jeudi 23 août 2012

Mutated genes in cancer (78) – BRCA2


In databases :

Ensembl ( ENSG00000139618
UniProt ( P51587
GeneCards ( BRCA2
HGNC ( 1101 or BRCA2

Gene locus:


Protein name:

Breast cancer 2, early onset

Protein Size:

3418 amino acids; about 384 kDa


BRCA2 is implicated in maintenance of genomic integrity and in the cellular response to DNA damage. The BRCA2 protein interacts with the RAD51 recombinase to regulate homologous recombination (HR). CHEK1 and CHEK2 both phosphorylate the RAD51/BRCA2 complex and regulate the functional association of this complex in response to DNA damage.

BRCA2 is also implicated in cell cycle checkpoints. Following exposure to X-rays or UV light, cells expressing truncated BRCA2 protein exhibit arrest in the G1 and G2/M phases. BRCA2 protein plays a role in mitotic spindle assembly checkpoints through modulation of the level of spindle assembly checkpoint proteins including Aurora A and Aurora B.

BRCA2 may also stimulate transcription. This function of BRCA2 is regulated by the binding of the EMSY protein to the region of BRCA2 responsible for transcriptional activation. An excess of EMSY results in silencing of BRCA2-driven transcriptional activation.

Cancer-related alterations:

Defects in BRCA2 are a cause of susceptibility to breast-ovarian cancer familial type 2 (BROVCA2), a condition associated with familial predisposition to cancer of the breast and ovaries (for BROVCA1, see BRCA1; for BROVCA3, see RAD51C). Mutations at more than one locus can be involved in different families or even in the same case. Characteristic features in affected families are an early age of onset of breast cancer (often before age 50), increased chance of bilateral cancers (cancer that develop in both breasts, or both ovaries, independently), frequent occurrence of breast cancer among men, increased incidence of tumors of other specific organs, such as the prostate, stomach, pharynx, gallbladder, bile duct, colon and pancreas. Cumulative risk of breast cancer in BRCA2 mutation carriers was estimated to 45% by the age of 70 years while ovarian cancer risk in carriers was estimated to 11%.

Somatic mutations in BRCA2 (substitutions, insertions, deletions) are infrequent in sporadic breast cancer. Methylation of the BRCA2 promoter has not been detected in normal tissues nor in breast and ovarian cancers. Loss of heterozygosity at the BRCA2 locus has been frequently found in sporadic breast and ovarian tumors.

Biallelic mutations of the BRCA2 gene are the cause of Fanconi anemia complementation group D type 1 (FANCD1) (see Fanconi-associated genes). Fanconi anemia (FA) is an autosomal recessive disorder affecting all bone marrow elements and associated with cardiac, renal and limb malformations as well as dermal pigmentary changes. The FANCD1 (and FANCN, see PALB2) subgroups are clinically different from other FA subgroups as these subgroups are associated with increased predisposition to solid childhood malignancies such as medulloblastoma and Wilms tumor.
At the cellular level, FA is a chromosomal fragility syndrome. FA cells are hypersensitive to DNA interstrand crosslinking agents such as mitomycin C, diepoxybutane and cisplatin. In addition to hypersensitivity to these agents, FA cells show an increased number of spontaneous breaks.

Note: information regarding breast cancer and BRCA2 mutations and polymorphisms are available in a central repository formed by the National Human Genome Research; National Institute of Health. This repository, named Breast Cancer Information Core (BIC) - NHGRI, is available at the following address:

Specific therapy:

Oral poly(ADP-ribose) polymerase (PARP) inhibitor olaparib shows activity in patients with advanced breast cancer or recurrent ovarian cancer and BRCA1 or BRCA2 mutations

References (open access):

Susceptibility pathways in Fanconi's anemia and breast cancer. D'Andrea AD. N Engl J Med. 2010 May 20;362(20):1909-19.

Pathology of hereditary breast cancer. Da Silva L, Lakhani SR. Mod Pathol. 2010 May;23 Suppl 2:S46-51.

PARP inhibitors: its role in treatment of cancer. Chen A. Chin J Cancer. 2011 Jul;30(7):463-71.

JAMA patient page. BRCA genes and breast cancer. Pluta RM, Golub RM. JAMA. 2011 Jun 1;305(21):2244.

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