The contribution of CHEK2to the TP53-negative Li-Fraumeni phenotype

Broeks Annegien, Ausems, Oldenburg Rogier, Van'T, Verhoef Senno, Ruijs, Menko, Wagner Anja, Meijers-Heijboer Hanne, Verhoef

Description

CHEK2 has previously been excluded as a major cause of Li-Fraumeni syndrome (LFS). One particular CHEK2 germline mutation, c.1100delC, has been shown to be associated with elevated breast cancer risk. The prevalence of CHEK2 *1100delC differs between populations and has been found to be relatively high in the Netherlands. The question remains nevertheless whether CHEK2 germline mutations contribute to the Li-Fraumeni phenotype. Methods We have screened 65 Dutch TP53 -negative LFS/LFL candidate patients for CHEK2 germline mutations to determine their contribution to the LFS/LFL phenotype. Results We identified six index patients with a CHEK2 sequence variant, four with the c.1100delC variant and two sequence variants of unknown significance, p.Phe328Ser and c.1096-?_1629+?del. Conclusion Our data show that CHEK2 is not a major LFS susceptibility gene in the Dutch population. However, CHEK2 might be a factor contributing to individual tumour development in TP53 -negative cancer-prone families.

Informations

• Publié par: biomed
• Publié le: 01 janvier 2009
• Nombre de lectures: 13
• Langue: English

Extrait

Hereditary Cancer in Clinical Practice

BioMedCentral

Open Access Research The contribution ofCHEK2to theTP53-negative Li-Fraumeni phenotype 1,3 23 Marielle WG Ruijs, Annegien Broeks, Fred H Menko, 4 55 Margreet GEM Ausems, Anja Wagner, Rogier Oldenburg, Hanne Meijers 3,5 21 Heijboer ,Laura J van't Veerand Senno Verhoef*

1 2 Address: FamilyCancer Clinic, The Netherlands Cancer Institute, Amsterdam, The Netherlands,Department of Experimental Therapy, The 3 Netherlands Cancer Institute, Amsterdam, The Netherlands,Department of Clinical Genetics and Human Genetics, VU University Medical 4 5 Centre, Amsterdam, The Netherlands,Department of Medical Genetics, University Medical Centre, Utrecht, The Netherlands andDepartment of Clinical Genetics, Erasmus Medical Centre, Rotterdam, The Netherlands Email: Marielle WG Ruijs  [e-mail]; Annegien Broeks  [e-mail]; Fred H Menko  [e-mail]; Margreet GEM Ausems  [e-mail]; Anja Wagner  [e-mail]; Rogier Oldenburg  [e-mail]; Hanne MeijersHeijboer  [e-mail]; Laura J van't Veer  [e-mail]; Senno Verhoef*  [e-mail] * Corresponding author

Published: 17 February 2009Received: 14 November 2008 Accepted: 17 February 2009 Hereditary Cancer in Clinical Practice2009,7:4 doi:10.1186/1897-4287-7-4 This article is available from: http://www.hccpjournal.com/content/7/1/4 © 2009 Ruijs et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract Background:CHEK2has previously been excluded as a major cause of Li-Fraumeni syndrome (LFS). One particularCHEK2germline mutation, c.1100delC, has been shown to be associated with elevated breast cancer risk. The prevalence ofCHEK2*1100delC differs between populations and has been found to be relatively high in the Netherlands. The question remains nevertheless whetherCHEK2germline mutations contribute to the Li-Fraumeni phenotype. Methods:We have screened 65 DutchTP53-negative LFS/LFL candidate patients forCHEK2 germline mutations to determine their contribution to the LFS/LFL phenotype. Results:We identified six index patients with aCHEK2sequence variant, four with the c.1100delC variant and two sequence variants of unknown significance, p.Phe328Ser and c.1096-?_1629+?del. Conclusion:Our data show thatCHEK2is not a major LFS susceptibility gene in the Dutch population. However,CHEK2might be a factor contributing to individual tumour development in TP53-negative cancer-prone families.

Background LiFraumeni syndrome (LFS) is a rare autosomal domi nant cancer syndrome predisposing for bone and soft tis sue sarcoma, breast cancer, brain tumour, adrenocortical carcinoma and leukaemia [1]. The classical LFS criteria are: a proband with sarcoma aged under 45 years and a firstdegree relative with any cancer aged under 45 years,

plus a first or seconddegree relative in the same lineage with any cancer under the age of 45 years or sarcoma at any age [2]. In addition, LiFraumenilike syndrome (LFL) criteria have been formulated as a proband with any child hood tumour or a sarcoma, brain tumour or adrenocorti cal tumour diagnosed under 45 years of age and a first or seconddegree relative in the same lineage with a typical

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