Analysis of FANCB and FANCN/PALB2 Fanconi Anemia genes in BRCA1/2-negative Spanish breast cancer families
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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.
KeywordsFANCN/PALB2 FANCB Fanconi Anemia Genotypic–phenotypic correlation Hereditary breast cancer PALB2 tumor
We are grateful to Prof. Nazneen Rahman for kindly providing us with DNA samples from carriers of the previously described c.3113G>A, c.3116delA and c.3549C>G PALB2 mutations used as positive controls in our screening; G. Ribas for valuable advise on DHPLC conditions and for helpful discussions; O. Díez and M. Baiget (Department of Genetics, La Santa Creu i Sant Pau Hospital) for their contribution in the ascertainment of part of the families included in the study; S.M. Rodríguez-Pinilla and M. Cañamero for histopathological revision of the PALB2 tumor and definition of areas for further macrodisecction; R.L. Milne for biostatistical support; S. Carilla for his contribution to this project; F. Fernández, C. Alonso and L. Moreno for excellent technical assistance. M.J. García is supported by the Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Spain. This work was partially supported by the Fancogene Project (Fundación Genoma España) Pharmamar and the Spanish Network of Cancer (Grant RTICC 06/0020/0021).
- 19.Foulkes WD, Ghadirian P, Akbari MR et al (2007) Identification of a novel truncating PALB2 mutation and analysis of its contribution to early-onset breast cancer in French-Canadian women. Breast Cancer Res. doi:10.1186/bcr1828. (in press)Google Scholar
- 25.Beristain E, Martinez-Bouzas C, Guerra I et al (2007) Differences in the frequency and distribution of BRCA1 and BRCA2 mutations in breast/ovarian cancer cases from the Basque country with respect to the Spanish population: implications for genetic counselling. Breast Cancer Res Treat 106:255–262PubMedCrossRefGoogle Scholar
- 28.Rahman N, Scott RH (2007) Cancer genes associated with phenotypes in monoallelic and biallelic mutation carriers: new lessons from old players. Hum Mol Genet 16 Spec No 1:R60–R66Google Scholar