Analysis of FANCB and FANCN/PALB2 Fanconi Anemia genes in BRCA1/2-negative Spanish breast cancer families

Recent reports have shown that mutations in the FANCJ/BRIP1 and FANCN/PALB2 Fanconi Anemia (FA) genes confer a moderate breast cancer risk. Discussion has been raised on the phenotypic characteristics of the PALB2-associated families and tumors. The role of FANCB in breast cancer susceptibility has...

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Bibliographic Details
Published in:Breast cancer research and treatment 2009-02, Vol.113 (3), p.545-551
Main Authors: García, María J, Fernández, Victoria, Osorio, Ana, Barroso, Alicia, LLort, Gemma, Lázaro, Conxi, Blanco, Ignacio, Caldés, Trinidad, de la Hoya, Miguel, Ramón y Cajal, Teresa, Alonso, Carmen, Tejada, María-Isabel, San Román, Carlos, Robles-Díaz, Luis, Urioste, Miguel, Benítez, Javier
Format: Article
Language:English
Subjects:
Aged
Anemias. Hemoglobinopathies
Biological and medical sciences
Breast cancer
Breast Neoplasms - genetics
Breast Neoplasms, Male - genetics
Cancer research
Diseases of red blood cells
Epidemiology
Fanconi Anemia Complementation Group N Protein
Fanconi Anemia Complementation Group Proteins - genetics
Female
Genes
Genes, BRCA1
Genes, BRCA2
Genetic disorders
Genetic Predisposition to Disease
Genetic Testing
Genotype & phenotype
Gynecology. Andrology. Obstetrics
Hematologic and hematopoietic diseases
Humans
Loss of Heterozygosity
Male
Mammary gland diseases
Medical sciences
Medicine
Medicine & Public Health
Middle Aged
Mutation
Neoplastic Syndromes, Hereditary - genetics
Nuclear Proteins - genetics
Oncology
Ovarian Neoplasms - genetics
Pedigree
Risk factors
Spain
Tumor Suppressor Proteins - genetics
Tumors
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Summary:Recent reports have shown that mutations in the FANCJ/BRIP1 and FANCN/PALB2 Fanconi Anemia (FA) genes confer a moderate breast cancer risk. Discussion has been raised on the phenotypic characteristics of the PALB2-associated families and tumors. The role of FANCB in breast cancer susceptibility has not been tested to date. Likewise PALB2 mutation frequency has not been studied in Spanish population. We analyzed the complete coding sequence and splicing sites of FANCB and PALB2 in 95 index cases of BRCA1/2-negative Spanish breast cancer families. We also performed an exhaustive screening of three previously described rare but recurrent PALB2 mutations in 725 additional probands. Pathogenic changes were not detected in FANCB. We found a novel PALB2 truncating mutation c.1056_1057delGA (p.K353IfsX7) in one of the 95 screened patients, accounting for a mutation frequency of 1% in our series. Further comprehensive screening of the novel mutation and of previously reported rare but recurrent PALB2 mutations did not reveal any carrier patient. We report the first example of LOH occurring in a PALB2-associated tumor. Our results rule out a major contribution of FANCB to hereditary breast cancer. Our data are consistent with the notion of individually rare PALB2 mutations, lack of mutational hot-spots in the gene and existence of between-population disease-allele heterogeneity. We show evidence that PALB2 loss of function might also conform to the inactivation model of a classic tumor-suppressor gene and present data that adds to the clinically relevant discussion about the existence of a PALB2-breast cancer phenotype.
ISSN:0167-6806
1573-7217
DOI:10.1007/s10549-008-9945-0