Single Nucleotide Polymorphisms Associated with Prostate Cancer Progression: A Systematic Review.

BACKGROUND: New biomarkers of progression in patients with prostate cancer (PCa) are needed to improve their classification and clinical management. This systematic review investigated the relationship between single nucleotide polymorphisms (SNPs) and PCa progression. METHODS: A keyword search was performed in Pubmed, EMBASE, Scopus, Web of Science, and Cochrane for publications between 2007 and 2022. We included articles with adjusted and significant associations, a median follow-up greater than or equal to 24 months, patients taken to radical prostatectomy (RP) as a first therapeutic option, and results presented based on biochemical recurrence (BCR). RESULTS: In the 27 articles selected, 73 SNPs were identified in 39 genes, organized in seven functional groups. Of these, 50 and 23 SNPs were significantly associated with a higher and lower risk of PCa progression, respectively. Likewise, four haplotypes were found to have a significant association with PCa progression. CONCLUSION: This article highlights the importance of SNPs as potential markers of PCa progression and their possible functional relationship with some genes relevant to its development and progression. However, most variants were identified only in cohorts from two countries; no additional studies reproduce these findings.

Evidence of epigenetic admixture in the Colombian population.

DNA methylation (DNAm) measured in lymphoblastoid cell lines has been repeatedly demonstrated to differ between various human populations. Due to the role that DNAm plays in controlling gene expression, these differences could significantly contribute to ethnic phenotypic differences. However, because previous studies have compared distinct ethnic groups where genetic and environmental context are confounded, their relative contribution to phenotypic differences between ethnicities remains unclear. Using DNAm assayed in whole blood and colorectal tissue of 132 admixed individuals from Colombia, we identified sites where differential DNAm levels were associated with the local ancestral genetic context. Our results are consistent with population specific DNAm being primarily driven by between population genetic differences in cis, with little environmental contribution, and with consistent effects across tissues. The findings offer new insights into a possible mechanism driving phenotypic differences among different ethnic groups, and could help explain ethnic differences in colorectal cancer incidence.

The heritability and patterns of DNA methylation in normal human colorectum.

DNA methylation (DNAm) has been linked to changes in chromatin structure, gene expression and disease. The DNAm level can be affected by genetic variation; although, how this differs by CpG dinucleotide density and genic location of the DNAm site is not well understood. Moreover, the effect of disease causing variants on the DNAm level in a tissue relevant to disease has yet to be fully elucidated. To this end, we investigated the phenotypic profiles, genetic effects and regional genomic heritability for 196080 DNAm sites in healthy colorectum tissue from 132 unrelated Colombian individuals. DNAm sites in regions of low-CpG density were more variable, on average more methylated and were more likely to be significantly heritable when compared with DNAm sites in regions of high-CpG density. DNAm sites located in intergenic regions had a higher mean DNAm level and were more likely to be heritable when compared with DNAm sites in the transcription start site (TSS) of a gene expressed in colon tissue. Within CpG-dense regions, the propensity of the DNAm level to be heritable was lower in the TSS of genes expressed in colon tissue than in the TSS of genes not expressed in colon tissue. In addition, regional genetic variation was associated with variation in local DNAm level no more frequently for DNAm sites within colorectal cancer risk regions than it was for DNAm sites outside such regions. Overall, DNAm sites located in different genomic contexts exhibited distinguishable profiles and may have a different biological function.

IL1B-CGTC haplotype is associated with colorectal cancer in admixed individuals with increased African ancestry.

Single-nucleotide polymorphisms (SNPs) in cytokine genes can affect gene expression and thereby modulate inflammation and carcinogenesis. However, the data on the association between SNPs in the interleukin 1 beta gene (IL1B) and colorectal cancer (CRC) are conflicting. We found an association between a 4-SNP haplotype block of the IL1B (-3737C/-1464G/-511T/-31C) and CRC risk, and this association was exclusively observed in individuals with a higher proportion of African ancestry, such as individuals from the Coastal Colombian region (odds ratio, OR 2.06; 95% CI 1.31-3.25; p < 0.01). Moreover, a significant interaction between this CRC risk haplotype and local African ancestry dosage was identified in locus 2q14 (p = 0.03). We conclude that Colombian individuals with high African ancestry proportions at locus 2q14 harbour more IL1B-CGTC copies and are consequently at an increased risk of CRC. This haplotype has been previously found to increase the IL1B promoter activity and is the most frequent haplotype in African Americans. Despite of limitations in the number of samples and the lack of functional analysis to examine the effect of these haplotypes on CRC cell lines, our results suggest that inflammation and ethnicity play a major role in the modulation of CRC risk.

Biomarcadores de pronóstico en pacientes con cáncer de próstata localizado / Prognostic biomarkers in patients with localised prostate cancer

Resumen El tratamiento para cáncer de próstata localizado (prostatectomía radical o radioterapia) ofrece unas altas tasas de curación; sin embargo, del 20 al 30% de los casos desarrollan recurrencia bioquímica. Actualmente, existen factores clínicos y patológicos que ayudan a predecir recurrencia; no obstante tanto el carácter heterogéneo de estos tumores, las diferencias en los tiempos de progresión de cáncer localizado a metastásico como la resistencia al tratamiento han dado lugar a imprecisiones en la predicción del pronóstico y a tratamientos insuficientes o excesivos. Debido a esto se han estudiado biomarcadores con el fin de estratificar más acertadamente el riesgo y mejorar las decisiones de tratamiento de una manera adecuada y oportuna. Este manuscrito presenta una revisión de marcadores moleculares de pronóstico que se han propuesto en los pacientes con cáncer de próstata localizado, lo que podría permitir establecer con mayor precisión el riesgo de recurrencia de la enfermedad.

Abstract Treatment for localised prostate cancer (radical prostatectomy or radiotherapy), offers high cure rates; nevertheless, 20% to 30% of the cases develop biochemical recurrence. There are clinical and pathological features that are currently being used to predict recurrence of the disease. However, tumour heterogeneity in prostate cancer, along with differences in time of progression to metastasis and treatment resistance, have led to inaccuracies in predicting the risk of biochemical relapse, and therefore, misleading in treatment decisions. Because of this, many genetic markers have been studied in order to refine risk stratification and improve treatment decisions in a suitable and opportune manner. This paper presents a review of molecular prognostic markers that have been proposed in patients with localised prostate cancer, which potentially could allow establishing the risk of recurrence of the disease more accurately.

ESTANDARIZACIÓN DEL PROTOCOLO PARA LA DETECCIÓN DE LAS FUSIONES TMPRSS2: ERG Y DE LA EXPRESIÓN DE LOS GENES EZH2, SPINK-1 y NKX3.1 EN CÁNCER DE PRÓSTATA (CaP) / Protocol Standardization for Detection of TMPRSS2 Fusions: ERG and Gene Expression of EZH2, SPINK-1 and NKX3.1 in Prostate Cancer (PCa)

En la actualidad no existe una herramienta que permita diferenciar pacientes con cáncer de próstata (CaP) de mal pronóstico de aquellos con enfermedad indolente que sólo requieren un seguimiento controlado de la enfermedad. Debido a la coexistencia de diferentes focos premalignos y malignos en el CaP, el entendimiento sobre el proceso de carcinogénesis requiere de un mejor conocimiento. Actualmente, la heterogeneidad morfológica en CaP es evaluada con la puntuación de Gleason, la cual está fuertemente relacionada con el pronóstico de la enfermedad, sin embargo, esto es insuficiente por lo que se trabaja actualmente en identificación de alteraciones moleculares que permitan identificar subtipos que puedan establecer de manera más precisa el pronóstico del paciente. Este estudio preliminar buscó la estandarización del método de cuantificación en muestras prostáticas de FFPE de la expresión de los transcritos de posibles biomarcadores, como los oncogenes SPINK-1 y EZH2, el supresor tumoral NKX3.1, en conjunto con la determinación de la presencia/ausencia del gen de fusión TMPRSS2:ERG, ya que estos transcritos se encuentran involucrados en aparentes eventos excluyentes de la evolución natural del CaP, que apoyan la posibilidad de una clasificación molecular para esta enfermedad.

At present doesn't exist tool to differentiate patients with prostate cancer (PCa) of poor prognosis of those with indolent disease that only require a controlled monitoring of the disease. Because of the coexistence of different premalignant and malignant foci in CaP, the understanding of the carcinogenesis process requires a better understanding. Currently, the morphological heterogeneity in PCa is evaluated with Gleason score, which is closely related to the prognosis of the disease, but this is insufficient so it is currently to work on identifying molecular alterations to identify subtypes that can establish more precisely the patient's prognosis. This preliminary study aimed to standardization of the method of quantification in prostatic samples of FFPE of expression of transcripts of possible biomarkers, such as the oncogenes, SPINK-1 y EZH2, the tumour suppressor, NKX3.1, together with the determination of the presence/absence of gene fusion, TMPRSS2:ERG, being that these transcripts are involved in apparent exclusive events of the natural evolution of PCa, that support the possibility of a molecular classification for this disease.

Aspectos éticos de la investigación en salud en niños / Ethical aspects on children’s health research / Aspectos éticos da pesquisa da saúde das crianças

La infancia es una etapa cuyo significado difiere alrededor del mundo. Los niños son un grupo particularmente vulnerable en investigación, ya que ellos no pueden dar un consentimiento informado y requieren decisiones de representación de padres o tutores. La investigación en niños es muy importante, ya que permite la generación de conocimiento que redunda en su beneficio, pero requiere especial cuidado con respecto a la protección contra los riesgos y a su autonomía. Las normas internacionales para investigación en niños están establecidas en varios documentos; sin embargo, los aspectos éticos en investigación están en constante evolución, relacionados con cambios en un contexto social e histórico particular. En Colombia, en el capítulo III de la Resolución 8430 de 1993, expedida por el Ministerio de Salud, se establecen las disposiciones generales de ética de cualquier investigación en seres humanos, incluidos los menores de edad. La investigación debe asegurar todos los lineamientos de las normas y no olvidar la valoración de la autonomía del niño, para la toma de decisiones en cada caso en particular, y contemplar el asentimiento en los casos pertinentes.

Childhood is a life stage with different meanings around the world. Children are a vulnerable research group, because they cannot give an informed consent, with the parents or tutors being the ones who make decisions. Pediatric research is very important as it generates knowledge and benefits for children; a very special care is needed regarding management of risk and respect for the children’s autonomy. International regulations for research in children are established in many documents. However, ethics matters in research are in constant evolution in relation to specific socio-historical changes. The Colombia Resolution 8430 of 1993, Chapter III, issued by the Health Secretary, establishes the mandatory ethical requirements for research with human beings including children. The research must comply with normativity and mind the value of the child’s autonomy to decide in each case, and request consent in appropriate cases.

Infância é uma fase de que o significado difere em todo o mundo. As crianças são um grupo particularmente vulnerável em pesquisas, por que eles não podem dar consentimento informado e necessitam do representação dos pais ou adultos responsáveis para dar consentimento. Pesquisa dobre crianças é muito importante, pois permite a produção de mais conhecimento em seu benefício, mas precisa cuidados especiais à proteção contra riscos a respeito da autonomia das crianças. Regulamento internacionais da pesquisa de crianças são estabelecidas em vários documentos; Mas as implicações éticas da investigação estão em constante evolução em relação com as mudanças do contexto social e histórico particular. Na Colômbia, Capítulo III da Resolução 8.430, de 1993, emitido pelo Ministério da Saúde, estabelece as regulamentos gerais da ética de qualquer pesquisa envolvendo seres humanos, também incluindo as menores de idade. O investigação deve garantir todas as regras e diretrizes, e não esquecer o valor da autonomia da criança para a tomada do decisão em cada caso particular, e pedir o consentimento se for o caso.

Consideraciones éticas y legales de los biobancos para investigación: [revisión] / Research biobanks: ethical and legal considerations: [review]

Un biobanco es una colección de muestras biológicas y datos asociados con fines diagnósticos, terapéuticos o de investigación. Las actividades llevadas a cabo por los bancos de muestras biológicas conllevan muchos dilemas éticos y legales, por lo que en el ámbito internacional existen diversas normas y recomendaciones establecidas para salvaguardar los derechos de los donantes. En Colombia, el Instituto Nacional de Cancerología considera prioritario la creación de un biobanco con fines de investigación. El propósito de este artículo es realizar una revisión de la literatura, internacional como nacional, sobre los aspectos éticos y legales relacionados con los biobancos para investigación científica. La adaptación de los requerimientos internacionales sería el primer paso para la implementación de los estándares éticos y legales de los biobancos en Colombia. Se hace necesario el establecimiento de regulaciones nacionales que controlen las actividades de dichos biobancos y de esta manera se contribuya a la participación activa de la sociedad colombiana.