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Plataformas genómicas específicas de puntuaciones de riesgo poligénico impactan la estratificación del riesgo de
Peh Joo Ho1,2, Alexis Jiaying Khng1, Joanna Hui Juan Tan1
1Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
Communications medicine
|December 12, 2025
Resumen
La elección de la plataforma genómica impacta significativamente la puntuación de riesgo poligénico (PRS) para el cáncer de mama, alterando potencialmente las clasificaciones de riesgo individuales. La estandarización de las plataformas PRS es crucial para una implementación clínica consistente y una estratificación precisa del riesgo.
Área de la Ciencia:
- Genómica
- Bioinformática
- Genética Clínica
Sus antecedentes:
- No existe un estándar establecido para las plataformas de genotipado en la implementación clínica de puntuaciones de riesgo poligénico (PRS).
- Estudios previos promediaron el rendimiento genómico, sin tener en cuenta los impactos específicos de la plataforma en la precisión del PRS.
- Es esencial evaluar un PRS de cáncer de mama de 313 variantes (PRS313) en diferentes plataformas para la estratificación del riesgo.
Objetivo del estudio:
- Comparar el rendimiento de PRS313 en varias matrices de genotipado y secuenciación del genoma completo de baja cobertura.
- Evaluar el impacto de la variabilidad de la plataforma en la clasificación de alto riesgo.
- Determinar la concordancia y el acuerdo entre diferentes plataformas genómicas para el cálculo de PRS.
Principales métodos:
- Se comparó el PRS313 derivado de Global Screening Array (GSA), OncoArray-500K, Global Diversity Array (GDA) y matrices Axiom personalizadas frente a la secuenciación del genoma completo de baja cobertura (lc-WGS).
- Se evaluó la concordancia de la clasificación de alto riesgo (PRS313 > 0.6) utilizando estadísticas Kappa.
- Se utilizaron modelos lineales para predecir el PRS313 entre plataformas y se analizó la concordancia antes y después de la corrección media.
Principales resultados:
- La concordancia de indels con la secuenciación Sanger varió ampliamente entre plataformas (Kappa: 0.007-1.000).
- Las matrices con alta imputación de solapamiento, como GDA y GSA, mostraron una mayor concordancia (pendiente=0.986).
- La concordancia de la clasificación de alto riesgo mejoró después de la corrección media (Kappa=0.650 frente a 0.552), pero persistieron diferencias sustanciales, con solo 7 de 92 individuos clasificados consistentemente como de alto riesgo en todas las plataformas.
Conclusiones:
- La variabilidad específica de la plataforma en genotipado y secuenciación puede influir significativamente en las estimaciones del PRS.
- Estas variaciones pueden conducir a la reclasificación de individuos alrededor de umbrales de riesgo clínicamente relevantes.
- Es necesaria la estandarización de las plataformas genómicas para una implementación clínica fiable del PRS.
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