NGS‐based multiple gene panel resequencing in combination with a high resolution CGH‐array was used to identify genetic risk factors for hereditary breast and/or ovarian cancer in 237 high risk patients who were previously tested negative for pathogenic BRCA1/2 variants. All patients were screened for pathogenic variants in 94 different cancer predisposing genes. We identified 32 pathogenic variants in 14 different genes (ATM, BLM, BRCA1, CDH1, CHEK2, FANCG, FANCM, FH, HRAS, PALB2, PMS2, PTEN, RAD51C and NBN) in 30 patients (12.7%). Two pathogenic BRCA1 variants that were previously undetected due to less comprehensive and sensitive methods were found. Five pathogenic variants are novel, three of which occur in genes yet unrelated to hereditary breast and/or ovarian cancer (FANCG, FH and HRAS). In our cohort we discovered a remarkably high frequency of truncating variants in FANCM (2.1%), which has recently been suggested as a susceptibility gene for hereditary breast cancer. Two patients of our cohort carried two different pathogenic variants each and 10 other patients in whom a pathogenic variant was confirmed also harbored a variant of unknown significance in a breast and ovarian cancer susceptibility gene. We were able to identify pathogenic variants predisposing for tumor formation in 12.3% of BRCA1/2 negative breast and/or ovarian cancer patients.
Complication rates using porcine acellular dermal matrix in breast reconstruction are comparable to complication rates reported in studies using human acellular dermal matrices. Thus, porcine acellular dermal matrices can safely be applied in breast reconstructive surgery.
Chronic arm and breast oedema were significantly influenced by the extent of surgery (AC). Ptotic and large breasts were significantly associated with unfavourable COs and chronic breast oedema. Late toxicities exclusive breast pain were not associated with radiotherapy parameters.
The multi-cancer susceptibility locus at 5p15.33 includes TERT, encoding the telomerase catalytic subunit. Genome-wide association studies (GWAS) have identified six single nucleotide polymorphisms (SNPs) in the TERT promoter associated with decreased breast cancer risk, although the precise causal variants and their mechanisms of action have remained elusive. Luciferase reporter assays indicated that the protective haplotype reduced TERT promoter activity in human mammary epithelial and cancer cells in an estrogen-independent manner. Using single variant constructs, we identified rs3215401 and rs2853669 as likely functional variants. Silencing of MYC decreased TERT promoter activity but neither MYC nor ETS2 silencing conferred allele-specificity. In chromatin immunoprecipitation experiments, the ETS protein GABPA, but not ETS2 or ELF1, bound rs2853669 in an allele-specific manner in mammary epithelial cells. Investigation of open chromatin in mammoplasty samples suggested involvement of three additional variants, though not rs3215401 or rs2853669. Chromosome conformation capture revealed no interaction of the TERT promoter with regulatory elements in the locus, indicating limited local impact of candidate variants on the TERT promoter. Collectively, our functional studies of the TERT-CLPTM1L breast cancer susceptibility locus describe rs2853669 as a functional variant of this association signal among three other potentially causal variants and demonstrate the versatile mechanisms by which TERT promoter variants may affect breast cancer risk.
!Introduction: Giant fibroadenoma (GFA) of the breast is defined as fibroadenoma larger than 5 cm, usually presenting unilaterally and manifesting as breast asymmetry or deformity of the breast. Material and Methods: A retrospective database search was done of all patients with giant fibroadenoma who underwent surgery for GFA in the breast center of Hanover Medical School between 2007 and 2014; all patients with GFA were followed up. Data were analyzed with regard to tumor and patient characteristics and esthetic outcome. Results: A total of 13 patients with symptomatic GFA underwent surgery between 2007 and 2014. Mean patient age was 21.2 years (range 14-31 years). In 8 of 13 patients the tumor had resulted in breast deformity and/or breast asymmetry. Average size of the mass was 10.2 cm (range 8.5-12 cm) and average weight was 203.6 g (range 151.2-323.5 g). Initial clinical suspicion of GFA was confirmed by ultrasound examination. Preoperative core biopsy revealed fibroadenoma in 8/13 cases, cellular fibroepithelial lesions with a differential diagnosis of benign phyllodes tumor in 3 cases and unspecific histological findings in the remaining 2 cases. Conclusion: Excision was done using an inframammary or periareolar approach without reconstructive plasty. The cosmetic results were good, as were the outcomes on follow-up. We therefore favor this surgical technique to treat giant fibroadenoma of similar size to those described above.
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