Fanconi anemia (FA) proteins function in a DNA
damage response pathway that appears to be part of the network including breast
cancer susceptibility gene products, BRCA1 and BRCA2. In response to DNA
damage or replication signals, a nuclear FA core complex of at least 6 FA
proteins (FANCA, FANCC, FANCE, FANCF, FANCG and FANCL) is activated and
leads to monoubiquitination of the downstream FA
protein, FANCD2. One puzzling question for this pathway is the role of
BRCA2. A previous study has proposed that BRCA2 could be identical to two
FA proteins: FANCD1, which functions either downstream or in a parallel
pathway; and FANCB, which functions upstream of the FANCD2 monoubiquitination. Now, a new study shows that the
real FANCB protein is not BRCA2, but a previously uncharacterized component
of the FA core complex, FAAP95, suggesting that BRCA2 does not act upstream
of the FA pathway. Interestingly, the newly discovered FANCB gene is
X-linked and subject to X-inactivation. The presence of a single active
copy of FANCB and its essentiality for a functional FA-BRCA pathway make it
a potentially vulnerable component of the cellular machinery that maintains
genomic integrity.
PMID: 15611632 [PubMed - as supplied by
publisher]
Mutations in BRCA1 and BRCA2 show different
expressivity wit
h respect to cancer risk, and allelic
heterogeneity may be present in both genes. We collected 179 pedigrees with
identified germline mutation (104 BRCA1 and 75 BRCA2), ascertained in six
collaborating centers of the Italian Consortium for Hereditary Breast and
Ovarian Cancer. Significant heterogeneity was detected for several
variables, and a logistic regression model including age of diagnosis in
the proband, presence of ovarian cancer in the family, presence of prostate
or pancreatic cancer in the family, and presence of male breast cancer in
the family proved to be effective in predicting the presence of a mutation
in a gene rather than the other. Excess of familial aggregation of both
breast and ovarian cancer was observed in both genes. Proportion of ovarian
cancer was increased in the 5' portion of BRCA1, and presence of prostate
or pancreatic cancer in a family was correlated with presence of ovarian
cancer in BRCA2
PMID: 14531499 [PubMed - in process]
