The past two decades have brought many important advances in our understanding of the hereditary susceptibility to cancer. Approximately 5-10% of all cancers are inherited, the majority in an ...autosomal dominant manner with incomplete penetrance. While this is a small fraction of the overall cancer burden worldwide, the molecular genetic discoveries that have resulted from the study of families with heritable cancer have not only changed the way these families are counselled and managed, but have shed light on molecular regulatory pathways important in sporadic tumour development as well. In this review, we consider 10 of the more highly penetrant cancer syndromes, with emphasis on those predisposing to breast, colon, and/or endocrine neoplasia. We discuss the prevalence, penetrance, and tumour spectrum associated with these syndromes, as well as their underlying genetic defects.
ABSTRACT
Purpose
This study examined whether a
CYP2D6
polymorphism (
CYP2D6
*4) was related to beta-blocker maintenance dose in patients with heart failure.
Methods
Logistic regression modeling was ...utilized in a retrospective chart-review analysis of heart-failure patients (60% Male, 90% of European descent) to assess whether
CYP2D6
*4 (non-functional
CYP2D6
allele present in 1 of 5 individuals of European descent) is associated with maintenance dose of carvedilol (
n
= 65) or metoprolol (
n
= 33).
Results
CYP2D6
*4 was associated with lower maintenance dose of metoprolol (OR 0.13 95% CI 0.02–0.75
p
= 0.023), and a trend was observed between
CYP2D6
*4 and higher maintenance dose of carvedilol (OR 2.94 95% CI 0.84–10.30
p
= 0.093). None of the patients that carried
CYP2D6
*4 achieved the recommended target dose of metoprolol (200 mg/day).
Conclusion
Consistent with the role of CYP2D6 in the metabolism of metoprolol, the tolerated maintenance dose of metoprolol was lower in
CYP2D6
*4 carriers compared to non-carriers. Consistent with the role of CYP2D6 in activation of carvedilol, tolerated maintenance dose of carvedilol was higher in
CYP2D6
*4 carriers compared to non-carriers. Further investigation is warranted to ascertain the potential of
CYP2D6
as a potential predictive biomarker of beta-blocker maintenance dose in heart failure patients.
Twenty percent of individuals with a strong family and/or personal history of breast and ovarian cancer carry a deleterious mutation in BRCA1 or BRCA2. Identification of mutations in these genes is ...extremely beneficial for patients pursuing risk reduction strategies. Approximately 7% of individuals who have genetic testing of BRCA1 and BRCA2 carry a variant of uncertain significance (VUS), making clinical management less certain. The majority of identified VUS occur only in one to two individuals; these variants are not able to be classified using current classification models with segregation analysis components.
To develop a clinically applicable method that can predict the pathogenicity of VUS that does not require familial information or segregation analysis, we identified characteristics of breast or ovarian tumors that distinguished sporadic tumors from tumors with BRCA1 or BRCA2 mutations. Study participants included individuals with known deleterious mutations in BRCA1 or BRCA2 and individuals with classified or unclassified BRCA variants.
We applied the models to 57 tumors with 43 different deleterious BRCA mutations and 57 tumors with 54 unique classified and unclassified BRCA variants. Of the 33 previously unclassified VUS studied, we found evidence of neutrality for 21.
Our models showed 98% sensitivity and 76% specificity for predicting classified DNA changes. We classified 64% of unknown variants as neutral. Classification of VUS as neutral will have immediate benefit for those individuals and their family members. These models are adaptable for the clinic and will be useful for individuals with limited available family history.
As software interfaces become more intuitive and require less technical expertise, the robotic arm is not only becoming a tool for automating bespoke construction, it is becoming a tool to help bring ...the concept of the “Master Builder” back to the architectural profession. Being analogous to a human arm, it is easy to imagine limitless possibilities the robotic arm. However, understanding and utilizing it for the purpose of construction requires more knowledge than just imagining it as prosthetic. Besides a fundamental understanding of the digital workflow from the initial design based data (3D modelling) to machine understandable data (proprietary output code), it requires the design and conception of the robot's physical environment from the tool at the end of its arm (end effector) to its physical surroundings(work cell). Contemporary software tools provide the capabilities for manufacturing purposes and allow for virtual simulations of the production process, ensuring higher rates of success for construction. It is the crossover between the virtual environment and the physical world that will empower architects of the future to reclaim the title of master builders as they will be required to not only comprehend but design and participate in the entire building process inclusive of the manufacturing of components. This paper outlines a pedagogical framework to introduce the multi-layered levels of knowledge to students of architecture that will allow them to use a 6-axis robotic arm for the purpose of automated construction, making them aware of a new and complex building process that will be integral to redefining architecture in the near future.
•Architectural curriculum needs to be redefined to provide for the complexity of future building techniques.•Understanding the entire workflow from design to manufacture will help architects become master builders again.•Pedagogical framework for contemporary architectural design and building strategies
Recent reports have observed that individuals with serrated polyps, some of whom meet the clinical diagnostic criteria for Serrated Polyposis Syndrome (SPS), are among those who carry germline ...mutations in genes associated with polyposis syndromes including; (1) genes known to underlie hamartomatous polyposes (SMAD4, BMPR1A, and PTEN), (2) MUTYH-associated polyposis and (3) GREM1 in Hereditary Mixed Polyposis Syndrome (HMPS). The aim of this study was to characterise individuals fulfilling the current WHO criteria for SPS for germline mutations in these polyposis-associated genes.
A total of 65 individuals with SPS (fulfilling WHO criteria 1 or 3), were recruited to the Genetics of Serrated Neoplasia study between 2000 and 2012, through multiple Genetics or Family Cancer Clinics within Australia, or from the New Zealand Familial Gastrointestinal Cancer Service. Individuals with SPS were tested for coding mutations and large deletions in the PTEN, SMAD4, and BMPR1A genes, for the MUTYH variants in exons 7 (Y179C) and 13 (G396D), and for the duplication upstream of GREM1.
We found no variants that were likely to be deleterious germline mutations in the SPS cases in the PTEN, SMAD4, and BMPR1A genes. A novel variant in intron 2 (c.164+223T>C) of PTEN was identified in one individual and was predicted by in silico analysis to have no functional consequences. One further individual with SPS was found to be mono-allelic for the MUTYH G396D mutation. No individuals carried the recently reported duplication within GREM1.
Genes involved in the gastrointestinal hamartomatous polyposis, Hereditary Mixed Polyposis Syndrome and MUTYH-associated polyposis syndromes are not commonly altered in individuals with SPS.
Abstract A 7-year-old boy with a history of spasticity, global developmental delay, and seizures was given the general diagnosis of cerebral palsy at an early age. Chromosomal array analysis ...performed at an outside center was normal. The patient's family sought neurodevelopmental pediatric care at a new institution following a move out of state. Electroencephalography confirmed abnormal epileptogenic activity. Brain magnetic resonance imaging showed findings consistent with a tubulin gene defect (tubulinopathy) and of focal cortical dysplasia, as well as evidence of a remote occipital lobe injury. This case report describes the various brain magnetic resonance findings suggestive of a tubulin gene defect and raises the possibility of focal cortical dysplasia manifesting as a result of tubulin dysfunction.
Genetic literacy is essential for the effective integration of genomic information into healthcare; yet few recent studies have been conducted to assess the current state of this knowledge base. ...Participants in the Coriell Personalized Medicine Collaborative (CPMC), a prospective study assessing the impact of personalized genetic risk reports for complex diseases and drug response on behavior and health outcomes, completed genetic knowledge questionnaires and other surveys through an online portal. To assess the association between genetic knowledge and genetic education background, multivariate linear regression was performed. 4 062 participants completed a genetic knowledge and genetic education background questionnaire. Most were older (mean age: 50), Caucasian (90 %), female (59 %), highly educated (69 % bachelor’s or higher), with annual household income over $100 000 (49 %). Mean percent correct was 76 %. Controlling for demographics revealed that health care providers, participants previously exposed to genetics, and participants with ‘better than most’ self-rated knowledge were significantly more likely to have a higher knowledge score (
p
< 0.001). Overall, genetic knowledge was high with previous genetic education experience predictive of higher genetic knowledge score. Education is likely to improve genetic literacy, an important component to expanded use of genomics in personalized medicine.
Information on patients' preferences is essential to guide the development of more efficient genomic counseling service delivery models. We examined patient preferences in the context of use of a ...post-test genomic counseling framework on patients (
= 44) with chronic disease receiving online test reports for eight different diseases and one drug-response result. We also explored patients' disease risk awareness, recall of test report information, and confidence in knowing what to do with their test results. Prior to the post-test genomic counseling session, all participants viewed at least one test report; 81.6% of available test reports were reviewed in total. Participants requested more phone (36) than in-person counseling sessions (8), and phone sessions were shorter (mean 29.1 min; range 12⁻75 min) than in-person sessions (mean 52.8 min; range 23⁻85 min). A total of 182 test reports were discussed over the course of 44 counseling sessions (mean 4.13, range 1⁻9). Thirty-six (81.8%) participants requested assessment for additional medical/family history concerns. In exploring patient experiences of disease risk awareness and recall, no significant differences were identified in comparison to those of participants (
= 199) that had received in-person post-test genomic counseling in a parent study randomized controlled trial (RCT). In summary, a novel post-test genomic counseling framework allowed for a tailored approach to counseling based on the participants' predetermined choices.
The general public continues to show increased interest and uptake of Direct-to-Consumer (DTC) genetic testing. We conducted an online survey (N = 405) to assess genetics knowledge, interest, and ...outcome expectancy of DTC genetic testing before and after exposure to a sample DTC disclaimer message. Descriptive statistics were used to analyze the relationship between previous genetic knowledge, attitudes and self-reported systematic processing of a sample DTC disclaimer message, outcome expectancies, and interest to pursue DTC genetic testing. Increased genetic knowledge and more positive attitudes towards DTC genetic testing were associated with increased self-reported systematic processing of the DTC disclaimer message. Further, self-reported systematic processing of the DTC disclaimer message was associated with greater interest in pursuing DTC genetic testing but did not predict outcome expectancies. As DTC genetic testing continues to gain in popularity and usage, additional research is imperative to better understand participants' motivations and processing of the DTC disclaimer messages to improve the user experience.
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