RESUMEN
This study examined prospectively the contribution of family functioning, differentiation to parents, family communication and support from relatives to psychological distress in individuals undergoing genetic susceptibility testing for a known familial pathogenic BRCA1/2 or Hereditary nonpolyposis colorectal cancer-related mutation. Family functioning, differentiation to parents, hereditary cancer-related family communication and perceived support from relatives were assessed in 271 participants for genetic testing before test result disclosure. Hereditary cancer distress (assessed by the Impact of Event Scale) and cancer worry (assessed by the Cancer Worry Scale) were assessed before, 1 week after, and 6 months after test result disclosure. Participants reporting more cancer-related distress over the study period more frequently perceived the communication about hereditary cancer with relatives as inhibited, the nuclear family functioning as disengaged-rigid or enmeshed-chaotic, the support from partner as less than adequate and the relationship to mother as less differentiated. Especially, open communication regarding hereditary cancer and partner support may be important buffers against hereditary cancer distress. Identifying individuals with insufficient sources of support and addressing the family communication concerning hereditary cancer in genetic counseling may help the counselee to adjust better to genetic testing.
Asunto(s)
Neoplasias de la Mama/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Familia/psicología , Genes BRCA1 , Genes BRCA2 , Predisposición Genética a la Enfermedad/genética , Pruebas Genéticas/psicología , Estrés Psicológico/psicología , Adulto , Neoplasias de la Mama/psicología , Neoplasias Colorrectales Hereditarias sin Poliposis/psicología , Comunicación , Femenino , Asesoramiento Genético/métodos , Humanos , Masculino , Persona de Mediana Edad , Países Bajos , Estudios Prospectivos , Apoyo Social , Encuestas y CuestionariosRESUMEN
BACKGROUND: This study explores the effect of age at the time of parental cancer diagnosis or death on psychological distress and cancer risk perception in individuals undergoing genetic testing for a specific cancer susceptibility. PATIENTS AND METHODS: Cancer-related distress, worry and risk perception were assessed in 271 applicants for genetic testing of an identified mutation in BRCA1/2 (BReast CAncer) or a HNPCC (Hereditary Nonpolyposis Colorectal Cancer) related gene before, one week after, and six months after genetic test disclosure. The course of distress and risk perception were compared between individuals having witnessed parental cancer or loss due to cancer in childhood, adolescence, adulthood and having unaffected parents. RESULTS: Individuals with parental cancer in childhood (under age 13) reported the highest level of cancer related distress, worry and risk perception. Women having their mother affected by breast cancer in puberty (aged 10-13 years) perceived higher breast cancer risks than women with an affected mother in adulthood or without an affected mother. Individuals with an affected parent perceived cancer risks as higher than individuals without an affected parent, but were not more distressed. CONCLUSIONS: Experience of parental cancer in childhood is a risk factor for psychological distress during the genetic testing process.
Asunto(s)
Neoplasias de la Mama/psicología , Neoplasias Colorrectales Hereditarias sin Poliposis/psicología , Pruebas Genéticas/psicología , Adolescente , Adulto , Factores de Edad , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética , Niño , Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Análisis Mutacional de ADN/psicología , Femenino , Humanos , Masculino , Padres , Pubertad , Medición de RiesgoRESUMEN
OBJECTIVE: To investigate the contribution of MYH associated polyposis coli (MAP) among polyposis families in the Netherlands, and the prevalence of colonic and extracolonic manifestations in MAP patients. METHODS: 170 patients with polyposis coli, who previously tested negative for APC mutations, were screened by denaturing gradient gel electrophoresis and direct sequencing to identify MYH germline mutations. RESULTS: Homozygous and compound heterozygous MYH mutations were identified in 40 patients (24%). No difference was found in the percentage of biallelic mutation carriers between patients with 10-99 polyps or 100-1000 polyps (29% in both groups). Colorectal cancer was found in 26 of the 40 patients with MAP (65%) within the age range 21 to 67 years (median 45). Complete endoscopic reports were available for 16 MAP patients and revealed five cases with gastro-duodenal polyps (31%), one of whom also presented with a duodenal carcinoma. Breast cancer occurred in 18% of female MAP patients, significantly more than expected from national statistics (standardised morbidity ratio = 3.75). CONCLUSIONS: Polyp numbers in MAP patients were equally associated with the attenuated and classical polyposis coli phenotypes. Two thirds of the MAP patients had colorectal cancer, 95% of whom were older than 35 years, and one third of a subset of patients had upper gastrointestinal lesions. Endoscopic screening of the whole intestine should be carried out every two years for all MAP patients, starting from age 25-30 years. The frequent occurrence of additional extraintestinal manifestations, such as breast cancer among female MAP patients, should be thoroughly investigated.
Asunto(s)
Poliposis Adenomatosa del Colon/genética , ADN Glicosilasas/genética , Adolescente , Adulto , Anciano , Niño , Neoplasias Colorrectales/genética , Análisis Mutacional de ADN , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Mutación de Línea Germinal , Humanos , Patrón de Herencia/genética , Masculino , Persona de Mediana Edad , Países Bajos , Fenotipo , RiesgoRESUMEN
OBJECTIVE: The aim of this study was to identify the prevalence of catecholamine excess and phaeochromocytomas in a well-defined population of people with hereditary head and neck paragangliomas. METHODS: We studied in a prospective follow-up protocol all consecutive patients referred to the Department of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands with documented head and neck paragangliomas and either a positive family history for paragangliomas or a proven SDHD gene mutation. Initial analysis included medical history, physical examination and the measurement of excretion of catecholamines in two 24-h urine collections. In the case of documented catecholamine excess iodinated meta-iodobenzylguanidine (123I-MIBG) scintigraphy and magnetic resonance imaging were done. RESULTS: Between 1988 and 2003, 40 consecutive patients (20 male and 20 female) with documented head and neck paragangliomas were screened. Biochemical screening revealed urinary catecholamine excess in 15 patients (37.5%). In nine of these 15 patients a lesion was found by 123I-MIBG scintigraphy. Exact localization by magnetic resonance imaging revealed phaeochromocytomas in seven of the 15 patients. One of the nine patients had an extra-adrenal paraganglioma. Histopathological examination in a subset of tumors displayed loss of heterozygosity of the wild-type SDHD allele in all cases. CONCLUSIONS: The prevalence of catecholamine excess (37.5%) and phaeochromocytomas (20.0%) is high in patients with familial head and neck paragangliomas. Therefore, patients with hereditary head and neck paragangliomas require lifelong follow up by biochemical testing for catecholamine excess.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales/orina , Catecolaminas/orina , Neoplasias de Cabeza y Cuello/orina , Proteínas de la Membrana/genética , Paraganglioma/orina , Feocromocitoma/orina , Neoplasias de las Glándulas Suprarrenales/genética , Neoplasias de las Glándulas Suprarrenales/metabolismo , Adulto , Estudios de Cohortes , ADN de Neoplasias/genética , Femenino , Mutación de Línea Germinal , Neoplasias de Cabeza y Cuello/genética , Humanos , Imidazoles , Pérdida de Heterocigocidad/genética , Masculino , Persona de Mediana Edad , Paraganglioma/genética , Feocromocitoma/genética , Estudios Prospectivos , Succinato DeshidrogenasaRESUMEN
Hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) is a dominantly inherited syndrome characterized by the development of colorectal cancer, endometrial cancer and other cancers and the presence of microsatellite instability (MSI) in tumors. The Bethesda guidelines have been proposed for the identification of families suspected of HNPCC that require further molecular analysis. We have evaluated the yield of MSI-analysis in a large series of Dutch families suspected of HNPCC. We also analysed whether the loss of mismatch repair (MMR) protein detected by immunohistochemistry (IHC) of colorectal cancer (CRC) and endometrial cancer correlated with the presence of MSI and/or a MMR gene mutation. The results showed that the Bethesda criteria with a few modifications are appropriate to identify families eligible for genetic testing. In addition, we found that MSI and IHC-analysis of CRC using antibodies against MLH1, MSH2, MSH6 and PMS2 proteins are equally effective for identifying carriers of the known MMR gene defects. However, as long as the role of other putative MMR genes in hereditary CRC has not been elucidated, IHC-analysis cannot completely replace MSI. For this reason, we prefer MSI-analysis as first step in families suspected of HNPCC. On the other hand, in families fulfilling the revised Amsterdam criteria in which the probability of detecting a mutation is relatively high, we would recommend IHC as first diagnostic step because the result might predict the specific underlying MMR gene mutation. MSI or IHC-analysis of endometrial cancer alone was found to be less sensitive compared with these tests performed in colorectal cancer. Therefore, probably the best approach in the analysis of this cancer is to perform both techniques. The identification of HNPCC is important as it makes it possible to target effective preventative measures. Our studies showed that MSI and IHC analysis of colorectal and endometrial cancer, are reliable cost-effective tools that can be used to identify patients with HNPCC.
Asunto(s)
Biomarcadores de Tumor , Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/genética , Neoplasias Endometriales/diagnóstico , Neoplasias Endometriales/genética , Repeticiones de Microsatélite , Adulto , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales Hereditarias sin Poliposis/metabolismo , Análisis Mutacional de ADN , Secuencia de ADN Inestable , Neoplasias Endometriales/metabolismo , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Mutación , Fenotipo , SíndromeRESUMEN
Bannayan-Riley-Ruvalcaba syndrome (BRRS) is characterised by macrocephaly, intestinal hamartomatous polyps, lipomas, pigmented maculae of the glans penis, developmental delay and mental retardation. The syndrome follows an autosomal dominant pattern of inheritance. In 1997 reports on two BRRS patients with a deletion at 10q23.2-q24.1 were published. In the same year, the first two families with BRRS and a mutation of the PTEN gene were reported. Mutations in the PTEN gene have also been demonstrated in patients with Cowden syndrome (CS), which shows partial clinical overlap with BRRS, and in families with cases both of BRRS and CS. PTEN mutation positive BRRS and CS are likely to be different phenotypic presentations of the same syndrome. If BRRS and CS are one single condition, the question arises whether patients with BRRS should be screened for malignant tumours, since patients with Cowden syndrome have an increased risk of breast, endometrial, thyroid and renal cancer. We present two isolated cases and one family and confirm that BRRS and CS are allelic. Furthermore, we review the PTEN mutation positive BRRS cases, to further delineate the phenotype and to compare the cases with a genomic deletion with the cases with a point mutation. We recommend offering BRRS cases with a mutation in PTEN the same surveillance protocol for (malignant) tumours as is currently recommended for CS. In addition, we propose a yearly haemoglobin test from early infancy for the early detection of intestinal hamartomas, which are likely to give severe complications, especially in BRRS cases.
Asunto(s)
Síndrome de Hamartoma Múltiple/genética , Monoéster Fosfórico Hidrolasas/genética , Proteínas Supresoras de Tumor/genética , Adulto , Niño , Preescolar , Anomalías Craneofaciales/genética , Discapacidades del Desarrollo/genética , Mutación de Línea Germinal/genética , Humanos , Pólipos Intestinales/genética , Masculino , Fosfohidrolasa PTEN , Linaje , Fenotipo , Trastornos de la Pigmentación/genética , SíndromeRESUMEN
Hereditary paragangliomas are rare benign tumours arising from neuroectodermal tissue in the head and neck region. In families with paraganglioma, occasionally adrenal and extra-adrenal pheochromocytomas are found. Paragangliomas, adrenal and extra-adrenal pheochromocytomas may be caused by mutations in the SDHB, SDHC and SDHD genes encoding different subunits of mitochondrial respiratory chain complex II. Most paraganglioma cases in the Netherlands are caused by SDHD mutations. Presymptomatic DNA diagnosis is available for families with paragangliomas caused by SDHD mutations.
Asunto(s)
Neoplasias de Cabeza y Cuello/genética , Enfermedades Mitocondriales/genética , Complejos Multienzimáticos/genética , Oxidorreductasas/genética , Paraganglioma/genética , Succinato Deshidrogenasa/genética , Análisis Mutacional de ADN , Transporte de Electrón , Complejo II de Transporte de Electrones , Pruebas Genéticas , Neoplasias de Cabeza y Cuello/diagnóstico , Humanos , Mutación , Paraganglioma/diagnóstico , Feocromocitoma/diagnóstico , Feocromocitoma/genéticaRESUMEN
Prenatal testing for a BRCA mutation, the hereditary trait for mammary and ovarian carcinoma, with the intention of selective termination of pregnancy in case of a female carrier is a controversial ethical issue. Based on a review of the (limited) medical literature as well as of Dutch policy statements relating to this subject, the following conclusions and recommendations are proposed: (a) the decision to opt for prenatal BRCA testing and selective termination of pregnancy in case of a BRCA mutation in the foetus cannot immediately be judged unacceptable from an ethical point of view; (b) prenatal BRCA testing is morally defensible only in case of a female foetus and if the parents at least have the intention to terminate the pregnancy if the foetus is a carrier, although the final decision is in any case up to the parents only; (c) prental testing for a BRCA mutation should only be done after extensive counselling of the parents, during which not only the medical genetic aspects but also the ethical aspects of prenatal BRCA testing are discussed.