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1.
Am J Gastroenterol ; 111(2): 275-84, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26729549

RESUMEN

OBJECTIVES: Hereditary biallelic mismatch repair deficiency (BMMRD) is caused by biallelic mutations in the mismatch repair (MMR) genes and manifests features of neurofibromatosis type 1, gastrointestinal (GI) polyposis, and GI, brain, and hematological cancers. This is the first study to characterize the GI phenotype in BMMRD using both retrospective and prospective surveillance data. METHODS: The International BMMRD Consortium was created to collect information on BMMRD families referred from around the world. All patients had germline biallelic MMR mutations or lack of MMR protein staining in normal and tumor tissue. GI screening data were obtained through medical records with annual updates. RESULTS: Thirty-five individuals from seven countries were identified with BMMRD. GI data were available on 24 of 33 individuals (73%) of screening age, totaling 53 person-years. The youngest age of colonic adenomas was 7, and small bowel adenoma was 11. Eight patients had 19 colorectal adenocarcinomas (CRC; median age 16.7 years, range 8-25), and 11 of 18 (61%) CRC were distal to the splenic flexure. Eleven patients had 15 colorectal surgeries (median 14 years, range 9-25). Four patients had five small bowel adenocarcinomas (SBC; median 18 years, range 11-33). Two CRC and two SBC were detected during surveillance within 6-11 months and 9-16 months, respectively, of last consecutive endoscopy. No patient undergoing surveillance died of a GI malignancy. Familial clustering of GI cancer was observed. CONCLUSIONS: The prevalence and penetrance of GI neoplasia in children with BMMRD is high, with rapid development of carcinoma. Colorectal and small bowel surveillance should commence at ages 3-5 and 8 years, respectively.


Asunto(s)
Adenocarcinoma/cirugía , Adenoma/cirugía , Neoplasias Encefálicas/fisiopatología , Neoplasias Colorrectales/cirugía , Intestino Delgado/cirugía , Síndromes Neoplásicos Hereditarios/fisiopatología , Proteínas Adaptadoras Transductoras de Señales/genética , Adenocarcinoma/etiología , Adenocarcinoma/genética , Adenoma/etiología , Adenoma/genética , Adenosina Trifosfatasas/genética , Adolescente , Adulto , Alelos , Neoplasias Encefálicas/complicaciones , Neoplasias Encefálicas/etiología , Neoplasias Encefálicas/genética , Niño , Preescolar , Neoplasias Colorrectales/complicaciones , Neoplasias Colorrectales/etiología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/fisiopatología , Enzimas Reparadoras del ADN/genética , Proteínas de Unión al ADN/genética , Femenino , Mutación de Línea Germinal , Glioma/etiología , Humanos , Neoplasias Intestinales/etiología , Neoplasias Intestinales/genética , Neoplasias Intestinales/cirugía , Neoplasias Renales/etiología , Leucemia/etiología , Linfoma/etiología , Masculino , Melanoma/etiología , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto , Homólogo 1 de la Proteína MutL , Síndromes Neoplásicos Hereditarios/complicaciones , Síndromes Neoplásicos Hereditarios/genética , Proteínas Nucleares/genética , Fenotipo , Estudios Prospectivos , Estudios Retrospectivos , Tumor de Wilms/etiología , Adulto Joven
2.
J Clin Oncol ; 37(6): 461-470, 2019 02 20.
Artículo en Inglés | MEDLINE | ID: mdl-30608896

RESUMEN

PURPOSE: Constitutional mismatch repair deficiency (CMMRD) is a highly penetrant cancer predisposition syndrome caused by biallelic mutations in mismatch repair (MMR) genes. As several cancer syndromes are clinically similar, accurate diagnosis is critical to cancer screening and treatment. As genetic diagnosis is confounded by 15 or more pseudogenes and variants of uncertain significance, a robust diagnostic assay is urgently needed. We sought to determine whether an assay that directly measures MMR activity could accurately diagnose CMMRD. PATIENTS AND METHODS: In vitro MMR activity was quantified using a 3'-nicked G-T mismatched DNA substrate, which requires MSH2-MSH6 and MLH1-PMS2 for repair. We quantified MMR activity from 20 Epstein-Barr virus-transformed lymphoblastoid cell lines from patients with confirmed CMMRD. We also tested 20 lymphoblastoid cell lines from patients who were suspected for CMMRD. We also characterized MMR activity from patients with neurofibromatosis type 1, Li-Fraumeni syndrome, polymerase proofreading-associated cancer syndrome, and Lynch syndrome. RESULTS: All CMMRD cell lines had low MMR activity (n = 20; mean, 4.14 ± 1.56%) relative to controls (n = 6; mean, 44.00 ± 8.65%; P < .001). Repair was restored by complementation with the missing protein, which confirmed MMR deficiency. All cases of patients with suspected CMMRD were accurately diagnosed. Individuals with Lynch syndrome (n = 28), neurofibromatosis type 1 (n = 5), Li-Fraumeni syndrome (n = 5), and polymerase proofreading-associated cancer syndrome (n = 3) had MMR activity that was comparable to controls. To accelerate testing, we measured MMR activity directly from fresh lymphocytes, which yielded results in 8 days. CONCLUSION: On the basis of the current data set, the in vitro G-T repair assay was able to diagnose CMMRD with 100% specificity and sensitivity. Rapid diagnosis before surgery in non-neoplastic tissues could speed proper therapeutic management.


Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/genética , Reparación de la Incompatibilidad de ADN , Enzimas Reparadoras del ADN/genética , Pruebas Genéticas , Mutación , Síndromes Neoplásicos Hereditarios/diagnóstico , Síndromes Neoplásicos Hereditarios/genética , Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas/metabolismo , Estudios de Casos y Controles , Línea Celular Tumoral , Neoplasias Colorrectales/metabolismo , Enzimas Reparadoras del ADN/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Predisposición Genética a la Enfermedad , Humanos , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto/genética , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto/metabolismo , Homólogo 1 de la Proteína MutL/genética , Homólogo 1 de la Proteína MutL/metabolismo , Proteína 2 Homóloga a MutS/genética , Proteína 2 Homóloga a MutS/metabolismo , Síndromes Neoplásicos Hereditarios/metabolismo , Fenotipo , Valor Predictivo de las Pruebas
3.
Eur J Cancer ; 50(5): 987-96, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24440087

RESUMEN

BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) is a devastating cancer predisposition syndrome for which data regarding clinical manifestations, molecular screening tools and management are limited. METHODS: We established an international CMMRD consortium and collected comprehensive clinical and genetic data. Molecular diagnosis of tumour and germline biospecimens was performed. A surveillance protocol was developed and implemented. RESULTS: Overall, 22/23 (96%) of children with CMMRD developed 40 different tumours. While childhood CMMRD related tumours were observed in all families, Lynch related tumours in adults were observed in only 2/14 families (p=0.0007). All children with CMMRD had café-au-lait spots and 11/14 came from consanguineous families. Brain tumours were the most common cancers reported (48%) followed by gastrointestinal (32%) and haematological malignancies (15%). Importantly, 12 (30%) of these were low grade and resectable cancers. Tumour immunohistochemistry was 100% sensitive and specific in diagnosing mismatch repair (MMR) deficiency of the corresponding gene while microsatellite instability was neither sensitive nor specific as a diagnostic tool (p<0.0001). Furthermore, screening of normal tissue by immunohistochemistry correlated with genetic confirmation of CMMRD. The surveillance protocol detected 39 lesions which included asymptomatic malignant gliomas and gastrointestinal carcinomas. All tumours were amenable to complete resection and all patients undergoing surveillance are alive. DISCUSSION: CMMRD is a highly penetrant syndrome where family history of cancer may not be contributory. Screening tumours and normal tissues using immunohistochemistry for abnormal expression of MMR gene products may help in diagnosis and early implementation of surveillance for these children.


Asunto(s)
Reparación de la Incompatibilidad de ADN/genética , Inestabilidad de Microsatélites , Mutación , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adenosina Trifosfatasas/genética , Adenosina Trifosfatasas/metabolismo , Adolescente , Manchas Café con Leche/diagnóstico , Manchas Café con Leche/genética , Manchas Café con Leche/metabolismo , Niño , Preescolar , Enzimas Reparadoras del ADN/genética , Enzimas Reparadoras del ADN/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Salud de la Familia , Femenino , Humanos , Inmunohistoquímica , Lactante , Masculino , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto , Homólogo 1 de la Proteína MutL , Proteína 2 Homóloga a MutS/genética , Proteína 2 Homóloga a MutS/metabolismo , Neoplasias/diagnóstico , Neoplasias/genética , Neoplasias/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Linaje , Síndrome
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