Characteristics of Chinese breast cancer patients with double heterozygosity for BRCA1 and BRCA2 germline pathogenic variants.

PURPOSE: Despite of very rare, breast cancer patients with double heterozygosity (DH) variants in BRCA1 and BRCA2 genes have been identified in other ethnic groups and seem to be associated with distinctive phenotypes. However, little is known about the frequency and clinical characteristics of Chinese breast cancer patients with BRCA1/2 DH variants. METHODS: Four hundred and eleven unrelated patients with BRCA1 or BRCA2 pathogenic variants (PVs) were identified in a large series of unselected breast cancer patients. Another two siblings with metachronous bilateral breast cancer were referred for genetic counseling, after which BRCA1/2 DH variants were detected. RESULTS: Four unrelated breast cancer patients with BRCA1/2 DH were identified in the cohort of 411 patients with BRCA1 or BRCA2 PVs, the frequency of BRCA1/2 DH was 0.97%. In total, six BRCA1/2 DH patients from five families were found in this study. In two families, the hereditary pattern of DH was speculated to have originated from both sides of the family. BRCA1/2 DH patients were more likely to have a family history of breast cancer than patients with a BRCA1 (100% vs. 29.2%, P = 0.004) or BRCA2 (100% vs. 29.6%, P = 0.004) single PV. BRCA1/2 DH patients were more likely to be triple-negative breast tumors than patients with single BRCA2 PVs (66.7% vs. 14.1%, P = 0.020), which was comparable to the findings in patients with single BRCA1 PVs (66.7% vs. 56.9%, P = 1.00). CONCLUSION: Chinese patients with BRCA1/2 DH exhibit a high percentage of family history of breast cancer. The tumor pathological features of BRCA1/2 DH carriers are similar to those of BRCA1 PV carriers.

Cancer risk in relatives of BRCA1/2 pathogenic variant carriers in a large series of unselected patients with breast cancer.

OBJECTIVE: The spectrum and risk of cancer in relatives of BRCA1/2 pathogenic variant carriers in the Chinese population have not been established. METHODS: A family history of cancer in 9903 unselected breast cancer patients was retrospectively analyzed. BRCA1/2 status was determined for all patients and relative risks (RRs) were calculated to evaluate cancer risk in relatives of the patients. RESULTS: The incidences of breast cancer in female relatives of BRCA1 carriers, BRCA2 carriers, and non-carriers were 33.0%, 32.2%, and 7.7%, respectively. The corresponding incidences of ovarian cancer were 11.5%, 2.4%, and 0.5%, respectively. The incidences of pancreatic cancer in male relatives of BRCA1 carriers, BRCA2 carriers, and non-carriers were 1.4%, 2.7%, and 0.6%, respectively. The corresponding incidences of prostate cancer were 1.0%, 2.1%, and 0.4%, respectively. The risks of breast and ovarian cancers in female relatives of BRCA1 and BRCA2 carriers were significantly higher than female relatives of non-carriers (BRCA1: RR = 4.29, P < 0.001 and RR = 21.95, P < 0.001; BRCA2: RR = 4.19, P < 0.001 and RR = 4.65, P < 0.001, respectively). Additionally, higher risks of pancreatic and prostate cancers were noted in male relatives of BRCA2 carriers than non-carriers (RR = 4.34, P = 0.001 and RR = 4.86, P = 0.001, respectively). CONCLUSIONS: Female relatives of BRCA1 and BRCA2 carriers are at increased risk for breast and ovarian cancers, and male relatives of BRCA2 carriers are at increased risk for pancreatic and prostate cancers.

Low Expression of PALB2 is Associated With Poor Survival in Chinese Women With Primary Breast Cancer.

BACKGROUND: PALB2 plays a crucial role in genome stability and the DNA repair process, and its mutation is associated with a moderate to high risk of breast cancer. However, the status and prognostic role of PALB2 expression in breast cancer are still unclear. MATERIALS AND METHODS: The expression level of PALB2 mRNA was evaluated by using quantitative real-time polymerase chain reaction in core biopsy samples from 563 primary breast cancer tissues. RESULTS: In the entire cohort, low expression of PALB2 mRNA was significantly associated with poor survival (low vs. intermediate: DFS, adjusted HR = 1.79, 95% CI = 1.21-2.65, P = .003; DDFS, adjusted HR = 2.07, 95% CI = 1.34-3.20, P = .001; DSS, adjusted HR = 2.59, 95% CI = 1.45-4.64, P = .001; OS, adjusted HR = 2.77, 95% CI = 1.56-4.92, P = .001; low vs. high: DFS, adjusted HR = 1.57, 95% CI = 1.06-2.35, P = .026; DDFS, adjusted HR = 1.66, 95% CI = 1.08-2.55, P = .020; DSS, adjusted HR = 1.74, 95% CI = 1.00-3.03, P = .048; OS, adjusted HR = 1.59, 95% CI = 0.95-2.67, P = .08). Notably, among hormone receptor (HR)-positive/HER2-negative subtype, patients with low PALB2 expression also had significantly worse outcomes (low vs. intermediate: DFS, adjusted HR = 2.33, 95% CI = 1.32-4.13, P = .004; DDFS, adjusted HR = 2.78, 95% CI = 1.47-5.27, P < .001; DSS, adjusted HR = 3.08, 95% CI = 1.27-7.43, P = .013; OS, adjusted HR = 3.15, 95% CI = 1.32-7.50, P = .010; low vs. high: DFS, adjusted HR = 1.84, 95% CI = 1.04-3.28, P = .04; DDFS, adjusted HR = 1.82, 95% CI = 0.99-3.36, P = .05; DSS, adjusted HR = 2.06, 95% CI = 0.87-4.86, P = .10; OS, adjusted HR = 1.54, 95% CI = 0.71-3.33, P = .28). CONCLUSION: Breast cancer patients with low expression of mRNA have a poor survival, suggesting that patients with PALB2 low expression may be the potential beneficiaries for PARP inhibitors therapy.

BRCA-CRisk: A Contralateral Breast Cancer Risk Prediction Model for BRCA Carriers.

PURPOSE: The absolute cumulative risk of contralateral breast cancer (CBC) for patients with BRCA1/2 variants is unknown. The purpose of this study was to develop a CBC risk prediction model for assessing CBC risk for BRCA1/2 carriers. METHODS: The primary cohort of 491 patients with BRCA1/2 variants was derived from a large series of unselected patients with breast cancer. A nomogram was established on the basis of the results of a multivariate Cox regression analysis from this cohort. This model, named BRCA-CRisk, was further validated by an independent cohort of 205 patients with BRCA1/2 variants. Discrimination and calibration of the model were assessed. RESULTS: In the primary cohort of 491 patients, 66 developed contralateral breast cancer after a median follow-up of 7.0 years. Four variables were significantly associated with risk of CBC and were incorporated in the establishment of the BRCA-CRisk prediction model: younger age at first breast cancer (with continuous variable, P = .002), positive first-degree family history of breast and/or ovarian cancer (hazard ratio [HR], 1.89; 95% CI, 1.16 to 3.08; P = .011), variant located near the 3' region of BRCA (HR, 2.01; 95% CI, 1.23 to 3.30; P = .006), and endocrine therapy (HR, 0.54; 95% CI, 0.33 to 0.88; P = .013). The area under the time-dependent curves for the 5- and 10-year cumulative risks of CBC were 0.775 and 0.702, respectively. The model was well validated in the independent cohort of 205 BRCA1/2 carriers, with area under the curves of 0.750 and 0.691 for 5 and 10 years, respectively. CONCLUSION: BRCA-CRisk model provides a useful tool for assessing the absolute cumulative risk of CBC for BRCA1/2 carriers and may help carriers and clinicians optimally select risk-reducing strategies on the basis of individual CBC risk.

Prevalence of BRCA1 and BRCA2 pathogenic variants in 8627 unselected patients with breast cancer: stratification of age at diagnosis, family history and molecular subtype.

PURPOSE: Comprehensively analyzing the prevalence of BRCA1/2 germline pathogenic variants (PVs) in a large cohort of unselected Chinese patients with breast cancer has great clinical importance. METHODS: Germline pathogenic variants in full-length BRCA1/2 genes were determined through next-generation sequencing and/or Sanger sequencing assays in 8627 unselected Chinese patients with breast cancer who were treated at the Breast Center of Peking University Cancer Hospital. The prevalence of BRCA1/2 PVs was further stratified by age at diagnosis, family history of cancer and molecular subtype. RESULTS: We found that the overall prevalence of BRCA1/2 PVs was 6.0% in the entire cohort, 2.4% in BRCA1 and 3.7% in BRCA2. The prevalence of BRCA1/2 PVs in patients with early-onset breast cancer (age at diagnosis ≤ 40 years) was significantly higher than that in patients over the age of 40 (9.7% vs. 5.1%). The prevalence rates of BRCA1/2 PVs in patients with a family history of breast, ovarian, pancreatic, and prostate cancer were 19.5%, 39.0%, 11.1%, and 12.8%, respectively. Moreover, the number of relatives affected by breast cancer was associated with a higher prevalence of BRCA1/2 PVs. Molecular subtypes were associated with the prevalence of BRCA1/2 PVs. Patients with the triple-negative phenotype had the highest prevalence of BRCA1/2 PVs (13.3%) among the three molecular groups, followed by the HR + and HER2- group (5.9%), and the lowest was in the HER2 + group (2.5%). CONCLUSION: Our study provides the most comprehensive information to date on the prevalence of BRCA1/2 PVs in unselected Chinese patients with breast cancer.

Ovarian cancer risk of Chinese women with BRCA1/2 germline pathogenic variants.

Estimating the lifetime risk of ovarian cancer in Chinese women with BRCA1/2 germline pathogenic variants (PVs) is of great importance for the clinical management of BRCA1/2 carriers. This cohort study recruited 9903 unselected Chinese breast cancer patients whose BRCA1/2 status was determined. Of these, 3984 probands completed family history questionnaires, which investigated the health status of their relatives, including 11,997 female first-degree relatives. The ovarian cancer risk of BRCA1/2 germline pathogenic carriers was estimated using the ovarian cancer history of proband first-degree female relatives via the Kin-cohort method. Of the 3984 probands, 126 (3.2%) carried BRCA1 PVs, and 183 (4.6%) carried BRCA2 PVs. The estimated cumulative risks of ovarian cancer by age 70 were 15.3% (95% CI 8.4-18.6%) for BRCA1 carriers, 5.5% (95% CI 2.0-10.2%) for BRCA2 carriers, and 0.4% (95% CI 0.3-0.7%) for noncarriers. The cumulative risks of ovarian cancer were very low before the age of 40 for both BRCA1 and BRCA2 carriers and were an increase up to age 45. The cumulative ovarian cancer risk of BRCA1 carriers was approximately three times higher than that of BRCA2 carriers, and BRCA1 and BRCA2 carriers had 38- and 14-fold higher risks than non-BRCA carriers, respectively. The findings indicate that Chinese women with BRCA1/2 PVs have high risks of ovarian cancer in their lifetime, especially BRCA1 carriers. These results are useful for devising optimal strategies to reduce ovarian cancer risk in BRCA1/2 carriers.

Comprehensive analysis of BRCA1 and BRCA2 germline mutations in a large cohort of 5931 Chinese women with breast cancer.

We determined the prevalence and characteristics of BRCA1/2 germline mutations in a large cohort of Chinese women with breast cancer. A total of 5931 unselected Chinese women with breast cancer were enrolled in this study and underwent testing for BRCA1/2 mutations. Of these, 543 patients were familial breast cancer, 1033 were early-onset disease (≤40 years) without family history of breast cancer, and 4355 were sporadic breast cancer. In total, 232 patients (3.9 %) carried a BRCA1 or BRCA2 mutation (110 in BRCA1and 122 in BRCA2) in this cohort of 5931 patients. BRCA1/2 mutation rate was 16.9 % (92/543) in familial breast cancers, 5.2 % (54/1033) in early-onset breast cancers (≤40 years), and 2.0 % in sporadic breast cancers (>40 years), respectively. The BRCA1/2 mutation rate was 27.0 % in 111 familial breast cancers diagnosed at and before the age of 40. 41.4 % of mutations in this cohort were specific for Chinese population. Recurrent mutations accounted for 44.8 % of the entire mutations in 2382 cases that BRCA1 and BRCA2 genes were fully sequenced in this study. Both BRCA1 and BRCA2 mutation carriers were significantly more likely to be early-onset and bilateral breast cancers, high-grade cancer, and to have a family history of breast cancer compared with non-carriers. BRCA1 mutation carriers were more likely to be triple-negative cancer than BRCA2 mutation carriers and non-carriers. Our data provide guidelines for Chinese women with breast cancer who should undergo BRCA1/2 genetic testing; additionally, recurrent mutations account for nearly half of the mutations and some of them are specific for Chinese women.

TP53 mutations are associated with higher rates of pathologic complete response to anthracycline/cyclophosphamide-based neoadjuvant chemotherapy in operable primary breast cancer.

The role of TP53 mutations in predicting response to neoadjuvant chemotherapy in breast cancer remains controversial. The aims of this study were to investigate whether TP53 mutations were associated with response and survival in breast cancer patients who received neoadjuvant chemotherapy. Therefore, we identified TP53 mutations in the core-needle biopsy tumor samples obtained before the neoadjuvant chemotherapy from 351 operable primary breast cancer patients who either received anthracycline/cyclophosphamide-based (n = 252) or paclitaxel (n = 99) neoadjuvant chemotherapy. We found that 41.0% (144 of 351) of patients harbored TP53 mutations, and 14.8% of patients achieved a pCR (pathologic complete response) after neoadjuvant chemotherapy. Among patients treated with anthracycline/cyclophosphamide (n = 252), patients with TP53 mutations had a significantly higher pCR rate than those with wild-type (28.6 vs.7.1%; p < 0.001), and TP53 mutation was an independent favorable predictor of pCR [odds ratio (OR) = 3.41; 95% confidence interval (CI) 1.50-7.77; p = 0.003] in this group; moreover, patients with TP53 mutation had a better distant recurrence-free survival (DRFS) than those with wild-type [unadjusted hazard ratio (HR) = 0.43; 95% CI 0.20-0.94; p = 0.030] in this group. Among patients treated with paclitaxel (n = 99), no significant difference in pCR rates was observed between patients with or without TP53 mutations (15.2 vs. 11.3%; p = 0.57). Our results suggested that patients with TP53 mutations are more likely to respond to anthracycline/ cyclophosphamide-based neoadjuvant chemotherapy and have a favorable survival.

Association of PIK3CA Mutation Status before and after Neoadjuvant Chemotherapy with Response to Chemotherapy in Women with Breast Cancer.

PURPOSE: The association between PIK3CA mutations and response to neoadjuvant chemotherapy in women with primary breast cancer is not fully elucidated. EXPERIMENTAL DESIGN: PIK3CA mutations in breast cancer tissues that were taken prior to the initiation of neoadjuvant chemotherapy were identified in 729 operable primary breast cancer patients who received neoadjuvant chemotherapy. Among these, the PIK3CA mutations were also reassessed in tumor tissues procured following operation in 102 patients after completion of neoadjuvant chemotherapy. RESULTS: A total of 206 out of 729 (28.3%) patients had PIK3CA mutations, and 19.5% of patients (142/729) in this cohort achieved a pathologic complete response (pCR) after neoadjuvant chemotherapy. Patients with PIK3CA mutations exhibited a lower pCR rate than did those with wild-type (14.6% vs. 21.4%, P = 0.035). No significant differences in disease-free survival (DFS) or distant disease-free survival (DDFS) were observed between PIK3CA mutant and wild-type in the entire study population. Among the 102 patients with PIK3CA mutation statuses available before and after neoadjuvant chemotherapy, 24 patients (23.5%) had PIK3CA mutations before neoadjuvant chemotherapy. Of these 24 patients, 15 patients retained their initial PIK3CA mutations and 9 patients lost their initial mutations after neoadjuvant chemotherapy. Patients who retained the initial mutations after neoadjuvant chemotherapy (n = 15) had a worse DDFS than the remaining patients (n = 87) in this subgroup [unadjusted HR, 2.34; 95% confidence interval (CI), 0.98-5.62; P = 0.050]. CONCLUSIONS: Patients with PIK3CA mutations are less likely to respond to neoadjuvant chemotherapy. Patients who retain their initial PIK3CA mutations after neoadjuvant chemotherapy have an unfavorable survival.

Surface characterization and monitoring of surface changes after conservation treatments of silver gelatin photographic papers using confocal microscopy.

Surface metrology techniques that are non-perturbing (non-contact, non-invasive, and non-destructive) are well suited to in situ surface studies of historical and fine art photographs. They allow for the quantitative examination of the microstructure of the photograph surface, thereby, offering an important advancement in the examination, documentation, and characterization of silver gelatin photographs and other modern and/or historic imaging materials. This article presents the application of an optical confocal scanning disk microscopy system to the qualitative and quantitative characterization and assessment of a silver gelatin photographic paper, Ilford Glossy, submitted to different humidification and flattening protocols.

Electrochemiluminescence from tris(2,2'-bipyridyl)ruthenium(II)-graphene-Nafion modified electrode.

An electrochemiluminescence (ECL) sensor based on Ru(bpy)(3)(2+)-graphene-Nafion composite film was developed. The graphene sheet was produced by chemical conversion of graphite, and was characterized by atomic force microscopy (AFM), scanning electron microscopy (SEM), and Raman spectroscopy. The introduction of conductive graphene into Nafion not only greatly facilitates the electron transfer of Ru(bpy)(3)(2+), but also dramatically improves the long-term stability of the sensor by inhibiting the migration of Ru(bpy)(3)(2+) into the electrochemically inactive hydrophobic region of Nafion. The ECL sensor gives a good linear range over 1x10(-7) to 1x10(-4)M with a detection limit of 50 nM towards the determination of tripropylamine (TPA), comparable to that obtained by Nafion-CNT. The ECL sensor keeps over 80% and 85% activity towards 0.1 mM TPA after being stored in air and in 0.1M pH 7.5 phosphate buffer solution (PBS) for a month, respectively. The long-term stability of the modified electrode is better than electrodes modified with Nafion, Nafion-silica, Nafion-titania, or sol-gel films containing Ru(bpy)(3)(2+). Furthermore, the ECL sensor was successfully applied to the selective and sensitive determination of oxalate in urine samples.

Hydrogen peroxide biosensor based on direct electrochemistry of soybean peroxidase immobilized on single-walled carbon nanohorn modified electrode.

Single-walled carbon nanohorns (SWCNHs) were used as a novel and biocompatible matrix for fabricating biosensing devices. The direct immobilization of acid-stable and thermostable soybean peroxidase (SBP) on SWCNH modified electrode surface can realize the direct electrochemistry of enzyme. Cyclic voltammogram of the adsorbed SBP displays a pair of redox peaks with a formal potential of -0.24 V in pH 5 phosphate buffer solution. The formal potential has a linear relationship with pH from 3 to 9 with a slope of -48.7 mV/pH, close to the value of -55.7 mV/pH expected at 18 degrees C for the reversible transfer of one proton and one electron. Bioactivity of SBP remains good in SWCNH microenvironment, along with effective catalysis of the reduction of H(2)O(2). In the absence of a mediator, this H(2)O(2) biosensor exhibited a high sensitivity (16.625 microAL/mmol), a linear range from 0.02 to 1.2 mmolL(-1), and a detection limit of 5.0 x 10(-7) mmolL(-1), as well as acceptable preparation reproducibility and excellent stability.

Selective synthesis of single-crystalline rhombic dodecahedral, octahedral, and cubic gold nanocrystals.

This paper reports a versatile seed-mediated growth method for selectively synthesizing single-crystalline rhombic dodecahedral, octahedral, and cubic gold nanocrystals. In the seed-mediated growth method, cetylpyridinium chloride (CPC) and CPC-capped single-crystalline gold nanocrystals 41.3 nm in size are used as the surfactant and seeds, respectively. The CPC-capped gold seeds can avoid twinning during the growth process, which enables us to study the correlations between the growth conditions and the shapes of the gold nanocrystals. Surface-energy and kinetic considerations are taken into account to understand the formation mechanisms of the single-crystalline gold nanocrystals with varying shapes. CPC surfactants are found to alter the surface energies of gold facets in the order {100} > {110} > {111} under the growth conditions in this study, whereas the growth kinetics leads to the formation of thermodynamically less favored shapes that are not bounded by the most stable facets. The competition between AuCl(4)(-) reduction and the CPC capping process on the {111} and {110} facets of gold nanocrystals plays an important role in the formation of the rhombic dodecahedral (RD) and octahedral gold nanocrystals. Octahedral nanocrystals are formed when the capping of CPC on {111} facets dominates, while RD nanocrystals are formed when the reduction of AuCl(4)(-) on {111} facets dominates. Cubic gold nanocrystals are formed by the introduction of bromide ions in the presence of CPC. The cooperative work of cetylpyridinium and bromide ions can stabilize the gold {100} facet under the growth condition in this study, thereby leading to the formation of cubic gold nanocrystals.