Li-Fraumeni-like syndrome associated with a large BRCA1 intragenic deletion.
BACKGROUND
Li-Fraumeni (LFS) and Li-Fraumeni-like (LFL) syndromes are associated to germline TP53 mutations, and are characterized by the development of central nervous system tumors, sarcomas, adrenocortical carcinomas, and other early-onset tumors. Due to the high frequency of breast cancer in LFS/LFL families, these syndromes clinically overlap with hereditary breast cancer (HBC). Germline point mutations in BRCA1, BRCA2, and TP53 genes are associated with high risk of breast cancer. Large rearrangements involving these genes are also implicated in the HBC phenotype.


METHODS
We have screened DNA copy number changes by MLPA on BRCA1, BRCA2, and TP53 genes in 23 breast cancer patients with a clinical diagnosis consistent with LFS/LFL; most of these families also met the clinical criteria for other HBC syndromes.


RESULTS
We found no DNA copy number alterations in the BRCA2 and TP53 genes, but we detected in one patient a 36.4 Kb BRCA1 microdeletion, confirmed and further mapped by array-CGH, encompassing exons 9-19. Breakpoints sequencing analysis suggests that this rearrangement was mediated by flanking Alu sequences.


CONCLUSIONS
This is the first description of a germline intragenic BRCA1 deletion in a breast cancer patient with a family history consistent with both LFL and HBC syndromes. Our results show that large rearrangements in these known cancer predisposition genes occur, but are not a frequent cause of cancer susceptibility.
International Center for Research and Training, A. C. Camargo Cancer Hospital, São Paulo, Brazil.
Amanda Gonçalves
AG
Silva
Ingrid Petroni
IP
Ewald
Marina
M
Sapienza
Manuela
M
Pinheiro
Ana
A
Peixoto
Amanda França
AF
de Nóbrega
Dirce M
DM
Carraro
Manuel R
MR
Teixeira
Patricia
P
Ashton-Prolla
Maria Isabel W
MI
Achatz
Carla
C
Rosenberg
Ana C V
AC
Krepischi
D000328:Adult; D019313:BRCA1 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics; D002869:Chromosome Aberrations; D002874:Chromosome Mapping; D056915:DNA Copy Number Variations; D005260:Female; D017353:Gene Deletion; D019398:Genes, BRCA1; D006801:Humans; D016864:Li-Fraumeni Syndrome / Q000235:genetics*; D008875:Middle Aged; D010375:Pedigree
D019313:BRCA1 Protein; C492913:BRCA1 protein, human