ABSTRACT
BACKGROUND: The impact of an inherited BRCA2 mutation on the prognosis of women with breast cancer has not been well documented. We studied the effects of oestrogen receptor (ER) status, other prognostic factors and treatments on survival in a large cohort of BRCA2 mutation carriers. METHODS: We identified 285 breast cancer patients with a 999del5 BRCA2 mutation and matched them with 570 non-carrier patients. Clinical information was abstracted from patient charts and pathology records and supplemented by evaluation of tumour grade and ER status using archived tissue specimens. Univariate and multivariate hazard ratios (HR) were estimated for breast cancer-specific survival using Cox regression. The effects of various therapies were studied in patients treated from 1980 to 2012. RESULTS: Among mutation carriers, positive ER status was associated with higher risk of death than negative ER status (HR=1.94; 95% CI=1.22-3.07, P=0.005). The reverse association was seen for non-carriers (HR=0.71; 95% CI: 0.51-0.97; P=0.03). CONCLUSIONS: Among BRCA2 carriers, ER-positive status is an adverse prognostic factor. BRCA2 carrier status should be known at the time when treatment decisions are made.
Subject(s)
Breast Neoplasms/genetics , Estrogens , Genes, BRCA2 , Mutation , Neoplasms, Hormone-Dependent/genetics , Neoplastic Syndromes, Hereditary/genetics , Receptors, Estrogen/analysis , Adult , Aged , Aged, 80 and over , Breast Neoplasms/chemistry , Breast Neoplasms/mortality , Breast Neoplasms/therapy , Female , Humans , Iceland/epidemiology , Male , Middle Aged , Neoplasms, Hormone-Dependent/chemistry , Neoplasms, Hormone-Dependent/mortality , Neoplasms, Hormone-Dependent/therapy , Neoplasms, Second Primary/epidemiology , Neoplasms, Second Primary/genetics , Neoplastic Syndromes, Hereditary/mortality , Neoplastic Syndromes, Hereditary/therapy , Prognosis , Proportional Hazards Models , Treatment Outcome , Young AdultABSTRACT
Like most other lentiviruses, maedi-visna virus (MVV) requires Vif for replication in natural target cells and in vivo. Here, we show that Vif-deficient MVV accumulates G-A mutations in the sequence context characteristic of ovine APOBEC3, consistent with a role of MVV Vif in neutralizing APOBEC3. We studied two point mutations in the vif gene of MVV. One was a tryptophan to arginine mutation that affects the interaction with APOBEC3 and caused G-A hypermutation. The other mutation was a proline to serine mutation that together with a mutation in the capsid protein caused attenuated replication in fetal ovine synovial (FOS) cells but not in sheep choroid plexus (SCP) cells. There was no hypermutation associated with this mutation. These results suggest that MVV Vif exerts more than one function and that there may be interaction between Vif and the capsid. The results also suggest the involvement of an unknown host factor in MVV Vif function.
Subject(s)
Gene Products, vif/genetics , Mutation, Missense , Point Mutation , Virus Replication , Visna-maedi virus/physiology , Capsid Proteins/genetics , Phenotype , Visna-maedi virus/geneticsABSTRACT
The construction of a molecular clone of maedi-visna virus (MVV) expressing the enhanced green fluorescent protein (EGFP) is described. The egfp gene was inserted into the gene for dUTPase since it has been shown that dUTPase is dispensable for MVV replication both in vitro and in vivo. MVV-egfp is infectious and EGFP expression is stable over at least six passages. This fluorescent virus will be a useful tool for monitoring MVV infections.
