Understanding cancer predisposition in Singapore: What's next

Knowledge of an underlying genetic predisposition to cancer allows the use of personalised prognostic, preventive and therapeutic strategies for the patient and carries clinical implications for family members. Despite great progress, we identified six challenging areas in the management of patients with hereditary cancer predisposition syndromes and suggest recommendations to aid in their resolution. These include the potential for finding unexpected germline variants through somatic tumour testing, optimal risk management of patients with hereditary conditions involving moderate-penetrance genes, role of polygenic risk score in an under-represented Asian population, management of variants of uncertain significance, clinical trials in patients with germline pathogenic variants and technology in genetic counselling. Addressing these barriers will aid the next step forward in precision medicine in Singapore. All stakeholders in healthcare should be empowered with genetic knowledge to fully leverage the potential of novel genomic insights and implement them to provide better care for our patients.

VALIDATION OF NCCN CRITERIA FOR GENETIC TESTING IN HBOC SYNDROME IN BRAZIL / Validação dos critérios da NCCN para testagem genética na Síndrome de Câncer de Mama e Ovário Hereditários no Brasil

Objective: To identify genetic mutations in BRCA1 and BRCA2 genes in women suspected of HBOC syndrome and to correlate them with NCCN testing criteria to verify its impact on mutation finding rates, as well as to identify the relevant criteria, the frequency and type of found mutations and the relative importance of each NCCN criteria. Methodology: A database with all the cases tested for HBOC by the second author from 2010 to 2016 was built, and the variables of interest were annotated and then analyzed with a statistical package to find the relevant variables. Results: A total of 171 patients was tested and 38 had deleterious mutations (22%). Criteria with significant association to the present mutations were the total numbers of relatives with cancer (p=0.02) and Ashkenazi lineage (p=0.001). Age of the youngest relative with cancer below 49 was not significant in this sample (p=0.1). There is a strong correlation between mutated patients and NCCN criteria (p=0.0001), but we found no such correlation between the presence of NCCN testing criteria and the presence of mutation (p=0.11). Regarding the use of NCCN criteria to find BRCA mutations, sensitivity was 0.947, specificity was 0.068, PPV was 0.225 and NPP was 0.818. Accuracy was 0.263. Conclusion: The incidence of BRCA1 and BRCA2 deleterious mutations in our study was similar to that found in other populations. NCCN criteria were a poor predictor of deleterious mutation in BRCA1 and BRCA2 in general, although most mutant patients had at least one NCCN testing criteria, specially increasing number of affected relatives and Ashkenazi lineage.

Objetivo: Identificar as mutações genéticas nos genes BRCA1 e BRCA2 em mulheres com suspeita de Síndrome de Câncer de Mama e Ovário Hereditários e correlacioná-las com os critérios de testagem da National Comprehensive Cancer Network (NCCN), a fim de verificar o seu impacto nas taxas de achados de mutação, bem como identificar os critérios relevantes, a frequência e o tipo de mutações encontradas e a importância relativa de cada critério da NCCN. Metodologia: Desenvolveu-se uma base de dados com todos os casos testados para a Síndrome de Câncer de Mama e Ovário Hereditários pelo segundo autor de 2010 a 2016. As variáveis de interesse foram anotadas e, em seguida, analisadas por meio de um pacote estatístico para encontrar variáveis relevantes. Resultados: Um total de 171 pacientes foi testado e 38 apresentavam mutações prejudiciais (22%). Os critérios com uma associação significativa às mutações presentes foram os números totais de parentes com câncer (p=0,02) e a descendência Ashkenazi (p=0,001). A idade do parente mais jovem com câncer abaixo de 49 anos não foi significativa nesta amostra (p=0,1). Houve uma forte correlação entre pacientes com mutações e os critérios da NCCN (p=0,0001), mas não encontramos tal correlação entre a presença de testes de NCCN e a presença de mutação (p=0,11). Com relação ao uso dos critérios da NCCN para encontrar mutações BRCA, a sensibilidade foi de 0,947, a especificidade foi de 0,068, PPV foi de 0,225 e NPP foi de 0,818. A acurácia foi de 0,263. Conclusão: A incidência de mutações prejudiciais de BRCA1 e BRCA2 em nosso estudo foi semelhante àquela encontrada em outras populações. Os critérios da NCCN foram preditores fracos de mutação prejudicial no BRCA1 e no BRCA2 no geral, embora a maioria dos pacientes mutantes tenha tido, no mínimo, um critério de teste da NCCN, especialmente aumentando o número de parentes afetados e a descendência Ashkenazi.

Translating genomics: cancer genetics, public health and the making of the (de)molecularised body in Cuba and Brazil / Convertendo a genômica: genética do câncer, saúde pública e a formação do corpo (des)molecularizado em Cuba e no Brasil

Abstract This article examines how cancer genetics has emerged as a focus for research and healthcare in Cuba and Brazil. Drawing on ethnographic research undertaken in community genetics clinics and cancer genetics services, the article examines how the knowledge and technologies associated with this novel area of healthcare are translated and put to work by researchers, health professionals, patients and their families in these two contexts. It illuminates the comparative similarities and differences in how cancer genetics is emerging in relation to transnational research priorities, the history and contemporary politics of public health and embodied vulnerability to cancer that reconfigures the scope and meaning of genomics as “personalised” medicine.

Resumo O artigo mostra como a genética do câncer, em Cuba e no Brasil, tornou-se matéria de pesquisa, despertando maior interesse da saúde pública. Foram usadas pesquisas etnográficas realizadas em clínicas de genética comunitária e serviços de genética do câncer para averiguar como o conhecimento e as tecnologias associadas à nova área da saúde são convertidos e empregados por pesquisadores, profissionais da saúde, pacientes e familiares nesses dois contextos. Destaca, comparativamente, as semelhanças e diferenças na maneira pela qual a genética do câncer se posiciona em relação às prioridades em pesquisas transnacionais, na história e na política contemporânea da saúde pública e a vulnerabilidade incorporada ao câncer que reconfigura o escopo e o significado da genômica como a medicina “personalizada”.

Molecular Dimensions of Gastric Cancer: Translational and Clinical Perspectives

Gastric cancer is a global health burden and has the highest incidence in East Asia. This disease is complex in nature because it arises from multiple interactions of genetic, local environmental, and host factors, resulting in biological heterogeneity. This genetic intricacy converges on molecular characteristics reflecting the pathophysiology, tumor biology, and clinical outcome. Therefore, understanding the molecular characteristics at a genomic level is pivotal to improving the clinical care of patients with gastric cancer. A recent landmark study, The Cancer Genome Atlas (TCGA) project, showed the molecular landscape of gastric cancer through a comprehensive molecular evaluation of 295 primary gastric cancers. The proposed molecular classification divided gastric cancer into four subtypes: Epstein-Barr virus-positive, microsatellite unstable, genomic stable, and chromosomal instability. This information will be taken into account in future clinical trials and will be translated into clinical therapeutic decisions. To fully realize the clinical benefit, many challenges must be overcome. Rapid growth of high-throughput biology and functional validation of molecular targets will further deepen our knowledge of molecular dimensions of this cancer, allowing for personalized precision medicine.

Association between polymorphisms of the androgen and vitamin D receptor genes with prostate cancer risk in a Mexican population / Asociación entre polimorfismo de andrógenos y receptores de vitamina D con riesgo de cáncer prostático en una población mexicana

Introduction. Prostate cancer (PCa) is a worldwide health issue, because of its high incidence and mortality. Its etiology is complex and includes certain risk factors such as age, hormonal status, ethnic origin and family history of PCa. Genetic predisposition is proposed as a major risk factor and there are several controversial reports on the association of PCa and gene polymorphism such as the receptors of the androgen receptor (AR) and the vitamin D (VDR). Objective. To evaluate the CAG triplets repetitions in the first exon of the AR and polymorphisms in the restriction site Taql in the VDR in Mexicans with PCa. Material and methods. A total of 68 Mexicans with histopathological diagnosis of PCa and 48 healthy Mexican with normal prostate specific antigen and rectal exam where included. 10ml of peripheral blood were extracted to isolate DNA and the polymorphisms were evaluated with specific primers for the AR and VDR. Results. The allelic and genetic distributions of the AR and VDR polymorphisms were consistent with the Hardy-Weinberg equilibrium, and there were no statistical differences between the PCa patients and controls (p > 0.05). However, there was a statistical difference between the number of CAG repeats in younger patients with PCa compared to controls (p = 0.045) but when the young patient group was compared versus the elder group there was not stadistically difference (p = 0.085), but the results showed a tendency towards less repetitions of CAG in elder patients. Concerning the VDR, when we analyzed the patients with PCa and a bad pathological prognosis they had a less frequent genotype of TT (p = 0.03). Conclusions. Our results suggest an association between the VDR and AR gene polymorphisms, and the hystopathological score and age at diagnosis in Mexican patients with PCa, respectively. However, it is important to confirm these results in a larger scale study.

Introducción. El cáncer de próstata (PCa) es un problema de salud mundial, tanto por su elevada incidencia como mortalidad. Su etiología es compleja e incluye factores de riesgo reconocidos como la edad, estado hormonal, origen étnico y antecedentes familiares de PCa. El fondo genético es un factor de riesgo y existen reportes controversiales de la asociación de PCa y polimorfismos en los genes como son los receptores de vitamina D (VDR) y el de andrógenos (AR). Objetivo. Evaluar las repeticiones de tripletes de CAG en el primer exon del AR y polimorfismos en el sitio de restricción Taql en el VDR en mexicanos con PCa. Material y métodos. Se incluyeron 68 mexicanos con diagnóstico histopatológico de PCa y 48 mexicanos con niveles normales de antígeno prostático y tacto rectal normal. Se les extrajo 10 mL de sangre periférica para aislar DNA y mediante olígos específicos se evaluaron los polimorfismos mencionados. Resultados. La distribución alélica y genotípica de los polimorfismos en el AR y VDR fueron consistentes con el equilibrio de Hardy-Weinberg, y no mostraron diferencias significativas entre los casos y controles (p > 0.05). Sin embargo, el número de repeticiones de CAG en el AR fueron estadísticamente diferentes en pacientes jóvenes con PCa comparados con los controles (p = 0.045), cuando se comparó el grupo de pacientes de jóvenes contra aquellos mayores de 60 años no se encontró diferencia estadísticamente significativa (p - 0.085); sin embargo, se observó una tendencia de un número menor de repetidos CAG en pacientes mayores con PCa. Por otra parte, al comparar VDR en los pacientes con PCa de mal pronóstico por el patrón histológico tenían menor frecuencia de genotipos TT (p - 0.03). Conclusiones. Nuestros resultados sugieren una asociación entre los polimorfismos de los genes del VDR y AR, y el patrón histológico y la edad al diagnóstico en pacientes mexicanos con PCa, respectivamente. Sin embargo, es necesario confirmar estos resultados en un estudio con mayor número de pacientes.