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.
What's new?
Risk for hereditary breast and ovarian cancer (HBOC) is mainly determined by BRCA1/2 mutations but in ~60% of cases the genetic predisposition remains unknown. The authors screened more than 200 women with BRCA1/2‐negative HBOC for new pathogenic variants using a combination of multi‐gene panel sequencing and comparative genomic hybridization. A remarkably high frequency of truncating variants in FANCM were discovered, a protein recently suggested as a susceptibility gene for hereditary breast cancer. The authors recommend that combined methods be used to identify new variants for HBOC risk assessment.
Breast cancer is the most prevalent tumor entity in Li-Fraumeni syndrome. Up to 80% of individuals with a Li-Fraumeni-like phenotype do not harbor detectable causative germline TP53 variants. Yet, no ...systematic panel analyses for a wide range of cancer predisposition genes have been conducted on cohorts of women with breast cancer fulfilling Li-Fraumeni(-like) clinical diagnostic criteria.
To specifically help explain the diagnostic gap of TP53 wild-type Li-Fraumeni(-like) breast cancer cases, we performed array-based CGH (comparative genomic hybridization) and panel-based sequencing of 94 cancer predisposition genes on 83 breast cancer patients suggestive of Li-Fraumeni syndrome who had previously had negative test results for causative BRCA1, BRCA2, and TP53 germline variants.
We identified 13 pathogenic or likely pathogenic germline variants in ten patients and in nine genes, including four copy number aberrations and nine single-nucleotide variants or small indels. Three patients presented as double-mutation carriers involving two different genes each. In five patients (5 of 83; 6% of cohort), we detected causative pathogenic variants in established hereditary breast cancer susceptibility genes (i.e., PALB2, CHEK2, ATM). Five further patients (5 of 83; 6% of cohort) were found to harbor pathogenic variants in genes lacking a firm association with breast cancer susceptibility to date (i.e., Fanconi pathway genes, RECQ family genes, CDKN2A/p14
, and RUNX1).
Our study details the mutational spectrum in breast cancer patients suggestive of Li-Fraumeni syndrome and indicates the need for intensified research on monoallelic variants in Fanconi pathway and RECQ family genes. Notably, this study further reveals a large portion of still unexplained Li-Fraumeni(-like) cases, warranting comprehensive investigation of recently described candidate genes as well as noncoding regions of the TP53 gene in patients with Li-Fraumeni(-like) syndrome lacking TP53 variants in coding regions.
The multi-cancer susceptibility locus at 5p15.33 includes
, encoding the telomerase catalytic subunit. Genome-wide association studies (GWAS) have identified six single nucleotide polymorphisms ...(SNPs) in the
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
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
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
promoter with regulatory elements in the locus, indicating limited local impact of candidate variants on the
promoter. Collectively, our functional studies of the
-
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
promoter variants may affect breast cancer risk.
Individuals carrying a pathogenic germline variant in the breast cancer predisposition gene
(g
+) are prone to developing breast cancer. Apart from its well-known role in DNA repair, BRCA1 has been ...shown to powerfully impact cellular metabolism. While, in general, metabolic reprogramming was named a hallmark of cancer, disrupted metabolism has also been suggested to drive cancer cell evolution and malignant transformation by critically altering microenvironmental tissue integrity. Systemic metabolic effects induced by germline variants in cancer predisposition genes have been demonstrated before. Whether or not systemic metabolic alterations exist in g
+ individuals independent of cancer incidence has not been investigated yet. We therefore profiled the plasma metabolome of 72 g
+ women and 72 age-matched female controls, none of whom (carriers and non-carriers) had a prior cancer diagnosis and all of whom were cancer-free during the follow-up period. We detected one single metabolite, pyruvate, and two metabolite ratios involving pyruvate, lactate, and a metabolite of yet unknown structure, significantly altered between the two cohorts. A machine learning signature of metabolite ratios was able to correctly distinguish between g
+ and controls in ~82%. The results of this study point to innate systemic metabolic differences in g
+ women independent of cancer incidence and raise the question as to whether or not constitutional alterations in energy metabolism may be involved in the etiology of
-associated breast cancer.
We compared a dermoglandular rotation flap (DGR) in the upper inner, lower inner, and upper outer quadrant regarding similar aesthetic results, patient satisfaction, and comfort after ...breast-conserving therapy with standard segmentectomy (SE). Between 2003 and 2011, 69 patients were treated with breast-conserving surgery using DGR for cancers with high tumor-to-breast volume ratios or skin resection in the three above mentioned quadrants; 161 patients with tumors in the same quadrants were treated with SE. The outcome of the procedures was assessed at least 7 months after completed radiation therapy using a patient and breast surgeon questionnaire and the BCCT.core software. Symmetry, visibility of the scars, the position of the nipple-areola complex, and the appearance of the treated breast were each assessed on a scale from 1 to 4 by an expert panel and by the patients. Univariate and multivariate analysis were used to evaluate the relationship between patient-, tumor-, and treatment-dependent factors and patient satisfaction. 94.2% of the patients with rotation flaps and 83.5% of the patients with lumpectomy were very satisfied with the cosmetic appearance of their breast. Younger patient age was significantly associated with a lower degree of satisfaction. DGR provides good cosmetic results compared with SE and shows high patient satisfaction despite longer scarring and higher median resection volume.
Invasive lobular carcinoma (ILC) of the breast is known to have typical molecular, clinical, and pathological characteristics that differ from invasive cancer of no special type (NST). In the German ...mammography screening program (MSP), we evaluated clinical differences between these tumor types at the time of their detection. Clinical features of NSTs (n = 785) and ILCs (n = 141) diagnosed in the MSP between 2009 and 2016 were compared. Compared to NST, ILC was significantly correlated with advanced age (59.1 years versus 60.6 years) and larger tumor size (1.5 cm versus 2.3 cm). ILC was significantly more frequently associated with moderate tumor differentiation (G2), whereas NST was associated with a higher rate of poorly differentiated tumors (p < .001). Furthermore, ILC presented more often as multifocal tumors (36% versus 11%, p < .001), and mastectomies were performed more often in the ILC group (27% versus 12%, p < .001). ILCs and NSTs had different clinical features at the time of detection. The pathological profile of ILC may explain some of these features. Specialists should be aware of the fact that ILC may escape detection by conventional imaging modalities for a long time, and may present later in life as more advanced multifocal disease.
Background and purpose
The purpose of this work was to identify parameters influencing the risk of late radiation side effects, fair or poor cosmetic outcomes (COs) and pain in breast cancer patients ...after breast-conserving therapy (BCT) and three-dimensional conformal radiotherapy (3D-CRT).
Patients and methods
Between 2006 and 2013, 159 patients were treated at the Hannover Medical School. Physician-rated toxicity according to the LENT-SOMA criteria, CO and pain were assessed by multivariate analysis.
Results
LENT-SOMA grade 1–4 toxicity was observed as follows: fibrosis 10.7 %, telangiectasia 1.2 %, arm oedema 8.8 % and breast oedema 5.0 %. In addition, 15.1 % of patients reported moderate or severe breast pain, and 21.4 % complained about moderate or severe pain in the arm or shoulder. In multivariate analysis, axillary clearing (AC) was significantly associated with lymphoedema of the arm odds ratio (OR) 4.37,
p
= 0.011, 95 % confidence interval (CI) 1.4–13.58. Breast oedema was also highly associated with AC (OR 10.59,
p
= 0.004, 95 % CI 2.1–53.36), a ptosis grade 2/3 or pseudoptosis and a bra size ≥ cup C (OR 5.34,
p
= 0.029, 95 % CI 1.2–24.12). A ptosis grade 2/3 or pseudoptosis and a bra size ≥ cup C were the parameters significantly associated with an unfavourable CO (OR 3.19,
p
= 0.019, 95 % CI 1.2–8.4). Concerning chronic breast pain, we found a trend related to the prescribed radiation dose including boost (OR 1.077,
p
= 0.060, 95 % CI 0.997–1.164). Chronic shoulder or arm pain was statistically significantly associated with lymphoedema of the arm (OR 3.9,
p
= 0.027, 95 % CI 1.17–13.5).
Conclusion
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.
Background: Prophylactic mastectomy is an effective approach to breast cancer risk reduction in patients at high risk. Further studies using standardized measures for quality of life are needed to ...better understand the effect of prophylactic mastectomy on individual patients and, thereby, allow for better patient counseling and selection. Methods: In this prospective study patients undergoing bilateral mastectomy were asked to complete the BREAST-Q questionnaire before and 1 year after surgery. All patients underwent bilateral mastectomy with implant-based breast reconstruction. Patient- and surgery-related information was collected in a database. Results: In total, 48 patients underwent bilateral skin-sparing mastectomy. Of these, 29 (60.4%) suffered from breast cancer. A 2-stage reconstruction with intermediate expander implantation was conducted in 19 (39.6%) patients. All patients completed the BREAST-Q questionnaire. The domain “psychosocial well-being” was significantly improved from a mean score of 74.98 preoperatively to a postoperative score of 81.56 (p = 0.021). In contrast, the domain “physical well-being” dropped –8.38 points on average to a postoperative score of 74.96 (p < 0.001). Interestingly, patients with the lowest preoperative score in the domain “satisfaction with breast” showed the greatest increase after surgery (50.31 vs. 67.25, p < 0.001). On the contrary, patients with the highest preoperative values experienced the strongest decrease in satisfaction (91.60 vs. 75.27, p = 0.012). Conclusion: Implant-based prophylactic mastectomy leads to good quality-of-life results in patients at high risk for breast cancer. Especially, patients with a low preoperative satisfaction with their breasts have a significantly higher chance of experiencing substantial improvements in their quality of life.
, located 470 kb downstream of
, encodes for the nuclear PSMC3-interacting protein, which functions as co-activator of steroid hormone-mediated gene expression, and is involved in RAD51 and ...DMC1-mediated homologous recombination during DNA repair of double-strand breaks. Recently, germline variants in
have been identified in hereditary breast and ovarian cancer (HBOC) patients, mainly in cases with early-onset. We screened a cohort of 166
mutation-negative HBOC patients, of which 56 developed early-onset breast cancer before the age of 36 years, for
variants. We identified 7 novel or rare
variants in 8 out of 166 index patients: c.-115G>A (rs191843707); c.-70T>A (rs752276800); c.-37A>T (rs199620968); c.-24C>G (rs200359709); c.519G>A p.(Trp173*); c.537+51G>C (rs375509656); c.*24G>A. Three out of 7 identified variants (c.-115G>A, c.519G>A and c.*24G>A) with putative pathogenic impact were found in HBOC patients with breast cancer onset at ≤ 36 years. The nonsense mutation c.519G>A p.(Trp173*) was located within the DNA binding domain of GT198 and is predicted to induce nonsense-mediated mRNA decay. Functional analyses of c.-115G>A, and c.*24A>G indicated an influence of these variants on gene expression. This is the second study that gives evidence for an association between pathogenic
germline variants and early-onset breast cancer in HBOC.
Background: The degree of error in subjective estimation of breast implant volume remains unknown. Methods: Nine silicone breast implants were used by 16 examiners for subjective, blinded, implant ...volume estimation. The figures on the stamps were taken as the true breast implant volumes for comparison. The examiners were divided into two groups of equal size: experienced examiners (consultant breast surgeons) and unexperienced examiners (trainees). Fourteen examiners repeated the tests after about 2 weeks.Results: In both groups of doctors, the implant volumes were underestimated by a mean ± standard deviation of 61.6 ± 58.1 cc (21.9% ± 20.1%) in the first test and 37.9 ± 59.1 cc (13.6% ± 20.7%) in the second test. The absolute deviation independent of volume overestimation or underestimation was 77.3 ± 36.9 cc (27.2% ± 12.8%) in the first test and 58.1 ± 41.3 cc (20.6% ± 14.6%) in the second test. In terms of absolute figures, the experienced examiners showed significantly better results than did the unexperienced examiners during the first test. The unexperienced examiners showed increasing deviations with increasing implant volumes. The degree of estimation error was lower in the second test.Conclusions: These blinded subjective estimations of breast implant volume exhibited limited accuracy and reproducibility. Estimation errors were quantified and increased with increasing implant volumes. Experienced examiners performed considerably better than unexperienced examiners, and results of the second test were better in both groups. The subjective volume estimations deviated from the true volumes by around 70 cc (underestimated by around 50 cc).Level of evidence: Level III
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