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TP53 and CHEK2 *1100delC gene mutation in North American
families suggestive Li-Fraumeni syndrome: Memorial Sloan-Kettering experience
R. Siddiqui, L. Robles Diaz, K. Nafa, N. Kauff, F. Facio, H. Huang, K. Onel, M.
Robson, N. Ellis, K. Offit
Memorial Sloan-Kettering Cancer Center, New York, NY; Hospital
Universitario Doce de Octubre, Madrid, Spain
Background.
Li-Fraumeni syndrome (LFS) is a dominantly inherited cancer
predisposition syndrome characterized by a wide spectrum of neoplasms including
soft-tissue and bone sarcomas, brain tumors, adrenocortical tumors, breast
cancers and leukemia occurring at young age.
Germline mutations in the tumor suppressor gene TP53 have been identified
in approximately 71% of LFS patients and 22% of Li-Fraumeni like (LFL) patients
meeting Eeles’s or Birch’s criteria.
Mutations within the checkpoint gene, CHEK2, encoding a kinase required
for cell cycle regulation have also been reported in some patients with LFS/LFL
not carrying TP53 mutation.
Methods.
We conducted a study to explore the possible association between
a specific CHEK2*1100delC mutation and LFS/LFL.
All patients who were evaluated for LFS/LFL at the Clinical Genetics Service at
MSKCC from 1994-2003, who underwent testing for a TP53 mutation, and did
not have a deleterious mutation identified were anonymously tested for CHEK2*1100delC.
Testing for the CHEK2*1100delC mutation was done by DNA sequencing.
Results.
A total of 23 patients who underwent TP53 testing were
identified.
M:F ratio was 6:17.
13% of the patients met LFS criteria, 78% LFL and 9% patients did not meet these
criteria.
All patients tested had at least one primary malignancy (14 breast, 7 sarcoma, 5
hematological, 4 brain, 3 melanoma and 4 other).
Median age at diagnosis of first tumor was 30.
57%, 30% and 9% of patients had a total of 2, 3 and 4 primary malignancies
respectively.
Overall, TP53 mutations were identified in 7 of 23 patients and variants
of unknown clinical significance in 2 patients.
TP53 germline mutations were identified in 2 of 3 LFS’s and 4 of 18
LFL’s patients.
15 of 16 patient who did not have a deleterious TP53 mutation were tested
for CHEK2*1100delC.
None of these TP53 negative patients were found to harbor CHEK2*1100delC.
Conclusions.
Our results do not support the causative role of the CHEK2*1100delC
mutation in patients with LFS/LFL not carrying a TP53 mutation.
Copyright 2004 American Society of Clinical Oncology All rights
reserved worldwide.
Source: http://www.asco.org/ac/1,1003,_12-002636-00_18-0026-00_19-00434,00.asp
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