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MMR-associated pediatric tumoral predisposition

Friday 17 September 2010

Biallelic mutations in PMS2, a gene usually associated in heterozygous form with hereditary nonpolyposis colorectal cancer (HNPCC), results in a recently described childhood cancer syndrome.

The tumor spectrum encompasses atypical brain cancers, hematologic malignancies, and colonic polyposis and cancer.

Cutaneous stigmata resembling café-au-lait macules with more diffuse margins are frequently seen. Onset is as young as 2 years. The risk of second malignancy is high.

Evidence exists for surveillance for bowel cancer, but surveillance for the wider tumor spectrum is of uncertain benefit.

Synopsis

- cafè-au-lait spots (CALS) (19156169)
- early onset adenomas, duodenal cancer
- early-onset haematological malignancy
- brain tumours

  • glioblastoma
    - HNPCC-associated tumours
    - signs of neurofibromatosis type 1

See also

- Turcot syndrome

  • APC-associated Turcot syndrome

References

- Homozygosity of MSH2 c.1906G—>C germline mutation is associated with childhood colon cancer, astrocytoma and signs of Neurofibromatosis type I. Toledano H, Goldberg Y, Kedar-Barnes I, Baris H, Porat RM, Shochat C, Bercovich D, Pikarsky E, Lerer I, Yaniv I, Abeliovich D, Peretz T. Fam Cancer. 2009;8(3):187-94. PMID: 19101824

- Type A microsatellite instability in pediatric gliomas as an indicator of Turcot syndrome. Giunti L, Cetica V, Ricci U, Giglio S, Sardi I, Paglierani M, Andreucci E, Sanzo M, Forni M, Buccoliero AM, Genitori L, Genuardi M. Eur J Hum Genet. 2009 Jul;17(7):919-27. PMID: 19156169

- Biallelic PMS2 mutations and a distinctive childhood cancer syndrome. Tan TY, Orme LM, Lynch E, Croxford MA, Dow C, Dewan PA, Lipton L. J Pediatr Hematol Oncol. 2008 Mar;30(3):254-7. PMID: 18376293

- Homozygous PMS2 germline mutations in two families with early-onset haematological malignancy, brain tumours, HNPCC-associated tumours, and signs of neurofibromatosis type 1. Krüger S, Kinzel M, Walldorf C, Gottschling S, Bier A, Tinschert S, von Stackelberg A, Henn W, Görgens H, Boue S, Kölble K, Büttner R, Schackert HK. Eur J Hum Genet. 2008 Jan;16(1):62-72. PMID: 17851451 (Free)

- Café-au-lait macules and pediatric malignancy caused by biallelic mutations in the DNA mismatch repair (MMR) gene PMS2. Jackson CC, Holter S, Pollett A, Clendenning M, Chou S, Senter L, Ramphal R, Gallinger S, Boycott K. Pediatr Blood Cancer. 2008 Jun;50(6):1268-70. PMID: 18273873

- PMS2 mutations in childhood cancer. 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. J Natl Cancer Inst. 2006 Mar 1;98(5):358-61. PMID: 16507833 [Free]

- A novel MSH2 germline mutation in homozygous state in two brothers with colorectal cancers diagnosed at the age of 11 and 12 years. Müller A, Schackert HK, Lange B, Rüschoff J, Füzesi L, Willert J, Burfeind P, Shah P, Becker H, Epplen JT, Stemmler S. Am J Med Genet A. 2006 Feb 1;140(3):195-9.PMID: 16372347

- Biallelic germline mutations of mismatch-repair genes: a possible cause for multiple pediatric malignancies. Poley JW, Wagner A, Hoogmans MM, Menko FH, Tops C, Kros JM, Reddingius RE, Meijers-Heijboer H, Kuipers EJ, Dinjens WN; Rotterdam Initiative on Gastrointestinal Hereditary Tumors. Cancer. 2007 Jun 1;109(11):2349-56. PMID: 17440981 [Free]

- Two PMS2 mutations in a Turcot syndrome family with small bowel cancers. Agostini M, Tibiletti MG, Lucci-Cordisco E, Chiaravalli A, Morreau H, Furlan D, Boccuto L, Pucciarelli S, Capella C, Boiocchi M, Viel A. Am J Gastroenterol. 2005 Aug;100(8):1886-91. PMID: 16144131

- A homozygous mutation in MSH6 causes Turcot syndrome. Hegde MR, Chong B, Blazo ME, Chin LH, Ward PA, Chintagumpala MM, Kim JY, Plon SE, Richards CS. Clin Cancer Res. 2005 Jul 1;11(13):4689-93. PMID: 16000562

- A homozygous MSH6 mutation in a child with café-au-lait spots, oligodendroglioma and rectal cancer. Menko FH, Kaspers GL, Meijer GA, Claes K, van Hagen JM, Gille JJ. Fam Cancer. 2004;3(2):123-7. PMID: 15340263

- Hereditary nonpolyposis colorectal cancer and related conditions. Lucci-Cordisco E, Zito I, Gensini F, Genuardi M. Am J Med Genet A. 2003 Nov 1;122A(4):325-34. PMID: 14518071

- Alterations of repeated sequences in 5’ upstream and coding regions in colorectal tumors from patients with hereditary nonpolyposis colorectal cancer and Turcot syndrome. Miyaki M, Iijima T, Shiba K, Aki T, Kita Y, Yasuno M, Mori T, Kuroki T, Iwama T. Oncogene. 2001 Aug 23;20(37):5215-8. PMID: 11526511

- Evidence for a recessive inheritance of Turcot’s syndrome caused by compound heterozygous mutations within the PMS2 gene. De Rosa M, Fasano C, Panariello L, Scarano MI, Belli G, Iannelli A, Ciciliano F, Izzo P. Oncogene. 2000 Mar 23;19(13):1719-23. PMID: 10763829 [Free]

- Chan TL, Yuen ST, Chung LP, Ho JWC, Kwan K, Fan YW, Chan ASY, Leung SY. Germline hMSH2 and differential somatic mutations in patients with Turcot’s syndrome. Genes, Chromosomes & Cancer 1999;25:75-81.

- Paraf F, Jothy S, Van Meir EG. Brain tumor-polyposis syndrome: two genetic diseases? J Clin Oncol. 1997 Jul;15(7):2744-58. PMID: 9215849