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.
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
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
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: http://research.nhgri.nih.gov/bic/
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