Increased CpG methylation of the estrogen receptor gene in BRCA1-linked estrogen receptor-negative breast cancers

A distinctive feature of BRCA1-linked breast cancers is that they typically do not express estrogen receptor-alpha (ERalpha). Previous investigation suggests that methylation of CpGs within the ERa promoter mediates repression of gene expression in some ERalpha-negative breast cancers. To determine if methylation of CpGs within the ERalpha promoter is associated with BRCA1-linked breast cancers, we evaluated methylation in exon 1 of the ERalpha gene in 40 ERalpha-negative breast cancers, 20 of which were non BRCA1-linked and 20 BRCA1-linked. CpG methylation was evaluated by either methylation-sensitive restriction digest (HpaII), methylation-sensitive PCR (MSP), or direct sequencing of bisulfite-treated genomic DNA. Results from HpaII digests and MSP documented a high degree of methylation, the MSP data showing slightly higher methylation in the BRCA1-linked group. CpGs analysed by direct sequencing showed an overall average methylation of 25% among non BRCA1-linked cancers and 40% among BRCA1-linked cancers (P=0.0031). The most notable difference was found at five particular CpGs, each of which exhibited a greater than twofold increase in methylation in the BRCA1-linked group compared to the non BRCA1-linked group (P < 0.03 for each CpG). Methylation of certain critical CpGs may represent an important factor in transcriptional repression of the ERa gene in BRCA1-linked breast cancers

Histopathological features of breast cancer in carriers of ATM gene variants

Journal compilation © 2009 Blackwell Publishing LtdAimsGermline variants in the ataxia telangiectasia mutated (ATM) gene have been implicated in increased breast cancer risk. The aim of this study was to determine whether the histopathology of breast cancers occurring in ATM variant carriers is distinctive or resembles the described BRCA1 mutation-associated phenotype.MethodsThe histopathological features of breast cancers occurring in ATM variant carriers from multiple-case breast cancer families were compared with matched controls. The test group included 21 cases of in situ and/or invasive cancer from carriers of either the IVS10-6T-->G, 2424V-->G or 1420L-->F ATM variants in the absence of BRCA1 or BRCA2 mutations. An additional four invasive cancers from carriers of a pathogenic BRCA1 mutation in the context of a familial ATM variant were also examined.ResultsThe histopathology of breast cancers in ATM variant-only carriers was not significantly different from controls and known features of BRCA1 mutation-associated cancer were rarely seen. In contrast, these features were prominent in the small group of cases with a pathogenic BRCA1 mutation.ConclusionsBreast cancer occurring in carriers of ATM variants is not associated with distinctive histopathological features and does not resemble the tumour phenotype commonly observed in BRCA1 mutation carriers.R L Balleine, R Murali, A M Bilous, G Farshid, P Waring, P Provan, K Byth, H Thorne, ConFab Investigators & J A Kir

VEGF and VEGFR polymorphisms affect clinical outcome in advanced renal cell carcinoma patients receiving first-line sunitinib

Background: Currently, sunitinib represents one of the therapeutic strongholds for renal cell carcinoma, but the criteria for treatment selection are lacking. We assessed the role of vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) polymorphisms in the prediction of the clinical outcome in metastatic renal cell carcinoma (mRCC) patients.Methods:A total of 84 tumour samples from mRCC patients receiving first-line sunitinib were tested for VEGF and VEGFR single-nucleotide polymorphisms (SNPs). The SNP results were correlated with progression-free survival (PFS) and overall survival (OS).Results:Median PFS was 8.22 months, although whereas median OS was 32.13 months. The VEGF A rs833061 resulted significant in PFS (17 vs 4 months; P<0.0001) and OS (38 vs 10 months; P<0.0001). The VEGF A rs699947 was significant for PFS (18 vs 4 months; P=0.0001) and OS (37 vs 16 months; P<0.0001). The VEGF A rs2010963 was significant in PFS (18 vs 8 vs 2 months; P=0.0001) and OS (31 vs 36 vs 9 months; P=0.0045). The VEGR3 rs6877011 was significant in PFS (12 vs 4 months; P=0.0075) and OS (36 vs 17 months; P=0.0001). At multivariate analysis, rs833061, rs2010963 and rs68877011 were significant in PFS, and rs833061 and rs68877011 were independent factors in OS.Conclusions:In our analysis, patients with TT polymorphism of rs833061, CC polymorphism of rs699947, CC polymorphism of rs2010963 and CG polymorphism of rs6877011 seem to have a worse PFS and OS when receiving first-line sunitinib. \uc2\ua9 2013 Cancer Research UK. All rights reserved