High proportion of recurrent germline mutations in the BRCA1 gene in breast and ovarian cancer patients from the Prague area

BACKGROUND: Germline mutations in the BRCA1 and BRCA2 genes have been shown to account for the majority of hereditary breast and ovarian cancers. The purpose of our study was to estimate the incidence and spectrum of pathogenic mutations in BRCA1/2 genes in high-risk Czech families. METHODS: A total of 96 Czech families with recurrent breast and/or ovarian cancer and 55 patients considered to be at high-risk but with no reported family history of cancer were screened for mutations in the BRCA1/2 genes. The entire coding sequence of each gene was analyzed using a combination of the protein truncation test and direct DNA sequencing. RESULTS: A total of 35 mutations in the BRCA1/2 genes were identified in high-risk families (36.5%). Pathogenic mutations were found in 23.3% of breast cancer families and in 59.4% of families with the occurrence of both breast and ovarian cancer. In addition, four mutations were detected in 31 (12.9%) women with early onset breast cancer. One mutation was detected in seven (14.3%) patients affected with both a primary breast and ovarian cancer and another in three (33.3%) patients with a bilateral breast cancer. A total of 3 mutations in BRCA1 were identified among 14 (21.4%) women with a medullary breast carcinoma. Of 151 analyzed individuals, 35 (23.2%) carried a BRCA1 mutation and 9 (6.0%) a BRCA2 mutation. One novel truncating mutation was found in BRCA1 (c.1747A>T) and two in BRCA2 (c.3939delC and c.5763dupT). The 35 identified BRCA1 mutations comprised 13 different alterations. Three recurrent mutations accounted for 71.4% of unrelated individuals with detected gene alterations. The BRCA1 c.5266dupC (5382insC) was detected in 51.4% of mutation positive women. The mutations c.3700_3704del5 and c.181T>G (300T>G) contributed to 11.4% and 8.6% of pathogenic mutations, respectively. A total of eight different mutations were identified in BRCA2. The novel c.5763dupT mutation, which appeared in two unrelated families, was the only recurrent alteration of the BRCA2 gene identified in this study. CONCLUSION: Mutational analysis of BRCA1/2 genes in 151 high-risk patients characterized the spectrum of gene alterations and demonstrated the dominant role of the BRCA1 c.5266dupC allele in hereditary breast and ovarian cancer

BRCA1 and BRCA2 5′ noncoding region variants identified in breast cancer patients alter promoter activity and protein binding

© 2018 The Authors. Human Mutation published by Wiley Periodicals, Inc. The widespread use of next generation sequencing for clinical testing is detecting an escalating number of variants in noncoding regions of the genome. The clinical significance of the majority of these variants is currently unknown, which presents a significant clinical challenge. We have screened over 6,000 early-onset and/or familial breast cancer (BC) cases collected by the ENIGMA consortium for sequence variants in the 5′ noncoding regions of BC susceptibility genes BRCA1 and BRCA2, and identified 141 rare variants with global minor allele frequency \u3c 0.01, 76 of which have not been reported previously. Bioinformatic analysis identified a set of 21 variants most likely to impact transcriptional regulation, and luciferase reporter assays detected altered promoter activity for four of these variants. Electrophoretic mobility shift assays demonstrated that three of these altered the binding of proteins to the respective BRCA1 or BRCA2 promoter regions, including NFYA binding to BRCA1:c.-287C\u3eT and PAX5 binding to BRCA2:c.-296C\u3eT. Clinical classification of variants affecting promoter activity, using existing prediction models, found no evidence to suggest that these variants confer a high risk of disease. Further studies are required to determine if such variation may be associated with a moderate or low risk of BC

Cancer risks associated with germline PALB2 pathogenic variants: An international study of 524 families

PURPOSE To estimate age-specific relative and absolute cancer risks of breast cancer and to estimate risks of ovarian, pancreatic, male breast, prostate, and colorectal cancers associated with germline PALB2 pathogenic variants (PVs) because these risks have not been extensively characterized. METHODS We analyzed data from 524 families with PALB2 PVs from 21 countries. Complex segregation analysis was used to estimate relative risks (RRs; relative to country-specific population incidences) and absolute risks of cancers. The models allowed for residual familial aggregation of breast and ovarian cancer and were adjusted for the family-specific ascertainment schemes. RESULTS We found associations between PALB2 PVs and risk of female breast cancer (RR, 7.18; 95% CI, 5.82 to 8.85; P = 6.5 × 10-76), ovarian cancer (RR, 2.91; 95% CI, 1.40 to 6.04; P = 4.1 × 10-3), pancreatic cancer (RR, 2.37; 95% CI, 1.24 to 4.50; P = 8.7 × 10-3), and male breast cancer (RR, 7.34; 95% CI, 1.28 to 42.18; P = 2.6 3 1022). There was no evidence for increased risks of prostate or colorectal cancer. The breast cancer RRs declined with age (P for trend = 2.0 × 10-3). After adjusting for family ascertainment, breast cancer risk estimates on the basis of multiple case families were similar to the estimates from families ascertained through population-based studies (P for difference = .41). On the basis of the combined data, the estimated risks to age 80 years were 53% (95% CI, 44% to 63%) for female breast cancer, 5% (95% CI, 2% to 10%) for ovarian cancer, 2%-3% (95% CI females, 1% to 4%; 95% CI males, 2% to 5%) for pancreatic cancer, and 1% (95% CI, 0.2% to 5%) for male breast cancer. CONCLUSION These results confirm PALB2 as a major breast cancer susceptibility gene and establish substantial associations between germline PALB2 PVs and ovarian, pancreatic, and male breast cancers. These findings will facilitate incorporation of PALB2 into risk prediction models and optimize the clinical cancer risk management of PALB2 PV carriers

Thermovision: a new diagnostic method for orofacial pain?

Jitka Fricova,1,2 Marketa Janatova,3 Martin Anders,4 Jakub Albrecht,4 Richard Rokyta2 1Charles University, 1st Faculty of Medicine, General University Hospital, Department of Anesthesiology, Resuscitation and Intensive Medicine, Pain Management Center, Prague, Czech Republic; 2Charles University, 3rd Faculty of Medicine, Department of Normal, Pathological and Clinical Physiology, Prague, Czech Republic; 3Charles University, 1st Faculty of Medicine, General University Hospital, Department of Rehabilitation Medicine, Prague, Czech Republic; 4Charles University, 1st Faculty of Medicine, General University Hospital, Department of Psychiatry, Prague, Czech Republic Background: Infrared thermography can be used to obtain more complete information about a patient’s condition. The method can be used in various medical applications for monitoring acute and chronic orofacial pain syndrome. With this diagnostic method, thermal differences in the examined region are usually compared to the same reference region on the opposite side of the body. Methods: Infrared quantitative thermography is a non-invasive method for contactless monitoring of dynamic thermal fields on a surface, or in this case, the human body. This method is based on detection of infrared radiation, which is naturally emitted from the surface of the body. In a pilot project with a patient having orofacial pain, changes before and after repetitive transcranial magnetic brain stimulation treatment were assessed. Results: First-day measurements found significantly higher maximum, minimum, and average temperatures, before and after therapy, in the area where the patient subjectively reported pain. The fifth and final measurements, before and after therapy, found only a slight elevation of the maximum temperature of the assessed regions, relative to the same regions on the opposite side of the face. Conclusion: During the measurements on the fifth day, a thermal difference greater than 0.4°C was only observed relative to the minimum temperatures associated with the regions of self-reported pain before and after therapy. For validation of the effects, this method will need to be tested using a randomized, double-blind study with a larger number of patients. Keywords: orofacial pain, thermovision, infrared thermography, transcranial stimulatio

Effect of Si Substitution and Annealing on Magnetocaloric Properties in TbCo 2

We report on magnetocaloric properties of the as-cast and annealed $TbCo_2$ with partial substitution of cobalt by silicon. The samples were characterized by powder X-ray diffraction and investigated by heat capacity measurements (8-300 K, in fields 0 T and 1 T). $TbCo_2$ undergoes a second-order type phase transition at $T_C$ = 240 K, from paramagnetic to ferrimagnetic state;similar behavior was revealed in the Si-doped compounds. The temperature dependence of magnetic entropy and the corresponding magnetocaloric effect were derived for all studied samples. The influence of the heat treatment and Si doping on magnetocaloric properties will be discussed in context of the analogue case $Er(Co_{1-x}Si_x)_2$

Effect of Si Substitution and Annealing on Magnetocaloric Properties in TbCo2TbCo_2

We report on magnetocaloric properties of the as-cast and annealed $TbCo_2$ with partial substitution of cobalt by silicon. The samples were characterized by powder X-ray diffraction and investigated by heat capacity measurements (8-300 K, in fields 0 T and 1 T). $TbCo_2$ undergoes a second-order type phase transition at $T_C$ = 240 K, from paramagnetic to ferrimagnetic state;similar behavior was revealed in the Si-doped compounds. The temperature dependence of magnetic entropy and the corresponding magnetocaloric effect were derived for all studied samples. The influence of the heat treatment and Si doping on magnetocaloric properties will be discussed in context of the analogue case $Er(Co_{1-x}Si_x)_2$