient children. Am J Hum Genet 72:213–216PubMedCrossRefGoogle Scholar
  8. Brems H, Chmara M, Sahbatou M, Denayer E, Taniguchi K, Kato R, Somers R, Messiaen L, De Schepper S, Fryns JP, Cools J, Marynen P, Thomas G, Yoshimura A, Legius E (2007) Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype. Nat Genet 39:1120–1126PubMedCrossRefGoogle Scholar
  9. Clendenning M, de la Chapelle A (2007) Response to: getting rid of the PMS2 pseudogenes: mission impossible? Hum Mutat 28:415CrossRefGoogle Scholar
  10. Clendenning M, Hampel H, LaJeunesse J, Lindblom A, Lockman J, Nilbert M, Senter L, Sotamaa K, de la Chapelle A (2006) Long-range PCR facilitates the identification of PMS2-specific mutations. Hum Mutat 27:490–495PubMedCrossRefGoogle Scholar
  11. De Rosa M, Fasano C, Panariello L, Scarano MI, Belli G, Iannelli A, Ciciliano F, Izzo P (2000) Evidence for a recessive inheritance of Turcot’s syndrome caused by compound heterozygous mutations within the PMS2 gene. Oncogene 19:1719–1723PubMedCrossRefGoogle Scholar
  12. De Vos M, Hayward BE, Picton S, Sheridan E, Bonthron DT (2004) Novel PMS2 pseudogenes can conceal recessive mutations causing a distinctive childhood cancer syndrome. Am J Hum Genet 74:954–964PubMedCrossRefGoogle Scholar
  13. De Vos M, Hayward BE, Charlton R, Taylor GR, Glaser AW, Picton S, Cole TR, Maher ER, McKeown CM, Mann JR, Yates JR, Baralle D, Rankin J, Bonthron DT, Sheridan E (2006) PMS2 mutations in childhood cancer. J Natl Cancer Inst 98:358–361PubMedCrossRefGoogle Scholar
  14. Etzler J, Peyrl A, Zatkova A, Schildhaus HU, Ficek A, Merkelbach-Bruse S, Kratz CP, Attarbaschi A, Hainfellner JA, Yao S, Messiaen L, Slavc I, Wimmer K (2008) RNA-based mutation analysis identifies an unusual MSH6 splicing defect and circumvents PMS2 pseudogene interference. Hum Mutat 29:299–305PubMedCrossRefGoogle Scholar
  15. Felton KE, Gilchrist DM, Andrew SE (2007a) Constitutive deficiency in DNA mismatch repair. Clin Genet 71:483–498PubMedCrossRefGoogle Scholar
  16. Felton KE, Gilchrist DM, Andrew SE (2007b) Constitutive deficiency in DNA mismatch repair: is it time for Lynch III? Clin Genet 71:499–500PubMedCrossRefGoogle Scholar
  17. Gallinger S, Aronson M, Shayan K, Ratcliffe EM, Gerstle JT, Parkin PC, Rothenmund H, Croitoru M, Baumann E, Durie PR, Weksberg R, Pollett A, Riddell RH, Ngan BY, Cutz E, Lagarde AE, Chan HS (2004) Gastrointestinal cancers and neurofibromatosis type 1 features in children with a germline homozygous MLH1 mutation. Gastroenterology 126:576–585PubMedCrossRefGoogle Scholar
  18. Hackman P, Tannergard P, Osei-Mensa S, Chen J, Kane MF, Kolodner R, Lambert B, Hellgren D, Lindblom A (1997) A human compound heterozygote for two MLH1 missense mutations. Nat Genet 17:135–136PubMedCrossRefGoogle Scholar
  19. Hamilton SR, Liu B, Parsons RE, Papadopoulos N, Jen J, Powell SM, Krush AJ, Berk T, Cohen Z, Tetu B, Burger PC, Wood PA, Taqi F, Booker SV, Petersen GM, Offerhaus GJA, Tersmette AC, Giardiello FM, Vogelstein B, Kinzler KW (1995) The molecular basis of Turcot’s syndrome. N Engl J Med 332:839–847PubMedCrossRefGoogle Scholar
  20. Hayward BE, De Vos M, Valleley EM, Charlton RS, Taylor GR, Sheridan E, Bonthron DT (2007) Extensive gene conversion at the PMS2 DNA mismatch repair locus. Hum Mutat 28:424–430PubMedCrossRefGoogle Scholar
  21. Hegde MR, Chong B, Blazo ME, Chin LH, Ward PA, Chintagumpala MM, Kim JY, Plon SE, Richards CS (2005) A homozygous mutation in MSH6 causes Turcot syndrome. Clin Cancer Res 11:4689–4693PubMedCrossRefGoogle Scholar
  22. Herman JG, Umar A, Polyak K, Graff JR, Ahuja N, Issa JP, Markowitz S, Willson JK, Hamilton SR, Kinzler KW, Kane MF, Kolodner RD, Vogelstein B, Kunkel TA, Baylin SB (1998) Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci USA 95:6870–6875PubMedCrossRefGoogle Scholar
  23. Hirsch B, Shimamura A, Moreau L, Baldinger S, Hag-alshiekh M, Bostrom B, Sencer S, D’Andrea AD (2004) Association of biallelic BRCA2/FANCD1 mutations with spontaneous chromosomal instability and solid tumors of childhood. Blood 103:2554–2559PubMedCrossRefGoogle Scholar
  24. Huson SM (2008) The neurofibromatoses: classification, clinical features and genetic counselling. In: Kaufmann D (ed) Neurofibromatoses, vol 16. Karger, Basel, pp 1–20CrossRefGoogle Scholar
  25. Jackson CC, Holter S, Pollett A, Clendenning M, Chou S, Senter L, Ramphal R, Gallinger S, Boycott K (2008) Café-au-lait macules and pediatric malignancy caused by biallelic mutations in the DNA mismatch repair (MMR) gene PMS2. Pediatr Blood Cancer 50:1268–1270PubMedCrossRefGoogle Scholar
  26. Jiricny J (2006a) The multifaceted mismatch-repair system. Nat Rev Mol Cell Biol 7:335–346PubMedCrossRefGoogle Scholar
  27. Jiricny J (2006b) MutLalpha: at the cutting edge of mismatch repair. Cell 126:239–241PubMedCrossRefGoogle Scholar
  28. Kadyrov FA, Dzantiev L, Constantin N, Modrich P (2006) Endonucleolytic function of MutLalpha in human mismatch repair. Cell 126:297–308PubMedCrossRefGoogle Scholar
  29. Korf BR (1992) Diagnostic outcome in children with multiple cafe au lait spots. Pediatrics 90:924–927PubMedGoogle Scholar
  30. Kratz CP, Niemeyer CM, Juttner E, Kartal M, Weninger A, Schmitt-Graeff A, Kontny U, Lauten M, Utzolino S, Radecke J, Fonatsch C, Wimmer K (2007) Childhood T-cell non-Hodgkin’s lymphoma, colorectal carcinoma and brain tumor in association with cafe-au-lait spots caused by a novel homozygous PMS2 mutation. Leukemia 22(5):1078–1080PubMedCrossRefGoogle Scholar
  31. Kruger S, Kinzel M, Walldorf C, Gottschling S, Bier A, Tinschert S, von Stackelberg A, Henn W, Gorgens H, Boue S, Kolble K, Buttner R, Schackert HK (2008) Homozygous PMS2 germline mutations in two families with early-onset haematological malignancy, brain tumours, HNPCC-associated tumours, and signs of neurofibromatosis type 1. Eur J Hum Genet 16:62–72PubMedCrossRefGoogle Scholar
  32. Le Beau MM, Albain KS, Larson RA, Vardiman JW, Davis EM, Blough RR, Golomb HM, Rowley JD (1986) Clinical and cytogenetic correlations in 63 patients with therapy-related myelodysplastic syndromes and acute nonlymphocytic leukemia: further evidence for characteristic abnormalities of chromosomes no. 5 and 7. J Clin Oncol 4:325–345PubMedGoogle Scholar
  33. Leung SY, Chan TL, Chung LP, Chan AS, Fan YW, Hung KN, Kwong WK, Ho JW, Yuen ST (1998) Microsatellite instability and mutation of DNA mismatch repair genes in gliomas. Am J Pathol 153:1181–1188PubMedGoogle Scholar
  34. Lindor NM, Petersen GM, Hadley DW, Kinney AY, Miesfeldt S, Lu KH, Lynch P, Burke W, Press N (2006) Recommendations for the care of individuals with an inherited predisposition to Lynch syndrome: a systematic review. JAMA 296:1507–1517PubMedCrossRefGoogle Scholar
  35. Liu T, Tannergard P, Hackman P, Rubio C, Kressner U, Lindmark G, Hellgren D, Lambert B, Lindblom A (1999) Missense mutations in hMLH1 associated with colorectal cancer. Hum Genet 105:437–441PubMedCrossRefGoogle Scholar
  36. Lynch HT, de la Chapelle A (2003) Hereditary colorectal cancer. N Engl J Med 348:919–932PubMedCrossRefGoogle Scholar
  37. Magnusson S, Borg A, Kristoffersson U, Nilbert M, Wiebe T, Olsson H (2008) Higher occurrence of childhood cancer in families with germline mutations in BRCA2, MMR and CDKN2A genes. Fam Cancer [Epub ahead of print]Google Scholar
  38. Maris JM, Wiersma SR, Mahgoub N, Thompson P, Geyer RJ, Hurwitz CG, Lange BJ, Shannon KM (1997) Monosomy 7 myelodysplastic syndrome and other second malignant neoplasms in children with neurofibromatosis type 1. Cancer 79:1438–1446PubMedCrossRefGoogle Scholar
  39. Menko FH, Kaspers GL, Meijer GA, Claes K, van Hagen JM, Gille JJ (2004) A homozygous MSH6 mutation in a child with cafe-au-lait spots, oligodendroglioma and rectal cancer. Fam Cancer 3:123–127PubMedCrossRefGoogle Scholar
  40. Muller A, Schackert HK, Lange B, Ruschoff J, Fuzesi L, Willert J, Burfeind P, Shah P, Becker H, Epplen JT, Stemmler S (2006) A novel MSH2 germline mutation in homozygous state in two brothers with colorectal cancers diagnosed at the age of 11 and 12 years. Am J Med Genet A 140:195–199PubMedGoogle Scholar
  41. Ostergaard JR, Sunde L, Okkels H (2005) Neurofibromatosis von Recklinghausen type I phenotype and early onset of cancers in siblings compound heterozygous for mutations in MSH6. Am J Med Genet A 139:96–105 discussion 96Google Scholar
  42. Parsons R, Myeroff LL, Liu B, Willson JK, Markowitz SD, Kinzler KW, Vogelstein B (1995) Microsatellite instability and mutations of the transforming growth factor beta type II receptor gene in colorectal cancer. Cancer Res 55:5548–5550PubMedGoogle Scholar
  43. Peltomaki P (2001) Deficient DNA mismatch repair: a common etiologic factor for colon cancer. Hum Mol Genet 10:735–740PubMedCrossRefGoogle Scholar
  44. Peltomaki P (2003) Role of DNA mismatch repair defects in the pathogenesis of human cancer. J Clin Oncol 21:1174–1179PubMedCrossRefGoogle Scholar
  45. Peltomaki P, Lothe RA, Aaltonen LA, Pylkkanen L, Nystrom-Lahti M, Seruca R, David L, Holm R, Ryberg D, Haugen A et al (1993) Microsatellite instability is associated with tumors that characterize the hereditary non-polyposis colorectal carcinoma syndrome. Cancer Res 53:5853–5855PubMedGoogle Scholar
  46. Perilongo G, Felix CA, Meadows AT, Nowell P, Biegel J, Lange BJ (1993) Sequential development of Wilms tumor, T-cell acute lymphoblastic leukemia, medulloblastoma and myeloid leukemia in a child with type 1 neurofibromatosis: a clinical and cytogenetic case report. Leukemia 7:912–915PubMedGoogle Scholar
  47. Plaschke J, Engel C, Kruger S, Holinski-Feder E, Pagenstecher C, Mangold E, Moeslein G, Schulmann K, Gebert J, von Knebel Doeberitz M, Ruschoff J, Loeffler M, Schackert HK (2004) Lower incidence of colorectal cancer and later age of disease onset in 27 families with pathogenic MSH6 germline mutations compared with families with MLH1 or MSH2 mutations: the German Hereditary Nonpolyposis Colorectal Cancer Consortium. J Clin Oncol 22:4486–4494PubMedCrossRefGoogle Scholar
  48. Plaschke J, Linnebacher M, Kloor M, Gebert J, Cremer FW, Tinschert S, Aust DE, von Knebel Doeberitz M, Schackert HK (2006) Compound heterozygosity for two MSH6 mutations in a patient with early onset of HNPCC-associated cancers, but without hematological malignancy and brain tumor. Eur J Hum Genet 14:561–566PubMedCrossRefGoogle Scholar
  49. Poley JW, Wagner A, Hoogmans MM, Menko FH, Tops C, Kros JM, Reddingius RE, Meijers-Heijboer H, Kuipers EJ, Dinjens WN (2007) Biallelic germline mutations of mismatch-repair genes: a possible cause for multiple pediatric malignancies. Cancer 109:2349–2356PubMedCrossRefGoogle Scholar
  50. Raevaara TE, Gerdes AM, Lonnqvist KE, Tybjaerg-Hansen A, Abdel-Rahman WM, Kariola R, Peltomaki P, Nystrom-Lahti M (2004) HNPCC mutation MLH1 P648S makes the functional protein unstable, and homozygosity predisposes to mild neurofibromatosis type 1. Genes Chromosomes Cancer 40:261–265PubMedCrossRefGoogle Scholar
  51. Rahman N, Scott RH (2007) Cancer genes associated with phenotypes in monoallelic and biallelic mutation carriers: new lessons from old players. Hum Mol Genet 16 Spec no 1:R60–R66PubMedCrossRefGoogle Scholar
  52. Rahner N, Hoefler G, Hogenauer C, Lackner C, Steinke V, Sengteller M, Friedl W, Aretz S, Propping P, Mangold E, Walldorf C (2008) Compound heterozygosity for two MSH6 mutations in a patient with early onset colorectal cancer, vitiligo and systemic lupus erythematosus. Am J Med Genet A 146A:1314–1319PubMedCrossRefGoogle Scholar
  53. Reid S, Renwick A, Seal S, Baskcomb L, Barfoot R, Jayatilake H, Pritchard-Jones K, Stratton MR, Ridolfi-Luthy A, Rahman N (2005) Biallelic BRCA2 mutations are associated with multiple malignancies in childhood including familial Wilms tumour. J Med Genet 42:147–151PubMedCrossRefGoogle Scholar
  54. Rey JM, Noruzinia M, Brouillet JP, Sarda P, Maudelonde T, Pujol P (2004) Six novel heterozygous MLH1, MSH2, and MSH6 and one homozygous MLH1 germline mutations in hereditary nonpolyposis colorectal cancer. Cancer Genet Cytogenet 155:149–151PubMedCrossRefGoogle Scholar
  55. Ricciardone MD, Ozcelik T, Cevher B, Ozdag H, Tuncer M, Gurgey A, Uzunalimoglu O, Cetinkaya H, Tanyeli A, Erken E, Ozturk M (1999) Human MLH1 deficiency predisposes to hematological malignancy and neurofibromatosis type 1. Cancer Res 59:290–293PubMedGoogle Scholar
  56. Rowley JD, Golomb HM, Vardiman JW (1981) Nonrandom chromosome abnormalities in acute leukemia and dysmyelopoietic syndromes in patients with previously treated malignant disease. Blood 58:759–767PubMedGoogle Scholar
  57. Scott RH, Homfray T, Huxter NL, Mitton SG, Nash R, Potter MN, Lancaster D, Rahman N (2007a) Familial T-cell non-Hodgkin lymphoma caused by biallelic MSH2 mutations. J Med Genet 44:e83PubMedCrossRefGoogle Scholar
  58. Scott RH, Mansour S, Pritchard-Jones K, Kumar D, MacSweeney F, Rahman N (2007b) Medulloblastoma, acute myelocytic leukemia and colonic carcinomas in a child with biallelic MSH6 mutations. Nat Clin Pract Oncol 4:130–134PubMedCrossRefGoogle Scholar
  59. Senter L, Clendenning M, Sotamaa K, Hampel H, Green J, Potter JD, Lindblom A, Lagerstedt K, Thibodeau SN, Lindor NM, Young J, Winship I, Dowty JG, White DM, Hopper JL, Baglietto L, Jenkins MA, de la Chapelle A (2008) The Clinical Phenotype of Lynch Syndrome Because of Germ-Line PMS2 Mutations. Gastroenterology 135:419–428PubMedCrossRefGoogle Scholar
  60. Shannon KM, O’Connell P, Martin GA, Paderanga D, Olson K, Dinndorf P, McCormick F (1994) Loss of the normal NF1 allele from the bone marrow of children with type 1 neurofibromatosis and malignant myeloid disorders. N Engl J Med 330:597–601PubMedCrossRefGoogle Scholar
  61. Smith SM, Le Beau MM, Huo D, Karrison T, Sobecks RM, Anastasi J, Vardiman JW, Rowley JD, Larson RA (2003) Clinical-cytogenetic associations in 306 patients with therapy-related myelodysplasia and myeloid leukemia: the University of Chicago series. Blood 102:43–52PubMedCrossRefGoogle Scholar
  62. Stephens K, Weaver M, Leppig KA, Maruyama K, Emanuel PD, Le Beau MM, Shannon KM (2006) Interstitial uniparental isodisomy at clustered breakpoint intervals is a frequent mechanism of NF1 inactivation in myeloid malignancies. Blood 108:1684–1689PubMedCrossRefGoogle Scholar
  63. Stojic L, Brun R, Jiricny J (2004) Mismatch repair and DNA damage signalling. DNA Repair (Amst) 3:1091–1101CrossRefGoogle Scholar
  64. Stumpf D (1988) Consensus developent conference of neurofibromatosis. Arch Neurol 45:575–578Google Scholar
  65. Tan TY, Orme LM, Lynch E, Croxford MA, Dow C, Dewan PA, Lipton L (2008) Biallelic PMS2 mutations and a distinctive childhood cancer syndrome. J Pediatr Hematol Oncol 30:254–257PubMedCrossRefGoogle Scholar
  66. Taylor MD, Perry J, Zlatescu MC, Stemmer-Rachamimov AO, Ang LC, Ino Y, Schwartz M, Becker LE, Louis DN, Cairncross JG (1999) The hPMS2 exon 5 mutation and malignant glioma. Case report. J Neurosurg 90:946–950PubMedGoogle Scholar
  67. Thirman MJ, Larson RA (1996) Therapy-related myeloid leukemia. Hematol Oncol Clin North Am 10:293–320PubMedCrossRefGoogle Scholar
  68. Trimbath JD, Petersen GM, Erdman SH, Ferre M, Luce MC, Giardiello FM (2001) Cafe-au-lait spots and early onset colorectal neoplasia: a variant of HNPCC? Fam Cancer 1:101–105PubMedCrossRefGoogle Scholar
  69. Truninger K, Menigatti M, Luz J, Russell A, Haider R, Gebbers JO, Bannwart F, Yurtsever H, Neuweiler J, Riehle HM, Cattaruzza MS, Heinimann K, Schar P, Jiricny J, Marra G (2005) Immunohistochemical analysis reveals high frequency of PMS2 defects in colorectal cancer. Gastroenterology 128:1160–1171PubMedCrossRefGoogle Scholar
  70. Vasen HF, Moslein G, Alonso A, Bernstein I, Bertario L, Blanco I, Burn J, Capella G, Engel C, Frayling I, Friedl W, Hes FJ, Hodgson S, Mecklin JP, Moller P, Nagengast F, Parc Y, Renkonen-Sinisalo L, Sampson JR, Stormorken A, Wijnen J (2007) Guidelines for the clinical management of Lynch syndrome (hereditary non-polyposis cancer). J Med Genet 44:353–362PubMedCrossRefGoogle Scholar
  71. Vilkki S, Tsao JL, Loukola A, Poyhonen M, Vierimaa O, Herva R, Aaltonen LA, Shibata D (2001) Extensive somatic microsatellite mutations in normal human tissue. Cancer Res 61:4541–4544PubMedGoogle Scholar
  72. Wagner A, Reddingius RE, Kros JM, Dinjens WN, Sleddens H, Hoogmans MM, v.d. Velde A, Tops C, Wijnen J, Meijers-Heijboer H, Menko F (2003) Wilms tumor and glioblastoma in a child with a double MLH1 germline mutation. Fam Cancer 2(Suppl 1):57Google Scholar
  73. Wang Q, Lasset C, Desseigne F, Frappaz D, Bergeron C, Navarro C, Ruano E, Puisieux A (1999) Neurofibromatosis and early onset of cancers in hMLH1-deficient children. Cancer Res 59:294–297PubMedGoogle Scholar
  74. Wang Q, Montmain G, Ruano E, Upadhyaya M, Dudley S, Liskay RM, Thibodeau SN, Puisieux A (2003) Neurofibromatosis type 1 gene as a mutational target in a mismatch repair-deficient cell type. Hum Genet 112:117–123PubMedGoogle Scholar
  75. Watson P, Lynch HT (1994) The tumor spectrum in HNPCC. Anticancer Res 14:1635–1639PubMedGoogle Scholar
  76. Whiteside D, McLeod R, Graham G, Steckley JL, Booth K, Somerville MJ, Andrew SE (2002) A homozygous germ-line mutation in the human MSH2 gene predisposes to hematological malignancy and multiple cafe-au-lait spots. Cancer Res 62:359–362PubMedGoogle Scholar
  77. Will O, Carvajal-Carmona LG, Gorman P, Howarth KM, Jones AM, Polanco-Echeverry GM, Chinaleong JA, Gunther T, Silver A, Clark SK, Tomlinson I (2007) Homozygous PMS2 deletion causes a severe colorectal cancer and multiple adenoma phenotype without extraintestinal cancer. Gastroenterology 132:527–530PubMedCrossRefGoogle Scholar

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© Springer-Verlag 2008

Authors and Affiliations

  1. 1.Department of Medical GeneticsMedical University of ViennaViennaAustria

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