A membrane-associated NAC domain transcription factor XVP interacts with TDIF co-receptor and regulates vascular meristem activity.

Vascular stem cell maintenance is regulated by a peptide signaling involving Tracheary Element Differentiation Inhibitory Factor (TDIF) and Receptor TDR/PXY (Phloem intercalated with Xylem) and co-receptor BAK1 (BRI1-associated receptor kinase1). The regulatory mechanism of this signaling pathway is largely unknown despite its importance in stem cell maintenance in the vascular meristem. We report that activation of a NAC domain transcription factor XVP leads to precocious Xylem differentiation, disruption of Vascular Patterning, and reduced cell numbers in vascular bundles. We combined molecular and genetic studies to elucidate the biological functions of XVP. XVP is expressed in the cambium, localized on the plasma membrane and forms a complex with TDIF co-receptors PXY-BAK1. Simultaneous mutation of XVP and its close homologous NAC048 enhances TDIF signaling. In addition, genetics analysis indicated that XVP promotes xylem differentiation through a known master regulator VASCULAR-RELATED NAC-DOMAIN6 (VND6). Expression analyses indicate that XVP activates CLAVATA3/ESR (CLE)-related protein 44 (CLE44), the coding gene of TDIF, whereas TDIF represses XVP expression, suggesting a feedback mechanism. Therefore, XVP functions as a negative regulator of the TDIF-PXY module and fine-tunes TDIF signaling in vascular development. These results shed new light on the mechanism of vascular stem cell maintenance.

Usefulness of Kinect sensor-based reachable workspace system for assessing upper extremity dysfunction in breast cancer patients.

PURPOSE: Recently, the utility of the Kinect sensor-based reachable workspace analysis system for measuring upper extremity outcomes of neuromuscular and musculoskeletal diseases has been demonstrated. Here, we investigated its usefulness for assessing upper extremity dysfunction in breast cancer patients. METHODS: Twenty unilateral breast cancer patients were enrolled. Upper extremity active range of motion was captured by the Kinect sensor, and reachable workspace relative surface areas (RSAs) were obtained. The QuickDASH was completed to assess upper extremity disability. General and breast cancer-specific quality of life (QOL) were assessed by the EORTC QLQ-C30 and EORTC QLQ-BR23. RESULTS: The total RSA ratio of the affected and unaffected sides ranges from 0.64 to 1.11. Total RSA was significantly reduced on the affected versus unaffected side (0.659 ± 0.105 vs. 0.762 ± 0.065; p = 0.001). Quadrant 1 and 3 RSAs were significantly reduced (0.135 ± 0.039 vs. 0.183 ± 0.040, p < 0.001; 0.172 ± 0.058 vs. 0.217 ± 0.031, p = 0.006). Total RSA of the affected side was strongly correlated with the numeric pain rating scale during movement (r = - 0.812, p < 0.001) and moderately with the QuickDASH (r = - 0.494, p = 0.027). Further, quadrant 3 RSA was correlated with EORTC QLQ-C30 role functioning (r = 0.576, p = 0.008) and EORTC QLQ-BR23 arm symptoms (r = - 0.588, p = 0.006) scales. CONCLUSIONS: The Kinect sensor-based reachable workspace analysis system was effectively applied to assess upper extremity dysfunction in breast cancer patients. This system could potentially serve as a quick and simple outcome measure that provides quantitative data for breast cancer patients.

Corrigendum to "Total Intravenous Anaesthesia with High-Dose Remifentanil Does Not Aggravate Postoperative Nausea and Vomiting and Pain, Compared with Low-Dose Remifentanil: A Double-Blind and Randomized Trial".

[This corrects the article DOI: 10.1155/2014/724753.].

Usefulness of abbreviated breast MRI screening for women with a history of breast cancer surgery.

PURPOSE: We investigated the usefulness of abbreviated breast MRI (AB-MRI), including fat-suppressed T2-weighted imaging, pre- and postcontrast image acquisition, and subtracted maximum-intensity projection imaging, for the screening of women with a history of breast cancer surgery. METHODS: Between October 2014 and March 2016, a total of 799 AB-MRI examinations were performed for 725 women with a history of breast cancer surgery. The image acquisition time was 8.5 min. Screening mammography, ultrasound, and AB-MRI were generally performed around the same time. The cancer detection rate, positive predictive values for recall and biopsy, sensitivity and specificity of screening MRI, and rate of malignancy belonging to each breast imaging reporting and data system (BI-RADS) category were assessed. RESULTS: AB-MRI detected 12 malignancies in 12 women (15.0 cancers per 1000 cases). Seven of these 12 malignancies were initially invisible on ultrasound and mammography, although subsequent targeted ultrasound revealed lesions corresponding to the MRI-detected lesions. The positive predictive values for recall and biopsy and sensitivity and specificity values for screening MRI were 12.4, 61.5, 100, and 89.2%, respectively. The rates of malignancies belonging to categories 1, 2, 3, and 4 of the BI-RADS were 0, 0, 4.8, and 57.1%, respectively. CONCLUSIONS: The diagnostic performance of screening AB-MRI for women with a history of breast cancer surgery is acceptable, with the advantages of short examination and interpretation times and low costs. Thus, it could be used as a main screening modality that may replace conventional imaging in breast cancer survivors.

Correction to: Usefulness of abbreviated breast MRI screening for women with a history of breast cancer surgery.

In the original publication of the article, the acknowledgment section was missed out inadvertently. The acknowledgement section is below.

The effect of propofol and sevoflurane on cancer cell, natural killer cell, and cytotoxic T lymphocyte function in patients undergoing breast cancer surgery: an in vitro analysis.

BACKGROUND: To clarify the effect of anaesthetic agents on cancer immunity, we evaluated the effects of propofol and sevoflurane on natural killer (NK) cell, cytotoxic T lymphocyte (CTL) counts and apoptosis rate in breast cancer and immune cells co-cultures from patients who underwent breast cancer surgery. METHODS: Venous blood samples were collected after inducing anaesthesia and at 1 and 24 h postoperatively in patients who had undergone breast cancer surgery. The patients were allocated randomly to the propofol- or sevoflurane-based anaesthesia groups. We counted and detected apoptosis in cancer cell, NK cell and CTL of patients with breast cancer by co-culture with a breast cancer cell line in both groups. We also evaluated changes in the cytokines tumour necrosis factor-alpha, interleukin (IL)-6 and IL-10 during the perioperative period. RESULTS: Forty-four patients were included in the final analysis. No difference in NK cell count, CTL count or apoptosis rate was detected between the groups. Furthermore, the number of breast cancer cells undergoing apoptosis in the breast cancer cell co-cultures was not different between the groups. No changes in cytokines were detected between the groups. CONCLUSION: Although basic science studies have suggested the potential benefits of propofol over a volatile agent during cancer surgery, propofol was not superior to sevoflurane, on the aspects of NK and CTL cells counts with apoptosis rate including breast cancer cell, during anaesthesia for breast cancer surgery in a clinical environment. TRIAL REGISTRATION: NCT02758249 on February 26, 2016.

Adjunctive Breast-Specific Gamma Imaging for Detecting Cancer in Women with Calcifications at Mammography.

BACKGROUND: Mammography detects calcium deposits sensitively, but the specificity for differentiating malignancy from benign calcifications is low. Thus, we investigated whether adjunctive breast-specific gamma imaging (BSGI) has incremental value for detecting cancer in women with suspicious calcifications detected by mammography, and compared BSGI with adjunctive ultrasonography (US). METHODS: The medical records of women without a personal history of breast cancer who underwent mammography for breast evaluation from 2009 to 2014 were reviewed retrospectively. Patients who had calcifications detected by mammography, with a result of Breast Imaging Reporting and Data System (BI-RADS) categories 3-5, underwent adjunctive US and BSGI and were included in this study. A total of 302 breast lesions in 266 women (mean age ± standard deviation 49 ± 9 years) were selected for this study. RESULTS: For detecting breast cancer using mammography plus BSGI, the sensitivity, specificity, positive predictive value, negative predictive value, and area under the receiver operating curve with 95% confidence intervals were 94% (91-96), 90% (86-93), 91% (87-94), 94% (90-96), and 0.92 (0.89-0.95), respectively. For mammography plus US, the respective values were 97% (94-98), 51% (46-57), 68% (63-73), 94% (90-96), and 0.74 (0.70-0.78). CONCLUSIONS: Adjunctive BSGI had higher specificity than adjunctive US without loss of sensitivity. This finding suggests that adjunctive BSGI may be a useful complementary initial imaging method to improve the detection of breast cancer in women who have calcifications with suspicious morphology at mammography.

Transcriptome analysis of secondary cell wall development in Medicago truncatula.

BACKGROUND: Legumes are important to humans by providing food, feed and raw materials for industrial utilizations. Some legumes, such as alfalfa, are potential bioenergy crops due to their high biomass productivity. Global transcriptional profiling has been successfully used to identify genes and regulatory pathways in secondary cell wall thickening in Arabidopsis, but such transcriptome data is lacking in legumes. RESULTS: A systematic microarray assay and high through-put real time PCR analysis of secondary cell wall development were performed along stem maturation in Medicago truncatula. More than 11,000 genes were differentially expressed during stem maturation, and were categorized into 10 expression clusters. Among these, 279 transcription factor genes were correlated with lignin/cellulose biosynthesis, therefore representing putative regulators of secondary wall development. The b-ZIP, NAC, WRKY, C2H2 zinc finger (ZF), homeobox, and HSF gene families were over-represented. Gene co-expression network analysis was employed to identify transcription factors that may regulate the biosynthesis of lignin, cellulose and hemicellulose. As a complementary approach to microarray, real-time PCR analysis was used to characterize the expression of 1,045 transcription factors in the stem samples, and 64 of these were upregulated more than 5-fold during stem maturation. Reverse genetics characterization of a cellulose synthase gene in cluster 10 confirmed its function in xylem development. CONCLUSIONS: This study provides a useful transcriptome and expression resource for understanding cell wall development, which is pivotal to enhance biomass production in legumes.

KOHBRA BRCA risk calculator (KOHCal): a model for predicting BRCA1 and BRCA2 mutations in Korean breast cancer patients.

The widely used Western BRCA mutation prediction models underestimated the risk of having a BRCA mutation in Korean breast cancer patients. This study aimed to identify predictive factors for BRCA1/2 mutations and to develop a Korean BRCA risk calculator. The model was constructed by logistic regression model, and it was based on the Korean Hereditary Breast Cancer study, in which 1669 female patients were enrolled between May 2007 and December 2010. A separate data set of 402 patients, who were enrolled from Jan 2011 to August 2012, was used to test the performance of our model. In total, 264 (15.8%) and 67 (16.7%) BRCA mutation carriers were identified in the model and validation set, respectively. Multivariate analysis showed that age at breast cancer diagnosis, bilateral breast cancer, triple-negative breast cancer (TNBC) and the number of relatives with breast or ovarian cancer within third-degree relatives were independent predictors of the BRCA mutation among familial breast cancer patients. An age <35 years at diagnosis, bilateral breast cancer, both breast and ovarian cancer and TNBC remained significant predictors in non-familial breast cancer cases. Our model was developed based on logistic regression models. The validation results showed no differences between the observed and expected carrier probabilities. This model will be a useful tool for providing genetic risk assessments in Korean populations.

RAS mutations in indeterminate thyroid nodules are predictive of the follicular variant of papillary thyroid carcinoma.

OBJECTIVE: RAS mutations are the most common mutations in thyroid nodules with indeterminate cytology by fine-needle aspiration cytology (FNAC), and are mutually exclusive with BRAF mutations. However, the diagnostic utility of RAS mutation analysis is uncertain. We evaluated the diagnostic utility of RAS mutation analysis in indeterminate thyroid nodules. DESIGN, PATIENTS, AND MEASUREMENTS: A total of 155 thyroid nodules (90 benign and 65 indeterminate) negative for BRAF(V) (600E) mutations on FNAC were analysed for mutations in RAS codon 61 using pyrosequencing methods. We evaluated diagnostic accuracy of RAS mutation for predicting thyroid malignancy based on the surgical pathologic diagnosis. RESULTS: Among the 65 BRAF(V) (600E) -negative indeterminate thyroid nodules identified by FNAC, 25 (38·5%) exhibited point mutations in RAS 61 consisting of 18 NRAS 61 (72%), and 7 HRAS 61 (28%) mutations. In contrast, only five of 90 (5·6%) nodules with benign cytology had RAS mutations. Only two of 25 (8·0%) RAS 61(+) indeterminate nodules exhibited malignant ultrasonographic features. Of the 15 patients with RAS 61(+) -indeterminate nodules who underwent thyroid surgery, 14 (93·3%) were diagnosed as malignant, including 13 follicular variant of papillary thyroid carcinomas (FVPTC), and one follicular thyroid carcinoma (FTC). The average tumour size was 1·79 ± 0·62 cm. Multifocality was seen in 28·6% of cases, with 7·1% exhibiting extrathyroidal extension; no lymph node or distant metastases were evident. Based on the surgical pathologic diagnosis results, preoperative RAS 61 mutation analysis on FNAC exhibited 93·3% sensitivity, 75·0% specificity, 93·3% positive predictive value, 75·0% negative predictive value and 89·5% diagnostic accuracy for predicting malignancies. CONCLUSION: Our results suggest that RAS mutation analysis holds great promise as a preoperative diagnostic tool for predicting FVPTC in cytologically and sonographically indeterminate nodules negative for BRAF mutations.

False positive or negative results of shear-wave elastography in differentiating benign from malignant breast masses: analysis of clinical and ultrasonographic characteristics.

BACKGROUND: Shear-wave elastography (SWE) has the potential to improve diagnostic performance of conventional ultrasound (US) in differentiating benign from malignant breast masses. PURPOSE: To investigate false positive or negative results of SWE in differentiating benign from malignant breast masses and to analyze clinical and imaging characteristics of the masses with false SWE findings. MATERIAL AND METHODS: From May to October 2013, 166 breast lesions of 164 consecutive women (mean age, 45.3 ± 10.1 years) who had been scheduled for biopsy were included. Conventional US and SWE were performed in all women before biopsy. Clinical, ultrasonographic morphologic features and SWE parameters (pattern classification and standard deviation [SD]) were recorded and compared with the histopathology results. Patient and lesion factors in the "true" and "false" groups were compared. RESULTS: Of the 166 masses, 118 (71.1%) were benign and 48 (28.9%) were malignant. False SWE features were more frequently observed in benign masses. False positive rates of benign masses and false negative rates of malignancy were 53% and 8.2%, respectively, using SWE pattern analysis and were 22.4% and 10.3%, respectively, using SD values. A lesion boundary of the masses on US (P = 0.039) and younger patient age (P = 0.047) were significantly associated with false SWE findings. CONCLUSION: These clinical and ultrasonographic features need to be carefully evaluated in performance and interpretation of SWE examinations.

Validation and comparison of CS-IHC4 scores with a nomogram to predict recurrence in hormone receptor-positive breast cancers.

The aim of this study was to both develop and validate a nomogram based on the Ki-67 index to predict recurrence. We constructed a nomogram using the Cox proportional hazards model with 953 N0 and N1 postoperative hormone receptor (HR)-positive breast cancer patients and validated it in an external cohort of 895 patients. A prognostic model that used classical variables, Adjuvant! Online, St. Gallen risk stratification, and the four immunohistochemistry (IHC) markers (IHC4 score) was created and assessed by the likelihood ratio χ(2) (LR-χ(2)) test using the bootstrapping method. The nomogram showed an area under the receiver operating characteristic curve (AUC) of 0.75 (95% CI 0.72-0.77) in the training set. The validation set showed good discrimination with an AUC of 0.63 (95% CI 0.60-0.66). In the LR-χ(2) test, the nomogram score was found to be more informative than the IHC4 with clinical score (CS) [LR-χ(2) 13.365 (1 d.f.); 95% CI 2.50-24.23 for CS-IHC4 + nomogram score vs. CS-IHC4] on distant recurrence-free survival. This study implies that the amount of prognostic information contained in the nomogram is superior to that in the CS-IHC4 score in HR-positive N0 and N1 breast cancer patients (NCT1273415).

Impact of chemotherapy-induced alopecia distress on body image, psychosocial well-being, and depression in breast cancer patients.

PURPOSE: This study aims to evaluate the impact of chemotherapy-induced alopecia (CIA) distress on body image, psychosocial well-being, and depression among breast cancer patients. METHODS: A cross-sectional survey was conducted at the breast cancer advocacy events held at 16 hospitals in Korea. Alopecia distress was assessed using the 'Chemotherapy-Induced Alopecia Distress Scale', body image and psychosocial well-being were measured by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and breast specific module (BR23), and depression was measured using the Center for Epidemiological Studies Depression scale. Means of outcomes were compared between low and high CIA distress groups. Univariable and multivariable linear regression models were used to analyze the relationship between the CIA distress and body image, psychosocial well-being, and depression. RESULTS: One hundred sixty-eight breast cancer patients participated in the study; the mean age was 48.4 (SD = 8.4) years, and 55.3% of the patients experienced higher distress from alopecia. In fully adjusted models, the high distress group was more likely to have a poorer body image than the low distress group (35.2 vs. 62.0; p < 0.001). Distressed patients were also more likely to report lower emotional (55.3 vs. 76.9; p < 0.001), role (58.6 vs. 72.0; p < 0.001), and social functioning (51.3 vs. 70.9; p < 0.001). The high distress group was also more likely to have depression compared with the low distress group (19.6 vs. 14.8; p < 0.001). CONCLUSIONS: Chemotherapy-induced alopecia distress was negatively associated with body image, psychosocial well-being, and depression in women with breast cancer. It is necessary to develop specific interventions to minimize distress due to alopecia for women with breast cancer.

Complementary role of semiquantitative analysis of breast-specific gamma imaging in the diagnosis of breast cancer.

OBJECTIVE: We investigated whether the interpretation of breast-specific gamma imaging (BSGI) with visual and semiquantitative analyses can improve the diagnosis of breast cancer. MATERIALS AND METHODS: The records of 114 women (mean age±SD, 49.6±9.8 years) who underwent BSGI, mammography, and ultrasound to evaluate a breast lesion or lesions were reviewed retrospectively. The breast lesions identified with BSGI were compared with those identified with mammography and ultrasound. BSGI was first interpreted visually, and then a semiquantitative analysis was performed. For the semiquantitative analysis, the uptake ratio for each breast lesion was calculated by dividing the tumor uptake by the contralateral normal breast uptake. RESULTS: Four of the 114 patients had two breast lesions, so a total of 118 breast lesions (42 malignant lesions and 76 benign lesions) were evaluated. A BSGI uptake ratio cutoff of 1.5, with values less than 1.5 indicating negative for cancer, as determined by receiver operating characteristic curve analysis of our data (area under curve, 0.874), was used for semi-quantitative analysis. The sensitivity and specificity of BSGI with visual analysis alone for assessing malignant breast lesions were 76.2% (32/42) and 81.6% (62/76), respectively. For BSGI with visual and semiquantitative analyses, the sensitivity and specificity were 76.2% (32/42) and 92.1% (70/76), respectively. The sensitivity and specificity for mammography were 57.1% (24/42) and 81.6% (62/76), respectively. For ultrasound, the respective values were 97.6% (41/42) and 61.8% (47/76). BSGI with visual and semiquantitative analyses had a significantly higher specificity than BSGI with visual analysis alone, mammography, and ultrasound (all, p<0.01). CONCLUSION: Semiquantitative analysis of BSGI with visual interpretation may be a useful complementary method for evaluating malignant breast lesions.

Total intravenous anaesthesia with high-dose remifentanil does not aggravate postoperative nausea and vomiting and pain, compared with low-dose remifentanil: a double-blind and randomized trial.

The study was designed to investigate postoperative nausea and vomiting (PONV) in low- and high-dose remifentanil regimens for total intravenous anaesthesia (TIVA) in adult female patients with American Society of Anaesthesiologists physical status classification I undergoing local breast excision. Propofol and remifentanil 5 ng · mL(-1) (L group) or 10 ng · mL(-1) (H group) were administered for anaesthesia induction and maintenance. Propofol was titrated within range of 0.1 µg · mL(-1) to maintain bispectral index (BIS) values between 40 and 60. Haemodynamic parameters during the intra- and postoperative periods and 24 h postoperative visual analogue scale (VAS) and PONV were evaluated. Each group with 63 patients was analyzed. The H group showed higher use of remifentanil and lower use of propofol, with similar recovery time. Mean systemic arterial blood pressure (MBP), heart rate, and BIS did not differ significantly before and after endotracheal intubation in the H group. However, significant increases in MBP and BIS were apparent in the L group. Postoperative VAS, PONV incidence and scale, and Rhodes index did not differ significantly between the two groups. In conclusion, TIVA with high-dose remifentanil did not aggravate PONV with similar postoperative pain, compared with low-dose remifentanil. Furthermore, high-dose remifentanil showed more haemodynamic stability after endotracheal intubation. This trial is registered with KCT0000185.

Exploring the Potential of Transcranial Direct Current Stimulation for Relieving Central Post-Stroke Pain: A Randomized Controlled Pilot Study.

The potential of transcranial direct current stimulation (tDCS) as a non-invasive brain stimulation technique for treating pain has been studied. However, its effectiveness in patients with central post-stroke pain (CPSP) and the impact of lesion location remain unclear. This study investigated tDCS's pain reduction effects in patients with CPSP. Twenty-two patients with CPSP were randomized into the tDCS or sham groups. The tDCS group received stimulation of the primary motor cortex (M1) for 20 min, five times weekly, for two weeks, and underwent evaluations at baseline, immediately after the intervention, and one week after the intervention. The tDCS group had no significant improvement compared to the sham group in pain, depression, and quality of life. Nevertheless, significant changes were identified within the tDCS group, and the pain trends appeared to be influenced by the lesion location. These findings provide important insights into the use of tDCS in patients with CPSP, which could inform further research and development of pain treatment options.

Comparison between screen-detected and symptomatic breast cancers according to molecular subtypes.

Breast cancer screening programs make it possible to detect early cancer, thus reducing breast cancer mortality. We studied the clinicopathologic characteristics and prognosis of screen-detected invasive breast cancer compared with symptomatic breast cancer. And we compared the result according to molecular subtypes (luminal A, luminal B, Her2, and triple negative), with the goal of identifying the role of screening in each subtypes. From January 2002 to June 2008, 3,141 patients who underwent surgery for the treatment of invasive ductal carcinoma at Samsung Medical Center were included. Among them, 1,025 patients were screen-detected, and 2,116 patients who were screened over 2 years or never were symptomatic. We retrospectively reviewed the clinical and pathologic data. Screen-detected breast cancer was associated with older age, smaller tumor size, more hormone-receptor positive, less lymph node involvement, earlier stage, and reduced mortality compared with symptomatic breast cancer (P < 0.001). According to the molecular subtype, luminal A was most common (63.6%) and showed the most obvious survival benefit in screen-detected tumors in comparison with symptomatic tumors (5-year OS: 99.7 vs. 96.5%, 5-year DFS: 96.4 vs. 90.7%). Screen detection was independently associated with improved overall and disease-free survival outcomes after adjustment for covariates (HR 0.32, P = 0.035; HR 0.58, P = 0.020, respectively) only in the luminal A subtype. Differences in pathological features such as tumor size, nodal status, grade, and age at diagnosis with different molecular subtype distributions may explain the survival advantage of patients with screen-detected breast cancer. Screening programs seem to have a different efficacy depending on the molecular subtype of the breast cancer, especially in the luminal A subtype, for which screen detection acts as an independent prognostic factor itself.

Small node-negative (T1b-cN0) invasive hormone receptor-positive breast cancers: is there a subpopulation that might have benefit from adjuvant chemotherapy?

The aims of the study were to identify a subpopulation more likely to be at greater risk of recurrence in small T1b-c node-negative hormone receptor (HR)-positive breast cancer, and which would benefit from adjuvant chemotherapy. Clinico-pathologic characteristics and clinical outcomes of 538 postoperative HR-positive T1b-cN0 breast cancer patients were retrospectively analyzed. High Ki67 index and a young age (< 35 years) were identified as independent risk factors for relapse (p < 0.0001 and 0.015, respectively). A nomogram based on Cox-regression model showed an area under the curve (AUC) of 0.73 in the training set. The validation set showed a good discrimination with an AUC of 0.65. In patients with high nomogram scores (≥ 100, n = 24, 4.5%) who had high Ki67 index with more than 75%, or young age (< 35 years) and a Ki67 index > 50%, the relapse-free survival curve of patients who had received anthracycline-containing adjuvant chemotherapy showed a better outcome than those who had not (p = 0.029). Ki67 index and age are valuable surrogate markers to predict recurrence and as indicators of tumors that could benefit from adjuvant chemotherapy in small T1b-c node-negative HR-positive breast cancer.

Prevalence of BRCA1 and BRCA2 mutations in non-familial breast cancer patients with high risks in Korea: the Korean Hereditary Breast Cancer (KOHBRA) Study.

Prevalence and phenotype of BRCA mutation can vary by race. The purpose of this study is to evaluate the prevalence of BRCA1/2 mutations in non-familial breast cancer patients with high risks in Korea. A subset of 758 patients was selected for this study from the KOHBRA nationwide multicenter prospective cohort study. Mutations in BRCA1/2 genes were tested using fluorescent-conformation sensitive gel electrophoresis, denaturing high performance liquid chromatography or direct sequencing. Mutation of BRCA1/2 genes were identified in 65 (8.6%) patients among total 758 patients [BRCA1 mutation: 25 (3.3%), BRCA2 mutation: 40 (5.3%)]. According to risk groups, mutation of BRCA1/2 genes were identified in 53 (8.5%) of 625 early onset patients (age ≤ 40), in 22 (17.7%) of 124 bilateral breast cancer patients, in 3 (50.0%) of 6 breast and ovarian cancer patients, in one (5.9%) of 17 male breast cancer patients, in 5 cases (7.6%) of 66 multiple organ cancer patients. The most common mutation was 509C>A for BRCA1 and 7708C>T for BRCA2. The prevalence of BRCA1/2 mutations by age in early onset patients was significantly different (age <35 vs age ≥35; 10.0 vs 2.9%, p = 0.0007). BRCA1/2 mutations for non-familial Korean breast cancer patients were detected at a high rate, particularly, in patients with early onset of less than 35 years of age, bilateral breast cancer, and breast and ovarian cancer. Individualized genetic counseling should be offered for non-familial breast cancer patients with these risk factors.

Spectra of BRCA1 and BRCA2 mutations in Korean patients with breast cancer: the importance of whole-gene sequencing.

The frequencies and spectra of germline mutations in the BRCA1 and BRCA2 genes vary among populations. In the present study, the mutation spectra of the BRCA1/BRCA2 genes in Korean breast cancer patients were investigated using whole-gene sequencing method. A total of 134 unrelated Korean breast cancer patients who were identified as being at high risk of carrying BRCA1/BRCA2 mutations were included. PCR amplification and direct sequencing were performed covering all exons and flanking intronic sequences of the BRCA1/BRCA2 genes. A total of 26 mutations were detected in 31 of 134 patients (23.1%). The mutation detection rate in the present study is higher than those of previous studies using screening methods (2.5-11.3%) and similar to that of a recent study, which used whole-gene sequencing (21.2%). The BRCA2: c.7480C>T mutation, which has been suggested to be a founder mutation in Koreans, was detected in only one patient. Five mutations were recurrent but observed in no more than two patients. Given that the mutation detection rates using whole-gene sequencing were much higher than for screening methods and that there were no consistent observations of founder mutations, whole-gene sequencing of both BRCA1 and BRCA2 genes should be the method of choice to identify mutations in high-risk Korean patients.