The prognostic value of vascular endothelial growth factors (VEGFs)-A and -B and their receptor, VEGFR-1, in invasive breast carcinoma

Objectives. Vascular endothelial growth factors A and B (VEGF-A and VEGF-B) play a major role in angiogenesis and activate VEGF receptor I (VEGFR-1). However, the clinicopathologic and clinical value of VEGF-B and VEGFR-I in invasive breast carcinoma remains unclear. Methods. We immunohistochemically examined the expression pattern of VEGF-A, VEGF-B and VEGFR-1 in 177 invasive breast carcinomas in relation to clinicopathological parameters, p53, c-erbB2 proteins expression and patients’ survival. Results. VEGF-A, VEGF-B and VEGFR-1 were immunodetected predominantly in the cytoplasm of the malignant cells. None of the studied markers correlated with any of the clinicopathological parameters, other than stromal VEGFR-1 which inversely correlated with PR (p=0.021). Cancerous VEGF-A and stromal VEGFR-1 were positively related to p53 (p=0.016 and p=0.033, respectively). Cancerous VEGF-B was positively associated with c-erbB-2 (p=0.045) and was found to exert an unfavorable impact on both disease-free and the overall survival of the node-positive patients (p=0.05 and p=0.029, respectively). Cancerous VEGFR-1 was recognized as being an independent poor prognostic indicator (p=0.037). Conclusion. These findings suggest that, while VEGF-B seems to be useful as a prognostic indicator only in node-positive patients, VEGFR-1 may be an independent poor prognosticator in patients with invasive breast carcinoma. (c) 2006 Elsevier Inc. All rights reserved

Germline mutations in a clinic-based series of pregnancy associated breast cancer patients

Background: Pregnancy-associated breast cancer (PABC) defined as breast cancer diagnosed during gestation, lactation or within 1 year after delivery, represents a truly challenging situation with significantly increasing incidence rate. The genomic background of PABC has only recently been addressed while the underlying mechanisms of the disease still remain unknown. This analysis aims to further elucidate the frequency of PABC cases attributable to genetic predisposition and identify specific cancer susceptibility genes characterizing PABC. Methods: A comprehensive 94-cancer gene panel was implemented in a cohort of 20 PABC patients treated in our clinic and descriptive correlation was performed among the results and the patients’ clinicopathological data. Results: In the present study, 35% of PABC patients tested carried pathogenic mutations in two known cancer predisposition genes (BRCA1 and CHEK2). In total, 30% of the patients carried BRCA1 pathogenic variants. An additional 5% carried pathogenic variants in the CHEK2 gene. Variants of unknown/uncertain significance (VUS) in breast cancer susceptibility genes BRCA2, CHEK2 and BRIP1 were also identified in three different PABC patients (15%). Not all patients carrying germline mutations reported known family history of cancer. Conclusions: Genetic testing should be considered as an option for PABC patients since the disease is highly associated with genetic susceptibility among other predisposing factors. Germline mutation identification may further modify PABC management approach and improve the prognostic outcome. © 2021, The Author(s)

Characterization of a novel large deletion and single point mutations in the <it>BRCA1 </it>gene in a Greek cohort of families with suspected hereditary breast cancer

Abstract Background Germline mutations in BRCA1 and BRCA2 predispose to breast and ovarian cancer. A multitude of mutations have been described and are found to be scattered throughout these two large genes. We describe analysis of BRCA1 in 25 individuals from 18 families from a Greek cohort. Methods The approach used is based on dHPLC mutation screening of the BRCA1 gene, followed by sequencing of fragments suspected to carry a mutation including intron – exon boundaries. In patients with a strong family history but for whom no mutations were detected, analysis was extended to exons 10 and 11 of the BRCA2 gene, followed by MLPA analysis for screening for large genomic rearrangements. Results A pathogenic mutation in BRCA1 was identified in 5/18 (27.7 %) families, where four distinct mutations have been observed. Single base putative pathogenic mutations were identified by dHPLC and confirmed by sequence analysis in 4 families: 5382insC (in two families), G1738R, and 5586G > A (in one family each). In addition, 18 unclassified variants and silent polymorphisms were detected including a novel silent polymorphism in exon 11 of the BRCA1 gene. Finally, MLPA revealed deletion of exon 20 of the BRCA1 gene in one family, a deletion that encompasses 3.2 kb of the gene starting 21 bases into exon 20 and extending 3.2 kb into intron 20 and leads to skipping of the entire exon 20. The 3' breakpoint lies within an AluSp repeat but there are no recognizable repeat motifs at the 5' breakpoint implicating a mechanism different to Alu-mediated recombination, responsible for the majority of rearrangements in the BRCA1 gene. Conclusions We conclude that a combination of techniques capable of detecting both single base mutations and small insertions / deletions and large genomic rearrangements is necessary in order to accurately analyze the BRCA1 gene in patients at high risk of carrying a germline mutation as determined by their family history. Furthermore, our results suggest that in those families with strong evidence of linkage to the BRCA1 locus in whom no point mutation has been identified re-examination should be carried out searching specifically for genomic rearrangements.</p