RESUMEN
We report an autosomal recessive, multi-organ tumor predisposition syndrome, caused by bi-allelic loss-of-function germline variants in the base excision repair (BER) gene MBD4. We identified five individuals with bi-allelic MBD4 variants within four families and these individuals had a personal and/or family history of adenomatous colorectal polyposis, acute myeloid leukemia, and uveal melanoma. MBD4 encodes a glycosylase involved in repair of G:T mismatches resulting from deamination of 5'-methylcytosine. The colorectal adenomas from MBD4-deficient individuals showed a mutator phenotype attributable to mutational signature SBS1, consistent with the function of MBD4. MBD4-deficient polyps harbored somatic mutations in similar driver genes to sporadic colorectal tumors, although AMER1 mutations were more common and KRAS mutations less frequent. Our findings expand the role of BER deficiencies in tumor predisposition. Inclusion of MBD4 in genetic testing for polyposis and multi-tumor phenotypes is warranted to improve disease management.
Asunto(s)
Poliposis Adenomatosa del Colon , Neoplasias Colorrectales , Neoplasias de la Úvea , Poliposis Adenomatosa del Colon/genética , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Endodesoxirribonucleasas/genética , Predisposición Genética a la Enfermedad , Células Germinativas/patología , Mutación de Línea Germinal/genética , Humanos , Neoplasias de la Úvea/genéticaAsunto(s)
Pólipos del Colon/genética , Neoplasias Colorrectales/genética , Desoxirribonucleasa (Dímero de Pirimidina)/genética , Adulto , Anciano , Alelos , Pólipos del Colon/epidemiología , Neoplasias Colorrectales/epidemiología , Femenino , Predisposición Genética a la Enfermedad , Heterocigoto , Humanos , Mutación con Pérdida de Función , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido SimpleRESUMEN
The somatic mutation spectrum imprinted in the genome of a tumor represents the mutational processes that have been active in that tumor. Large sequencing efforts in various cancer types have resulted in the identification of multiple mutational signatures, of which several have been linked to specific biological mechanisms. Several pan-cancer mutational signatures have been identified, while other signatures are only found in specific tissue types. Research on tumors from individuals with specific DNA repair defects has led to links between specific mutational signatures and mutational processes. Studying mutational signatures in cancers that are likely the result of a genetic predisposition may represent an interesting strategy to identify constitutional DNA repair defects, including those underlying polyposis and colorectal cancer.
Asunto(s)
Poliposis Adenomatosa del Colon/genética , Neoplasias Colorrectales/genética , Predisposición Genética a la Enfermedad , Mutación , Poliposis Adenomatosa del Colon/diagnóstico , Envejecimiento/genética , Neoplasias Colorrectales/diagnóstico , Reparación del ADN , Estudios de Asociación Genética , Mutación de Línea Germinal , Humanos , Mutágenos , Especificidad de Órganos/genéticaRESUMEN
Biallelic germline mutations affecting NTHL1 predispose carriers to adenomatous polyposis and colorectal cancer, but the complete phenotype is unknown. We describe 29 individuals carrying biallelic germline NTHL1 mutations from 17 families, of which 26 developed one (n = 10) or multiple (n = 16) malignancies in 14 different tissues. An unexpected high breast cancer incidence was observed in female carriers (60%). Mutational signature analysis of 14 tumors from 7 organs revealed that NTHL1 deficiency underlies the main mutational process in all but one of the tumors (93%). These results reveal NTHL1 as a multi-tumor predisposition gene with a high lifetime risk for extracolonic cancers and a typical mutational signature observed across tumor types, which can assist in the recognition of this syndrome.
Asunto(s)
Biomarcadores de Tumor/genética , Análisis Mutacional de ADN , Desoxirribonucleasa (Dímero de Pirimidina)/genética , Perfilación de la Expresión Génica , Mutación de Línea Germinal , Síndromes Neoplásicos Hereditarios/genética , Transcriptoma , Adulto , Anciano , Biomarcadores de Tumor/deficiencia , Reparación del ADN/genética , Desoxirribonucleasa (Dímero de Pirimidina)/deficiencia , Europa (Continente) , Femenino , Regulación Neoplásica de la Expresión Génica , Predisposición Genética a la Enfermedad , Herencia , Humanos , Masculino , Persona de Mediana Edad , Síndromes Neoplásicos Hereditarios/enzimología , Síndromes Neoplásicos Hereditarios/patología , Linaje , Fenotipo , Medición de Riesgo , Factores de Riesgo , Adulto JovenRESUMEN
Mutational processes underlie cancer initiation and progression. Signatures of these processes in cancer genomes may explain cancer etiology and could hold diagnostic and prognostic value. We developed a strategy that can be used to explore the origin of cancer-associated mutational signatures. We used CRISPR-Cas9 technology to delete key DNA repair genes in human colon organoids, followed by delayed subcloning and whole-genome sequencing. We found that mutation accumulation in organoids deficient in the mismatch repair gene MLH1 is driven by replication errors and accurately models the mutation profiles observed in mismatch repair-deficient colorectal cancers. Application of this strategy to the cancer predisposition gene NTHL1, which encodes a base excision repair protein, revealed a mutational footprint (signature 30) previously observed in a breast cancer cohort. We show that signature 30 can arise from germline NTHL1 mutations.