BRCA2 gene mutations and coagulation-associated biomarkers

Abstract

Thromboembolic events are the second cause of death in cancer patients, although the mechanisms underlying this increased thromboembolic risk remain unclear. The aims of this study were to examine whether BRCA2 gene mutations may modify the circulating levels of thrombocoagulation biomarkers and whether breast cancer development may influence changes in such circulating biomarkers. The study was performed in 25 women with mutations in the BRCA2 gene (n=12 breast cancer, n=13 breast cancer-free) and in 13 BRCA2 non-mutant controls. Results revealed that plasma levels of fibrinogen gamma chain isotypes 2 and 3, haptoglobin isotypes 4 and 5, serotransferrin isotypes 3 and 4 and convertase C3/C5 isotypes 4 and 5 were significantly higher in BRCA2 mutation carriers compared to controls. However, plasma levels of vitamin D binding protein isotype 1 and alpha1-antitrypsin isotypes 2, 3 and 4 were significantly decreased in BRCA2 mutation carriers compared to controls. Plasma expression of PF4 and P-selectin was significantly higher in BRCA2 mutations carriers than in controls. BRCA2 truncated mutations conserving a binding region for RAD51 were associated with increased plasma levels of alpha1-antitrypsin isotypes 3 and 4 with respect to women showing BRCA2 mutations that loss the binding RD51 region to BRCA2. Only plasma levels of vitamin D binding protein isotypes 1 and 3 were significantly reduced and alpha 1-antitrypsin isotype 1 was increased in cancer-free BRCA2 mutation carriers compared to BRCA2 mutation carriers with breast cancer. The presence of BRCA2 mutations is associated with increased plasma levels of thrombo-coagulating-related proteins, which are independent to breast cancer development.

Systemic hyperfibrinolysis after trauma: a pilot study of targeted proteomic analysis of superposed mechanisms in patient plasma

“…54 The deficiency of GC has not been linked to trauma before, and may be involved in coagulation. 55,56 Similar to RBP4 and TTR, both TF and CP contain beta sheets amenable to common amyloid formation. 57 In contrast HPX (like CLU), could stabilize certain mis-folded plasma proteins.…”

The Impact of Breast Cancer Type, Staging, and Treatment on Vascular Complications of Immediate Free-Flap Breast Reconstruction

“…Interestingly, there are also differences in protein expression between BRCA-positive women who have cancer compared with those who are cancer-free. 45,46 This literature, coupled with our results, suggests future research is warranted to better explore the relationship BRCA mutations may have with coagulopathy and ABR. Our study is mainly limited as a retrospective study.…”

“…BRCA status may be an important concern for plastic surgeons as previous literature has shown BRCA1/2 mutations are associated with changes in expression of thrombosis-related proteins including fibrinogen, vitamin D-binding protein, α1-antitrypsin, and others. 45,46 These changes are suggestive of increased coagulability and risk of thrombosis. Interestingly, there are also differences in protein expression between BRCA-positive women who have cancer compared with those who are cancer-free.…”

A new classification of cardio-oncology syndromes

“…Because BRCA1/2 mediates DNA-repair and other vital pathways, it has been previously hypothesized that these genetic variants could be linked to other diseases. Indeed, several studies reported higher levels of proteins or biomarkers associated with elevated thrombotic risk in patients with BRCA1/2 mutations compared to controls with no mutations, independent of breast cancer [ 100 , 101 ]. These results suggest that the carriers of the mutations are prone to have coagulation-related problems independently of malignancies.…”

“…These results suggest that the carriers of the mutations are prone to have coagulation-related problems independently of malignancies. Further, low levels of insulin-like growth factor 1 (IGF-1) were detected in individuals carrying BRCA1/2 mutations, while high levels of IGF-1 were detected in BRCA1/2 mutation carriers with breast cancer; abnormal concentrations of IGF-1 have been associated with higher risks to develop insulin resistance, which contributes to the pathophysiology of many CVDs [ 100 , 102 ].…”