Training in genetics and genomics for primary health care workers

Cornel, M.C. [Promotor]Dinant, G.J. [Promotor]Vleuten, C.P.M. van der [Copromotor]Henneman, L. [Copromotor

Assessing associations between the AURKAHMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers

While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood appr

A literature review

Introduction: Genetic counselling is an increasingly current subject area especially its branch of oncogenetics due to the prevalence of hereditary neoplastic syndromes. The scientific and technological evolution associated with this matter has made genetic testing available to the population, increasing the need and importance of introducing genetic counselling into the national health system (NHS) for appropriate guidance and support of patients and their families. However, this is still an area with little visibility and awareness by other medical professionals, which translates as few specialised professionals, and therefore, scarce specialised services. This portrays that the awareness for the inclusion of these services within the national health system (NHS) is present, however, there are still barriers that need to be overcome to fully reach all the patients and families in need. Objective: The main objective of this study is to understand how Portugal has developed its genetic counselling practice and how it is organised at a national level. As secondary objectives this review aims to Identify development of genetic counselling in Portugal, and how it has been able to reach all the patients and families in need of these services, identify new opportunities for development and enhancement of genetic counselling practice in Portugal and compare genetic counselling practice in Portugal with other European countries, through a descriptive literature review. Methods: Research of scientific articles in the Pubmed, ResearchOnly, Google Scholar and UpToDate databases, and use of bibliographic references. Results: Portugal has initiated this introduction by creating a master’s degree, having legislation related to the subject, having developed guidelines and recommendation for oncogenetic patients, and by having a national association of genetic counsellors (APPAcGen), as well as be part of international associations, such as the European Society of Human Genetics. Genetic counselling is integrated into some medical services and is part of the medical practice in Portugal, however, there is still a lack of specialised professionals and integration of these in multidisciplinary teams within the NHS. Conclusion: Portugal has initiated the development of this area within its services, however, as it still is an unrecognised medical profession, its inclusion within the NHS is hard and has shown to have many barriers. At a European level, Portugal is heading the right direction, accompanying many other European countries in the development of this subject area.Introdução: Aconselhamento genético é uma área cada vez mais presente, especialmente o ramo de oncogenética devido à prevalência das síndromes neoplásicos hereditários. Dado o desenvolvimento de técnicas de identificação e diagnóstico de variantes patogénicas, levou a que mais utentes e as suas famílias tivessem ao seu dispor testes genéticos. Neste sentido, a introdução de aconselhamento genético (AG) nos serviços de saúde tornou-se imprescindível para que os utentes e suas famílias que passam por este processo possam ter algum acompanhamento especializado que os ajude a nível psicológico, social, pessoal e profissional durante todo o processo. Em Portugal, a especialidade de Genética Médica foi reconhecida pela Ordem dos Médicos em 1998, disponibilizando desde essa data a consulta de AG a todos os utentes, não obstante, esta continua a ser uma área com pouca visibilidade e conhecimento por parte da população médica, assim como da população em geral. Objetivos: O objetivo principal desta revisão é perceber a organização dos serviços de AG na área oncológica em Portugal, quais as organizações e recomendações existentes. Compreender a envolvência desta temática no SNS, e a sua participação a nível europeu. Métodos: Pesquisa bibliográfica na base de dados Pubmed, ResearchOnly, UptoDate e Google Scholar. Uso de referências bibliográficas de artigos selecionados, como também o uso de livros e jornais indexados, relacionados com a temática da dissertação. Resultados: Portugal encontra-se numa fase de desenvolvimento, com legislação publicada referente a testes genéticos e AG. Iniciou também um mestrado profissionalizante nesta área, de maneira a aumentar a formação que é escassa. Portugal faz parte de associações europeias que visam desenvolver diretrizes consensuais a nível internacional, como também tem uma associação de profissionais de AG a nível nacional (APPAcGen). Esta associação engloba todos os aspetos de AG, como a organização dos serviços no SNS, critérios de referência dos utentes, entre outras informações relevantes tanto para profissionais de saúde como para a população em geral. Na área de oncogenética, o facto de no SNS haver hospitais oncológicos levou a que esta área fosse desenvolvida e fosse criado guias de orientação terapêutica para estes pacientes e suas famílias. Estes guias ajudam os profissionais de saúde a referenciar os pacientes quando necessário, como também a identificar a necessidade de AG para estes casos. Existe neste momentos alguns serviços com AG integrado, porém continua a ser escasso e pouco suficiente para toda a população que necessita destes cuidados. Conclusão: Em Portugal, diferente do que acontece em outros países europeus, o AG é da responsabilidade do médico geneticista e não de um técnico de AG. Há um grande desconhecimento no que concerne a esta área quer pela população em geral, quer pelos próprios profissionais de saúde, como uma necessidade cada vez maior de ter equipas multidisciplinares nesta área

The CHEK2 Variant C.349A>G Is Associated with Prostate Cancer Risk and Carriers Share a Common Ancestor.

The identification of recurrent founder variants in cancer predisposing genes may have important implications for implementing cost-effective targeted genetic screening strategies. In this study, we evaluated the prevalence and relative risk of the CHEK2 recurrent variant c.349A>G in a series of 462 Portuguese patients with early-onset and/or familial/hereditary prostate cancer (PrCa), as well as in the large multicentre PRACTICAL case-control study comprising 55,162 prostate cancer cases and 36,147 controls. Additionally, we investigated the potential shared ancestry of the carriers by performing identity-by-descent, haplotype and age estimation analyses using high-density SNP data from 70 variant carriers belonging to 11 different populations included in the PRACTICAL consortium. The CHEK2 missense variant c.349A>G was found significantly associated with an increased risk for PrCa (OR 1.9; 95% CI: 1.1-3.2). A shared haplotype flanking the variant in all carriers was identified, strongly suggesting a common founder of European origin. Additionally, using two independent statistical algorithms, implemented by DMLE+2.3 and ESTIAGE, we were able to estimate the age of the variant between 2300 and 3125 years. By extending the haplotype analysis to 14 additional carrier families, a shared core haplotype was revealed among all carriers matching the conserved region previously identified in the high-density SNP analysis. These findings are consistent with CHEK2 c.349A>G being a founder variant associated with increased PrCa risk, suggesting its potential usefulness for cost-effective targeted genetic screening in PrCa families

Assessing Associations between the AURKA-HMMR-TPX2-TUBG1 Functional Module and Breast Cancer Risk in BRCA1/2 Mutation Carriers

While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04-1.15, p = 1.9 x 10(-4) (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03-1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted pinteraction values > 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients' survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers

Chemometrics Methods for Specificity, Authenticity and Traceability Analysis of Olive Oils: Principles, Classifications and Applications

International audienceBackground. Olive oils (OOs) show high chemical variability due to several factors of genetic, environmental and anthropic types. Genetic and environmental factors are responsible for natural compositions and polymorphic diversification resulting in different varietal patterns and phenotypes. Anthropic factors, however, are at the origin of different blends' preparation leading to normative, labelled or adulterated commercial products. Control of complex OO samples requires their (i) characterization by specific markers; (ii) authentication by fingerprint patterns; and (iii) monitoring by traceability analysis.Methods. These quality control and management aims require the use of several multivariate statistical tools: specificity highlighting requires ordination methods; authentication checking calls for classification and pattern recognition methods; traceability analysis implies the use of network-based approaches able to separate or extract mixed information and memorized signals from complex matrices. Results. This chapter presents a review of different chemometrics methods applied for the control of OO variability from metabolic and physical-chemical measured characteristics. The different chemometrics methods are illustrated by different study cases on monovarietal and blended OO originated from different countries.Conclusion. Chemometrics tools offer multiple ways for quantitative evaluations and qualitative control of complex chemical variability of OO in relation to several intrinsic and extrinsic factors

The CHEK2 Variant C.349A>G Is Associated with Prostate Cancer Risk and Carriers Share a Common Ancestor

Simple SummaryIt is well-recognised the strong contribution of genetic factors to prostate cancer (PrCa) susceptibility, thus genetic screening is critical for presymptomatic diagnosis and identification of individuals at high-risk. In this context, recurrent founder variants in cancer predisposing genes, by providing specific targets for early identification of carriers at risk of developing the disease, may be leveraged to implement cost-efficient targeted genetic screening strategies. The goal of this study was to investigate whether CHEK2 c.349A>G, the only recurrent "likely pathogenic" variant in CHEK2 gene reported in the Portuguese population, plays an important role in PrCa development, and the possibility of a founder effect behind its origin. Our results clearly demonstrate that c.349A>G in the CHEK2 tumour-suppressor gene is a founder variant significantly associated with an increased risk of PrCa, suggesting its potential usefulness for cost-effective targeted genetic screening in PrCa families.The identification of recurrent founder variants in cancer predisposing genes may have important implications for implementing cost-effective targeted genetic screening strategies. In this study, we evaluated the prevalence and relative risk of the CHEK2 recurrent variant c.349A>G in a series of 462 Portuguese patients with early-onset and/or familial/hereditary prostate cancer (PrCa), as well as in the large multicentre PRACTICAL case-control study comprising 55,162 prostate cancer cases and 36,147 controls. Additionally, we investigated the potential shared ancestry of the carriers by performing identity-by-descent, haplotype and age estimation analyses using high-density SNP data from 70 variant carriers belonging to 11 different populations included in the PRACTICAL consortium. The CHEK2 missense variant c.349A>G was found significantly associated with an increased risk for PrCa (OR 1.9; 95% CI: 1.1-3.2). A shared haplotype flanking the variant in all carriers was identified, strongly suggesting a common founder of European origin. Additionally, using two independent statistical algorithms, implemented by DMLE+2.3 and ESTIAGE, we were able to estimate the age of the variant between 2300 and 3125 years. By extending the haplotype analysis to 14 additional carrier families, a shared core haplotype was revealed among all carriers matching the conserved region previously identified in the high-density SNP analysis. These findings are consistent with CHEK2 c.349A>G being a founder variant associated with increased PrCa risk, suggesting its potential usefulness for cost-effective targeted genetic screening in PrCa families

Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Peer reviewe