Genotype-phenotype correlations among <Emphasis Type="Italic">BRCA1</Emphasis>4153delA and 5382insC mutation carriers from Latvia

Background

Mutations in the high penetrance breast and ovarian cancer susceptibility gene BRCA1 account for a significant percentage of hereditary breast and ovarian cancer cases. Genotype-phenotype correlations of BRCA1 mutations located in different parts of the BRCA1 gene have been described previously; however, phenotypic differences of specific BRCA1 mutations have not yet been fully investigated. In our study, based on the analysis of a population-based series of unselected breast and ovarian cancer cases in Latvia, we show some aspects of the genotype-phenotype correlation among the BRCA1 c.4034delA (4153delA) and c.5266dupC (5382insC) founder mutation carriers.

Methods

We investigated the prevalence of the BRCA1 founder mutations c.4034delA and c.5266dupC in a population-based series of unselected breast (n = 2546) and ovarian (n = 795) cancer cases. Among the BRCA1 mutation carriers identified in this analysis we compared the overall survival, age at diagnosis and family histories of breast and ovarian cancers.

Results

We have found that the prevalence of breast and ovarian cancer cases (breast: ovarian cancer ratio) differs significantly among the carriers of the c.5266dupC and c.4034delA founder mutations (OR = 2.98, 95%CI = 1.58 to 5.62, P < 0.001). We have also found a difference in the prevalence of breast and ovarian cancer cases among the 1^st and 2^nd degree relatives of the c.4034delA and c.5266dupC mutation carriers. In addition, among the breast cancer cases the c.4034delA mutation has been associated with a later age of onset and worse clinical outcomes in comparison with the c.5266dupC mutation.

Conclusions

Our data suggest that the carriers of the c.4034delA and c.5266dupC founder mutations have different risks of breast and ovarian cancer development, different age of onset and prognosis of breast cancer.

     

Population screening for hereditary and familial cancer syndromes in Valka district of Latvia

Background

The growing possibilities of cancer prevention and treatment as well as the increasing knowledge about hereditary cancers require proper identification of the persons at risk. The aim of this study was to test the outcome of population screening in the scientific and practical evaluation of hereditary cancer.

Methods

Population screening for hereditary cancer was carried out retrospectively in a geographic area of Latvia. Family cancer histories were collected from 18642 adults representing 76.6% of the population of this area. Hereditary cancer syndromes were diagnosed clinically. Molecular testing for BRCA1 founder mutations 300 T/G, 4153delA and 5382insC was conducted in 588 persons who reported at least one case of breast or ovary cancer among blood relatives.

Results

Clinically, 74 (0.40%; 95% confidence interval (CI): 0.32 - 0.50%) high-risk and 548 (2.94%, 95% CI: 2.71 - 3.19) moderate-risk hereditary cancer syndromes were detected covering wide cancer spectrum. All syndromes were characterised by high cancer frequency among blood relatives ranging 8.6 - 46.2% in contrast to spouse correlation of 2.5 - 3.6%. The mean age of cancer onset ranged 38.0 - 72.0 years in different syndromes. The BRCA1 gene mutations were identified in 10 (1.7%; 95% CI: 0.9 - 3.1%) probands. Families with established BRCA1 gene founder mutations were identified with the frequency 1:2663 clinically screened persons.

Conclusions

Population screening is a useful practical tool for the identification of persons belonging to families with high frequency of malignant tumours. The whole hereditary and familial cancer spectrum along with the age structure was identified adjusting follow-up guidelines. Another benefit of the population screening is the possibility to identify oncologically healthy persons belonging to hereditary and familial cancer families so that appropriate surveillance can be offered. Clinical diagnostics is appropriate for population screening purposes; molecular investigation provides additional information. In collaboration with family doctors, the screening is technically manageable as characterised by high compliance.     

Underestimated survival predictions of the prognostic tools Adjuvant! Online and PREDICT in BRCA1-associated breast cancer patients

BRCA1-associated breast cancer is considered an unique clinical entity with its own specific histopathological characteristics. Several recently published large studies have shown that overall survival of BRCA1 mutation carriers having breast cancer is similar to sporadic breast cancer patients. It was also suggested that better response to chemotherapy is one of the most important factors that improves the clinical outcome of breast cancers with unfavorable histopathological subtypes in BRCA1 mutation carriers. Adjuvant! Online and PREDICT are web-based prognostic tools that estimate the survival benefit of adjuvant chemotherapy in primary breast cancer patients. These tools have been extensively validated in different populations; however, the accuracy of the predictions made by Adjuvant! Online and PREDICT among BRCA1 mutation carriers has not yet been investigated. In this study we have found, that predictions of overall and breast cancer-specific survival obtained from Adjuvant! Online and PREDICT were significantly lower than the observed survival percentages in the study population [predicted—observed difference for 10–year overall survival: ?9.75 %, P < 0.0001 (Adjuvant! Online); ?10.21 %, P < 0.0001 (PREDICT)]. Thus this study suggests that Adjuvant! Online and PREDICT should be used with caution in this group of patients. Further updating of adjuvant therapy benefit calculation tools by inclusion of the information about inherited genetic alterations should be considered to improve the performance of the prognostic programs among hereditary breast cancer patients.     

Threaded versus porous-surfaced implants as anchorage units for orthodontic treatment: three-dimensional finite element analysis of peri-implant bone tissue stresses

PURPOSE: A 3-dimensional finite element model was developed to investigate the cause of different crestal bone loss patterns observed around sintered porous-surfaced and machined (turned) threaded dental implants used for orthodontic anchorage in a previously reported animal study. MATERIALS AND METHODS: Twenty-noded structural solid elements with parabolic interpolation between nodes were used for modeling the bone-implant interface zone. A 3-N traction force acting between either 2 porous-surfaced or 2 machined threaded implants placed in canine premolar mandibular sites and bone profiles observed at initiation and 22 weeks of orthodontic loading were modeled. RESULTS: Higher maximum stresses in peri-implant bone next to the coronal region of the implants were predicted with the machined threaded implants at both the initial and final time points, with the values 20% greater than those predicted after the 22-week loading period. These values were approximately 200% greater than those predicted for the porous-surfaced implants, for which a more uniform stress distribution was predicted. DISCUSSION: The finite element model results indicated that the observed greater retention of crestal bone next to the porous-surfaced implants was attributable to lower peak stresses developing in crestal peri-implant bone with this design, which decreased the probability of bone loss related to local overstressing and bone microfracture. CONCLUSION: The predicted lower stresses were a result of the more uniform transfer of force from implant to bone with the porous-surfaced implants, which was a consequence of the interlocking of bone and implant possible with this design.     

Modification of the Structure and Properties of Lightweight Cement Composite with PVA Fibers

This study addresses the application of polyvinyl alcohol (PVA) fibers to improve the performance of lightweight cement composites with pozzolans. Blended cement mixes based on expanded glass granules were modified with PVA fibers (Type A: Ø40 µm, L = 8 mm and Type B: Ø200 µm, L = 12 mm). The following research methods were used to analyse the effect of the fibers on the structure of cement matrix and physical-mechanical properties of lightweight composite: SEM, XRD, DTG, calorimetry tests, and standard test methods of physical and mechanical properties. Results from the tests showed that a denser layer of hydrates was formed around the PVA fiber and the amounts of portlandite, CSH, and CASH formed in the specimens with PVA were found to be higher. PVA fibers of Type A accelerated hydration of the cement paste, slightly increased the compressive strength of the lightweight composite, but had no significant effect on the values of density, ultrasonic pulse velocity and flexural strength. The shrinkage of cement composite was significantly reduced using both types of PVA fiber and both types of PVA fibers increased the fracture energy of lightweight cement composite with expanded granules.     

Creep and Shrinkage Behaviour of Disintegrated and Non-Disintegrated Cement Mortar

One way to prevent cement from ending up in landfills after its shelf life is to regain its activity and reuse it as a binder. As has been discovered, milling by planetary ball mill is not effective. Grinding by collision is considered a more efficient way to refine brittle material and, in the case of cement, to regain its activity. There has been considerable research regarding the partial replacement of cement using disintegrated cement in mortar or concrete in the past few decades. This article determines and compares the creep and shrinkage properties of cement mortar specimens made from old disintegrated, old non-disintegrated, and new non-disintegrated Portland cement. The tests show that the creep strains for old disintegrated and old non-disintegrated cement mortars are close, within a 2% margin of each other. However, the creep strains for new non-disintegrated cement mortar are 30% lower. Shrinkage for old disintegrated and non-disintegrated cement mortar is 20% lower than for new non-disintegrated cement mortar. The research shows that disintegration is a viable procedure to make old cement suitable for structural application from a long-term property standpoint. Additionally, it increases cement mortar compressive strength by 49% if the cement is disintegrated together with sand.