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Beyond the genetic lesions: gene inactivation by promoter hypermethylation in human cancer

Más allá de las lesiones genéticas: inactivación genética por hipermetilación del promotor en cáncer humano

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Abstract

Genetic alterations in key genes are distinctive of a cancer cell. But the tumors also undergo other changes specific of the malignant transformation that do not affect the sequence of DNA. These are given the term epigenetic lesions, and the main one is aberrant methylation. In this review we focus in how promoter hypermethylation silences the expression of genes contributing to the neoplastic phenotype. Well recognized tumor suppressor genes such asp16/INK4a, BRCA1, Rb andVHL became hypermethylated in sporadic tumors with very selective patterns. Other genes recently characterized such asp14/ARF, LKB1, p73, E-cadherin andDAP-Kinase are also epigenetically inactivated in tumors. Furthermore, the methylation mediated silencing of DNA repair and detoxifier genes, such as the mismatch repair genehMLH1, the alkylrepairMGMT and the carcinogen-protectorGSTP1, may cause important genomic damage and mutations. All this recent data may provide a new avenue in how we understand the development, diagnosis and treatment of cancer.

Resumen

Las alteraciones genéticas que afectan a genes transformantes son distintivas de la célula cancerosa. Pero los tumores también sufren otra serie de cambios propios de la malignización que no cambian la secuencia de ADN. Estas lesiones son denominadas epigenéticas y la principal es el tratorno de la metilación del ADN. En esta revisión nos centraremos sólo en cómo el silenciamiento de los genes por hipermetilación de sus promotores contribuye al fenotipo neoplásico. Genes supresores tumorales importantes comop16INK4a, BRCA1, Rb yVHL están hipermetilados en ciertos tumores esporádicos con patrones muy específicos. Otros genes recientemente caracterizados comop14/ARF, LKB1, p73, E-cadherin yDAP-Kinase también están inactivados epigenéticamente en tumores. Un fenómeno interesante es que el silenciamiento por metilación de ciertos genes reparadores del ADN y detoxificadores, como el gen de reparación demismatch hMLH1, el reparador de ciertos grupos alkilantesMGMT y el protector de carcinógenosGSTP1, puede originar lesiones genéticas y mutaciones. Los recientes descubrimientos en este campo nos pueden proporcionar mejores formas de entender y controlar el problema del cáncer.

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Authors and Affiliations

  1. Tumor Biology, The Johns Hopkins Oncology Center, Room 541, 5th Floor, 1650 Orleans Street, 4231, Baltimore, MD, USA

    Manel Esteller, Stephen B. Baylin & James G. Herman

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  1. Manel Esteller
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  2. Stephen B. Baylin
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  3. James G. Herman
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Correspondence to Manel Esteller.

Additional information

Part of the work included in this review received the First Prize in Basic Research at The Johns Hopkins Oncology Center Fellows Day in the summer of 1999 awarded to Dr. Manel Esteller.

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Esteller, M., Baylin, S.B. & Herman, J.G. Beyond the genetic lesions: gene inactivation by promoter hypermethylation in human cancer. Rev Oncología 2, 61–66 (2000). https://doi.org/10.1007/BF02979467

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