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Females with PTEN Hamartoma Tumor Syndrome (PHTS) have breast cancer risks up to 76%. This study assessed associations between breast cancer and lifestyle in European female adult PHTS patients. Data were collected via patient questionnaires (July 2020-March 2023) and genetic diagnoses from medical files. Associations between lifestyle and breast cancer were calculated using logistic regression corrected for age. Index patients with breast cancer before PHTS diagnosis (breast cancer index) were excluded for ascertainment bias correction. In total, 125 patients were included who completed the questionnaire at a mean age of 44 years (SD = 13). This included 21 breast cancer indexes (17%) and 39 females who developed breast cancer at 43 years (SD = 9). Breast cancer patients performed about 1.1 times less often 0-1 times/week physical activity than ≥2 times (ORtotal-adj = 0.9 (95%CI 0.3-2.6); consumed daily about 1.2-1.8 times more often ≥1 than 0-1 glasses of alcohol (ORtotal-adj = 1.2 (95%CI 0.4-4.0); ORnon-breastcancer-index-adj = 1.8 (95%CI 0.4-6.9); were about 1.04-1.3 times more often smokers than non-smokers (ORtotal-adj = 1.04 (95%CI 0.4-2.8); ORnon-breastcancer-index-adj = 1.3 (95%CI 0.4-4.2)); and overweight or obesity (72%) was about 1.02-1.3 times less common (ORtotal-adj = 0.98 (95%CI 0.4-2.6); ORnon-breastcancer-index-adj = 0.8 (95%CI 0.3-2.7)). Similar associations between lifestyle and breast cancer are suggested for PHTS and the general population. Despite not being statistically significant, results are clinically relevant and suggest that awareness of the effects of lifestyle on patients' breast cancer risk is important.
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BACKGROUND: PTEN Hamartoma Tumor Syndrome (PHTS) is a rare syndrome with a broad phenotypic spectrum, including increased risks of breast (BC, 67%-78% at age 60 years), endometrial (EC, 19%-28%), and thyroid cancer (TC, 6%-38%). Current risks are likely overestimated due to ascertainment bias. We aimed to provide more accurate and personalized cancer risks. METHODS: This was a European, adult PHTS cohort study with data from medical files, registries, and/or questionnaires. Cancer risks and hazard ratios were assessed with Kaplan-Meier and Cox regression analyses, and standardized incidence ratios were calculated. Bias correction consisted of excluding cancer index cases and incident case analyses. RESULTS: A total of 455 patients were included, including 50.5% index cases, 372 with prospective follow-up (median 6 years, interquartile range = 3-10 years), and 159 of 281 females and 39 of 174 males with cancer. By age 60 years, PHTS-related cancer risk was higher in females (68.4% to 86.3%) than males (16.4% to 20.8%). Female BC risks ranged from 54.3% (95% confidence interval [CI] = 43.0% to 66.4%) to 75.8% (95% CI = 60.7% to 88.4%), with two- to threefold increased risks for PTEN truncating and approximately twofold for phosphatase domain variants. EC risks ranged from 6.4% (95% CI = 2.1% to 18.6%) to 22.1% (95% CI = 11.6% to 39.6%) and TC risks from 8.9% (95% CI = 5.1% to 15.3%) to 20.5% (95% CI = 11.3% to 35.4%). Colorectal cancer, renal cancer, and melanoma risks were each less than 10.0%. CONCLUSIONS: Females have a different BC risk depending on their PTEN germline variant. PHTS patients are predominantly at risk of BC (females), EC, and TC. This should be the main focus of surveillance. These lower, more unbiased and personalized risks provide guidance for optimized cancer risk management.
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Síndrome de Hamartoma Múltiple , Neoplasias Renales , Neoplasias de la Tiroides , Adulto , Masculino , Humanos , Femenino , Persona de Mediana Edad , Síndrome de Hamartoma Múltiple/epidemiología , Síndrome de Hamartoma Múltiple/genética , Síndrome de Hamartoma Múltiple/patología , Estudios de Cohortes , Estudios Prospectivos , Fosfohidrolasa PTEN/genética , Neoplasias Renales/epidemiología , Mutación de Línea GerminalRESUMEN
Universal mismatch repair deficiency (dMMR) testing of colorectal cancer (CRC) is promoted as routine diagnostics to prescreen for Lynch syndrome. We evaluated the yield and experience of age-related molecular investigation for heritable and nonheritable causes of dMMR in CRC below age 70 to identify Lynch Syndrome. In a prospective cohort of 3602 newly diagnosed CRCs below age 70 from 19 hospitals, dMMR, MLH1 promoter hypermethylation, germline MMR gene and somatic MMR gene testing was assessed in daily practice. Yield was evaluated using data from the Dutch Pathology Registry (PALGA) and two regional genetic centers. Experiences of clinicians were evaluated through questionnaires. Participating clinicians were overwhelmingly positive about the clinical workflow. Pathologists routinely applied dMMR-testing in 84% CRCs and determined 10% was dMMR, largely due to somatic MLH1 hypermethylation (66%). Of those, 69% with dMMR CRC below age 70 without hypermethylation were referred for genetic testing, of which 55% was due to Lynch syndrome (hereditary) and 43% to somatic biallelic pathogenic MMR (nonhereditary). The prevalence of Lynch syndrome was 18% in CRC < 40, 1.7% in CRC age 40-64 and 0.7% in CRC age 65-69. Age 65-69 represents most cases with dMMR, in which dMMR due to somatic causes (13%) is 20 times more prevalent than Lynch syndrome. In conclusion, up to age 65 routine diagnostics of (non-)heritable causes of dMMR CRCs effectively identifies Lynch syndrome and reduces Lynch-like diagnoses. Above age 64, the effort to detect one Lynch syndrome patient in dMMR CRC is high and germline testing rarely needed.
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Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias Colorrectales/genética , Reparación de la Incompatibilidad de ADN/genética , Adolescente , Adulto , Anciano , Metilación de ADN/genética , Femenino , Pruebas Genéticas/métodos , Humanos , Masculino , Persona de Mediana Edad , Homólogo 1 de la Proteína MutL/genética , Mutación/genética , Regiones Promotoras Genéticas/genética , Estudios Prospectivos , Adulto JovenRESUMEN
BACKGROUND: Women with epithelial ovarian cancer (OC) have a higher chance to benefit from poly (ADP-ribose) polymerase inhibitor (PARPi) therapy if their tumor has a somatic or hereditary BRCA1/2 pathogenic variant. Current guidelines advise BRCA1/2 genetic predisposition testing for all OC patients, though this does not detect somatic variants. We assessed the feasibility of a workflow for universal tumor DNA BRCA1/2 testing of all newly diagnosed OC patients as a prescreen for PARPi treatment and cancer predisposition testing. METHODS: Formalin-fixed paraffin-embedded tissue was obtained from OC patients in seven hospitals immediately after diagnosis or primary surgery. DNA was extracted, and universal tumor BRCA1/2 testing was then performed in a single site. Diagnostic yield, uptake, referral rates for genetic predisposition testing, and experiences of patients and gynecologists were evaluated. RESULTS: Tumor BRCA1/2 testing was performed for 315 (77.6%) of the 406 eligible OC samples, of which 305 (96.8%) were successful. In 51 of these patients, pathogenic variants were detected (16.7%). Most patients (88.2%) went on to have a genetic predisposition test. BRCA1/2 pathogenic variants were shown to be hereditary in 56.8% and somatic in 43.2% of patients. Participating gynecologists and patients were overwhelmingly positive about the workflow. CONCLUSIONS: Universal tumor BRCA1/2 testing in all newly diagnosed OC patients is feasible, effective, and appreciated by patients and gynecologists. Because many variants cannot be detected in DNA from blood, testing tumor DNA as the first step can double the identification rate of patients who stand to benefit most from PARP inhibitors.
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Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias Ováricas/epidemiología , Neoplasias Ováricas/etiología , Anciano , Manejo de la Enfermedad , Femenino , Asesoramiento Genético , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Humanos , Persona de Mediana Edad , Terapia Molecular Dirigida , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/tratamiento farmacológico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/administración & dosificación , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéuticoRESUMEN
BACKGROUND: Basal cell nevus syndrome (BCNS) is an autosomal dominant disorder characterized by multiple basal cell carcinomas (BCCs), maxillary keratocysts, and cerebral calcifications. BCNS most commonly is caused by a germline mutation in the patched-1 (PTCH1) gene. PTCH1 mutations are also described in patients with holoprosencephaly. METHODS: We have established a locus-specific database for the PTCH1 gene using the Leiden Open Variation Database (LOVD). We included 117 new PTCH1 variations, in addition to 331 previously published unique PTCH1 mutations. These new mutations were found in 141 patients who had a positive PTCH1 mutation analysis in either the VU University Medical Centre (VUMC) or Maastricht University Medical Centre (MUMC) between 1995 and 2015. RESULTS: The database contains 331 previously published unique PTCH1 mutations and 117 new PTCH1 variations. CONCLUSION: We have established a locus-specific database for the PTCH1 gene using the Leiden Open Variation Database (LOVD). The database provides an open collection for both clinicians and researchers and is accessible online at http://www.lovd.nl/PTCH1.
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Mutación , Receptor Patched-1/genética , Síndrome del Nevo Basocelular/genética , Análisis Mutacional de ADN , Bases de Datos Genéticas , Mutación de Línea Germinal , Humanos , Receptores Patched/genética , Receptor Patched-1/clasificación , Receptores de Superficie Celular/genéticaRESUMEN
Context: Paraganglioma (PGL) has the highest degree of heritability among human neoplasms. Current clinical understanding of germline SDHA mutation carriers is limited. Objective: To estimate the contribution of SDHA mutations in PGL and to assess clinical manifestations and age-related penetrance. Design: Nationwide retrospective cohort study. Setting: Tertiary referral centers in the Netherlands (multicenter). Patients: Germline SDHA analysis was performed in 393 patients with genetically unexplained PGL. Subsequently, 30 index SDHA mutation carriers and 56 nonindex carriers were studied. Main Outcome Measures: SDHA mutation detection yield, clinical manifestations, and SDHA-related disease penetrance. Results: Pathogenic germline SDHA variants were identified in 30 of the 393 referred patients with PGL (7.6%), who had head and neck PGL (21 of 174 [12%]), pheochromocytoma (4 of 191 [2%]), or sympathetic PGL (5 of 28 [18%]). The median age at diagnosis was 43 years (range, 17 to 81 years) in index SDHA mutation carriers compared with 52 years (range, 7 to 90 years) in nonmutation carriers (P = 0.002). The estimated penetrance of any SDHA-related manifestation was 10% at age 70 years (95% confidence interval, 0% to 21%) in nonindex mutation carriers. Conclusion: Germline SDHA mutations are relatively common (7.6%) in patients with genetically unexplained PGL. Most index patients presented with apparently sporadic PGL. In this SDHA series, the largest assembled so far, we found the lowest penetrance of all major PGL predisposition genes. This suggests that recommendations for genetic counseling of at-risk relatives and stringency of surveillance for SDHA mutation carriers might need to be reassessed.
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Neoplasias de las Glándulas Suprarrenales/genética , Complejo II de Transporte de Electrones/genética , Mutación de Línea Germinal , Paraganglioma/genética , Feocromocitoma/genética , Adolescente , Neoplasias de las Glándulas Suprarrenales/epidemiología , Neoplasias de las Glándulas Suprarrenales/patología , Adulto , Anciano , Anciano de 80 o más Años , Niño , Análisis Mutacional de ADN , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Países Bajos/epidemiología , Paraganglioma/epidemiología , Paraganglioma/patología , Penetrancia , Feocromocitoma/epidemiología , Feocromocitoma/patología , Estudios Retrospectivos , Adulto JovenRESUMEN
INTRODUCTION: When hemoptysis complicates pulmonary arterial hypertension (PAH), it is assumed to result from bronchial artery hypertrophy. In heritable PAH, the most common mutation is in the BMPR2 gene, which regulates growth, differentiation and apoptosis of mesenchymal cells. The aim of this study is to determine the relationship in PAH between the occurrence of hemoptysis, and disease progression, bronchial artery hypertrophy, pulmonary artery dilation and BMPR2 mutations. METHODS: 129 IPAH patients underwent baseline pulmonary imaging (CT angio or MRI) and repeated right-sided heart catheterization. Gene mutations were assessed in a subset of patients. RESULTS: Hemoptysis was associated with a greater presence of hypertrophic bronchial arteries and more rapid hemodynamic deterioration. The presence of a BMPR2 mutation did not predispose to the development of hemoptysis, but was associated with a greater number of hypertrophic bronchial arteries and a worse baseline hemodynamic profile. CONCLUSION: Hemoptysis in PAH is associated with bronchial artery hypertrophy and faster disease progression. Although the presence of a BMPR2 mutation did not correlate with a greater incidence of hemoptysis in our patient cohort, its association with worse hemodynamics and a trend of greater bronchial arterial hypertrophy may increase the risk of hemoptysis.
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Receptores de Proteínas Morfogenéticas Óseas de Tipo II/genética , Arterias Bronquiales/patología , Hemoptisis/epidemiología , Hemoptisis/etiología , Hipertensión Pulmonar/complicaciones , Hipertensión Pulmonar/genética , Arteria Pulmonar/patología , Cateterismo Cardíaco , Hemodinámica , Humanos , Hipertensión Pulmonar/patología , Imagen por Resonancia Magnética , Factores de Riesgo , Tomografía Computarizada por Rayos XRESUMEN
A subgroup of patients with idiopathic pulmonary arterial hypertension (IPAH) has severely reduced diffusing capacity of the lung for carbon monoxide (DLCO) and poor prognosis. Their characteristics are currently unknown. The aim of this study is to contrast clinical characteristics and treatment responses of IPAH-patients with a severely reduced and more preserved DLCO. Retrospectively, 166 IPAH patients were included and grouped based on a DLCO cut-off value of 45% pred (IPAH(<45%) and IPAH(≥45%)). Clinical characteristics, treatment responses and survival were compared. IPAH(<45%) were older, more often male, had a more frequent history of coronary disease and a higher tobacco exposure. Forced expiratory volume in 1 s (FEV1), FEV1/forced vital capacity, total lung capacity and alveolar volume values were slightly lower and computed tomography scan abnormalities more prevalent in patients with a low DLCO. Age and number of pack years were independently associated with DLCO < 45% pred. IPAH(<45%) showed no different haemodynamic profile, yet worse exercise performance and a worse survival rate, which were both related to age, sex and the presence of coronary disease. To conclude, a severely reduced DLCO in IPAH is associated with advanced age and a greater tobacco exposure. These patients have a worse exercise performance despite a similar hemodynamic profile. We confirm the decreased survival in this patient group and now show that this poor outcome is related to age, sex and the presence of coronary disease.
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Hipertensión Pulmonar/fisiopatología , Hipertensión Pulmonar/terapia , Adulto , Anciano , Monóxido de Carbono/química , Enfermedad de la Arteria Coronaria/complicaciones , Hipertensión Pulmonar Primaria Familiar , Femenino , Volumen Espiratorio Forzado , Humanos , Pulmón/fisiopatología , Masculino , Persona de Mediana Edad , Pronóstico , Alveolos Pulmonares/fisiología , Capacidad de Difusión Pulmonar , Fibrosis Pulmonar/patología , Estudios Retrospectivos , Fumar/efectos adversos , Tomografía Computarizada por Rayos X , Capacidad Pulmonar Total , Resultado del Tratamiento , Capacidad VitalRESUMEN
BACKGROUND: Childhood-onset pulmonary arterial hypertension (PAH) is rare and differs from adult-onset disease in clinical presentation, with often unexplained mental retardation and dysmorphic features (MR/DF). Mutations in the major PAH gene, BMPR2, were reported to cause PAH in only 10-16% of childhood-onset patients. We aimed to identify more genes associated with childhood-onset PAH. METHODS: We studied 20 consecutive cases with idiopathic or heritable PAH. In patients with accompanying MR/DF (n=6) array-comparative genomic hybridisation analysis was performed, with the aim of finding common deletion regions containing candidate genes for PAH. Three patients had overlapping deletions of 17q23.2. TBX2 and TBX4 were selected from this area as candidate genes and sequenced in all 20 children. After identifying TBX4 mutations in these children, we subsequently sequenced TBX4 in a cohort of 49 adults with PAH. Because TBX4 mutations are known to cause small patella syndrome (SPS), all patients with newly detected TBX4 mutations were screened for features of SPS. We also screened a third cohort of 23 patients with SPS for PAH. RESULTS: TBX4 mutations (n=3) or TBX4-containing deletions (n=3) were detected in 6 out of 20 children with PAH (30%). All living patients and two parents with TBX4 mutations appeared to have previously unrecognised SPS. In the adult PAH-cohort, one TBX4 mutation (2%) was detected. Screening in the cohort of (predominantly adult) SPS patients revealed no PAH. CONCLUSIONS: These data indicate that TBX4 mutations are associated with childhood-onset PAH, but that the prevalence of PAH in adult TBX4 mutation carriers is low.
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Enfermedades del Desarrollo Óseo/genética , Cadera/anomalías , Hipertensión Pulmonar/genética , Isquion/anomalías , Mutación , Rótula/anomalías , Proteínas de Dominio T Box/genética , Enfermedades del Desarrollo Óseo/complicaciones , Niño , Preescolar , Estudios de Cohortes , Hipertensión Pulmonar Primaria Familiar , Femenino , Predisposición Genética a la Enfermedad , Humanos , Hipertensión Pulmonar/complicaciones , Hipertensión Pulmonar/epidemiología , Lactante , MasculinoRESUMEN
Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant condition due to germline FLCN (folliculin) mutations, characterized by skin fibrofolliculomas, lung cysts, pneumothorax and renal cancer. We identified a de novo FLCN mutation, c.499C>T (p.Gln167X), in a patient who presented with spontaneous pneumothorax. Subsequently, typical skin features and asymptomatic renal cancer were diagnosed. Probably, de novo FLCN mutations are rare. However, they may be under-diagnosed if BHD is not considered in sporadic patients who present with one or more of the syndromic features. Genetic and immunohistochemical analysis of the renal tumour indicated features compatible with a tumour suppressor role of FLCN. The finding that mutant FLCN was expressed in the tumour might indicate residual functionality of mutant FLCN, a notion which will be explored in future studies.
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Mutación de Línea Germinal/genética , Neoplasias Renales/genética , Neumotórax/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Supresoras de Tumor/genética , Adulto , Humanos , Técnicas para Inmunoenzimas , Neoplasias Renales/diagnóstico , Imagen por Resonancia Magnética , Masculino , Neumotórax/diagnóstico , Pronóstico , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: Previously, we proposed that familial multiple trichodiscomas (OMIM 190340) is distinct from Birt-Hogg-Dubé syndrome (BHD) (OMIM #135150). BHD is characterized by multiple fibrofolliculomas/trichodiscomas, lung cysts, pneumothorax, and renal cell cancer. Germline FLCN mutations can be detected in most but not all BHD families. OBJECTIVE: We sought to evaluate familial multiple trichodiscomas at a clinical and genetic level. We now renamed this condition "familial multiple discoid fibromas" (FMDF) to emphasize the distinction from BHD. METHODS: In 8 additional families with an autosomal dominant pattern of multiple discoid fibromas we assessed the clinical findings and the histopathological features of skin lesions. FLCN germline mutation analysis was completed in 7 families. In two of these families segregation analysis was performed using polymorphic DNA markers in and around the FLCN locus. RESULTS: The clinical findings in FMDF are different from those in BHD with early onset of skin lesions, prominent involvement of the pinnae, and discoid fibromas without the follicular epithelial component characteristic of the fibrofolliculoma/trichodiscoma spectrum of BHD. In addition, there were no evident pulmonary or renal complications. In none of the families were pathogenic FLCN germline mutations identified. Using segregation analysis we could exclude involvement of the FLCN locus in the two kindreds tested. LIMITATIONS: The prevalence of FMDF is presently unknown. The underlying gene defect has not yet been identified. CONCLUSIONS: FMDF is clinically distinct from BHD and is not linked to the FLCN locus.
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Síndrome de Birt-Hogg-Dubé/diagnóstico , Fibroma/diagnóstico , Fibroma/genética , Proteínas Proto-Oncogénicas/genética , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/genética , Proteínas Supresoras de Tumor/genética , Adolescente , Adulto , Edad de Inicio , Síndrome de Birt-Hogg-Dubé/patología , Niño , Preescolar , Femenino , Fibroma/clasificación , Fibroma/patología , Mutación de Línea Germinal , Humanos , Lactante , Masculino , Persona de Mediana Edad , Linaje , Neoplasias Cutáneas/clasificación , Neoplasias Cutáneas/patologíaRESUMEN
BACKGROUND: Lynch syndrome is caused by germline mutations in MSH2, MLH1, MSH6, and PMS2 mismatch-repair genes and leads to a high risk of colorectal and endometrial cancer. We previously showed that constitutional 3' end deletions of EPCAM can cause Lynch syndrome through epigenetic silencing of MSH2 in EPCAM-expressing tissues, resulting in tissue-specific MSH2 deficiency. We aim to establish the risk of cancer associated with such EPCAM deletions. METHODS: We obtained clinical data for 194 carriers of a 3' end EPCAM deletion from 41 families known to us at the Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands and compared cancer risk with data from a previously described cohort of 473 carriers from 91 families with mutations in MLH1, MSH2, MSH6, or a combined EPCAM-MSH2 deletion. FINDINGS: 93 of the 194 EPCAM deletion carriers were diagnosed with colorectal cancer; three of the 92 women with EPCAM deletions were diagnosed with endometrial cancer. Carriers of an EPCAM deletion had a 75% (95% CI 65-85) cumulative risk of colorectal cancer before the age of 70 years (mean age at diagnosis 43 years [SD 12]), which did not differ significantly from that of carriers of combined EPCAM-MSH2 deletion (69% [95% CI 47-91], p=0·8609) or mutations in MSH2 (77% [64-90], p=0·5892) or MLH1 (79% [68-90], p=0·5492), but was higher than noted for carriers of MSH6 mutation (50% [38-62], p<0·0001). By contrast, women with EPCAM deletions had a 12% [0-27] cumulative risk of endometrial cancer, which was lower than was that noted for carriers of a combined EPCAM-MSH2 deletion (55% [20-90], p<0·0001) or of a mutation in MSH2 (51% [33-69], p=0·0006) or MSH6 (34% [20-48], p=0·0309), but did not differ significantly from that noted for MLH1 (33% [15-51], p=0·1193) mutation carriers. This risk seems to be restricted to deletions that extend close to the MSH2 gene promoter. Of 194 carriers of an EPCAM deletion, three had duodenal cancer and four had pancreatic cancer. INTERPRETATION: EPCAM deletion carriers have a high risk of colorectal cancer; only those with deletions extending close to the MSH2 promoter have an increased risk of endometrial cancer. These results underscore the effect of mosaic MSH2 deficiency, leading to variable cancer risks, and could form the basis of an optimised protocol for the recognition and targeted prevention of cancer in EPCAM deletion carriers.
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Antígenos de Neoplasias/genética , Moléculas de Adhesión Celular/genética , Neoplasias Colorrectales/genética , Neoplasias Endometriales/genética , Eliminación de Secuencia , Adolescente , Adulto , Anciano , Estudios de Cohortes , Neoplasias Colorrectales/etiología , Neoplasias Endometriales/etiología , Molécula de Adhesión Celular Epitelial , Femenino , Eliminación de Gen , Humanos , Masculino , Persona de Mediana Edad , Proteína 2 Homóloga a MutS/genética , Regiones Promotoras Genéticas , RiesgoRESUMEN
Birt-Hogg-Dubé syndrome (BHD) is an autosomal-dominant genodermatosis characterized by skin fibrofolliculomas and an increased risk of spontaneous pneumothorax, renal and possibly other tumors. A causative gene (FLCN) on chromosome 17p has recently been identified. We here report clinical and genetic studies of 20 BHD families ascertained by the presence of multiple fibrofolliculomas or trichodiscomas in the proband. Pathogenic FLCN germline mutations were found in 11 (69%) of 16 probands tested and in 14 family members. Six different FLCN germline mutations were detected, four of which have not been reported previously. The clinical features were variable. None and less than 10 skin lesions were observed in two mutation carriers at the age of 67 and 29 years, respectively. Spontaneous pneumothorax was reported in four and renal carcinoma of mixed histological types in two of 36 BHD-affected individuals and/or FLCN mutation carriers. Both the prevalence of spontaneous pneumothorax and renal tumors appeared to be relatively low compared with previously reported data. Various other extracutaneous tumors were observed in 11 of 36 BHD-affected individuals and/or FLCN mutation carriers. This study of the second largest cohort to date contributes to the expanding data on the variable phenotype and underlying gene defects in BHD.
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Neoplasias Renales/genética , Neumotórax/genética , Proteínas/genética , Proteínas Proto-Oncogénicas/genética , Enfermedades de la Piel/genética , Proteínas Supresoras de Tumor/genética , Adulto , Anciano , Cromosomas Humanos Par 17 , Mutación de Línea Germinal , Humanos , Persona de Mediana EdadRESUMEN
PURPOSE: We used four-dimensional multislice spiral computed tomography (MSCT) to determine respiratory lung-tumor motion and compared this strategy to common clinical practice in conformal radiotherapy treatment-planning imaging. METHODS AND MATERIALS: The entire lung volume of 10 consecutive patients with 14 lung metastases were scanned by a 16-slice MSCT. During the scans, patients were instructed to breathe through a spirometer that was connected to a laptop computer. For each patient, 10 stacks of 1.5-mm slices, equally distributed throughout the respiratory cycle, were reconstructed from the acquired MSCT data. The lung tumors were manually contoured in each data set. For each patient, the tumor-volume contours of all data sets were copied to 1 data set, which allowed determination of the volume that encompassed all 10 lung-tumor positions (i.e., the tumor-traversed volume [TTV]) during the respiratory cycle. The TTV was compared with the 10 tumor volumes contoured for each patient, to which an empiric respiratory-motion margin was added. The latter target volumes were designated internal-motion included tumor volume (IMITV). RESULTS: The TTV measurements were significantly smaller than the reference IMITV measurements (5.2 +/- 10.2 cm(3) and 10.1 +/- 13.7 cm(3), respectively). All 10 IMITVs for 2 of the 4 tumors in 1 subject completely encompassed the TTV. All 10 IMITVs for 3 tumors in 2 patients did not show overlap with up to 35% of the corresponding TTV. The 10 IMITVs for the remaining tumors either completely encompassed the corresponding TTV or did not show overlap with up to 26% of the corresponding TTV. CONCLUSIONS: We found that individualized determination of respiratory lung-tumor motion by four-dimensional respiratory-gated MSCT represents a better and simple strategy to incorporate periodic physiologic motion compared with a generalized approach. The former strategy can, therefore, improve common and state-of-the-art clinical practice in conformal radiotherapy.
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Neoplasias Pulmonares/diagnóstico por imagen , Movimiento , Radioterapia Conformacional , Respiración , Tomografía Computarizada por Rayos X/métodos , Anciano , Femenino , Humanos , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/secundario , Masculino , Persona de Mediana EdadRESUMEN
PURPOSE: High-precision external beam radiotherapy (EBRT) has been suggested as a potential alternative to endovascular brachytherapy for the treatment of coronary artery in-stent restenosis. The purpose of our study was to investigate and compare different options to define a smallest feasible target volume. METHODS AND MATERIALS: The cardiac motion of 17 coronary artery stents in 17 patients was studied by use of biplane conventional angiography, recorded during breath-hold. Each stent was reconstructed in three dimensions by use of biplane sets of frames covering an entire cardiac cycle. The volume traversed by the stent during the entire or part of the cardiac cycle was determined. Four options to define the stent-traversed volume (STV) as a target for high-precision EBRT were investigated. RESULTS: The mean STV during the entire cardiac cycle was 3.5 cm3; the STV represented less than 1% of the heart volume in all patients. The STV during the diastolic and systolic phase resulted in a mean reduction of 26.6% and 29.1%, respectively, compared with the STV during the entire cardiac cycle. The smallest STV, measured during a 160-ms interval within the cardiac cycle, resulted in a mean maximal reduction of 75.9% compared with the STV during the entire cardiac cycle. CONCLUSIONS: The STV during the entire cardiac cycle represents a small potential target volume for high-precision EBRT. A significant reduction of this target volume is possible in case of definition during a selected interval within the cardiac cycle.
Asunto(s)
Reestenosis Coronaria/radioterapia , Contracción Miocárdica , Angiografía Coronaria , Reestenosis Coronaria/diagnóstico por imagen , Diástole , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Persona de Mediana Edad , Movimiento , Stents , SístoleRESUMEN
PURPOSE: Several drawbacks of endovascular brachytherapy for the treatment of coronary artery in-stent restenosis may be addressed by high-precision external beam radiotherapy (EBRT). The dosimetric characteristics of both treatment techniques were compared. METHODS AND MATERIALS: The traversed volume of 10 coronary artery stents during the cardiac cycle was determined by electrocardiographically gated multislice spiral CT in 10 patients. By use of this traversed volume, high-precision EBRT treatment plans were generated for stents in the left circumflex (LCx), left anterior descending (LAD), and right coronary artery (RCA). The maximum dose to the nontargeted major coronary arteries was determined and compared to similar data calculated for endovascular brachytherapy. RESULTS: High-precision EBRT targeted at LCx stents contributed a mean maximum dose (D(max)) of 83.5% (range: 71.6-95.3%) and 16.3% to the LAD and RCA, respectively. Targeted LAD stents contributed a mean D(max) of 39.3% (range: 14.5-94.8%) and 5.2% (range: 0-13.4%) to the LCx and RCA, respectively. Targeted RCA stents contributed a mean D(max) of 6.2% (range: 0-12.4%) and 5.8% (range: 0-11.5%) to the LCx and LAD, respectively. Endovascular brachytherapy targeted at LCx stents contributed a mean D(max) of 1.7% (range: 0.7-2.7%) and 1.0% (range: 0.6-1.4%) to the LAD and RCA, respectively. Targeted LAD stents contributed a mean D(max) of 5.2% (range: 0.5-11.4%) and 0.7% (range: 0.4-1.1%) to the LCx and RCA, respectively; targeted RCA stents contributed a mean D(max) of 0.3% (range: 0.2-0.5%) and 0.2% (range: 0.1-0.3%) to the LCx and LAD, respectively. CONCLUSIONS: Although the doses distributed throughout the heart were higher for high-precision EBRT compared to endovascular brachytherapy, they are expected to be clinically irrelevant when nontargeted major coronary arteries are not closely situated to the targeted vessel segment. These encouraging results warrant further investigation of high-precision EBRT as a potential alternative to endovascular brachytherapy for the treatment of coronary artery in-stent restenosis.
Asunto(s)
Braquiterapia/métodos , Reestenosis Coronaria/radioterapia , Vasos Coronarios/efectos de la radiación , Stents , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Radiometría , Dosificación RadioterapéuticaRESUMEN
Three-dimensional reconstructions of 19 coronary artery stents from biplane angiograms were used for measurement of the volume through which the stents traversed during the cardiac cycle. This volume, less than 0.8% of the whole heart volume in all patients, represents a target volume for high-precision radiotherapy to treat coronary artery in-stent restenosis.
Asunto(s)
Braquiterapia/métodos , Volumen Cardíaco , Angiografía Coronaria/métodos , Reestenosis Coronaria/rehabilitación , Radioterapia Conformacional/métodos , Stents/efectos adversos , Anciano , Reestenosis Coronaria/etiología , Reestenosis Coronaria/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Dosificación RadioterapéuticaRESUMEN
PURPOSE: To measure the effect of cardiac motion on coronary artery stent position during the cardiac cycle as a first step toward exploring the feasibility of stereotactic external beam radiation therapy targeted at restenotic stented coronary arteries. METHODS AND MATERIALS: The three-dimensional (3D) position of eight coronary artery stents in 8 patients immobilized in a stereotactic body frame was studied noninvasively by single-breathhold ECG-gated multislice spiral computed tomography (MSCT) during 10 retrospectively selected phases, equally distributed throughout the R-R interval of consecutive cardiac cycles. The volume encompassing all measured 3D positions of the stent was measured. RESULTS: Stent volumes measured by MSCT closely agreed with measurements by quantitative coronary angiography (r > 0.99). The mean of the maximum 3D stent center of mass displacement between any two phases during the cardiac cycle for all eight coronary arteries was 7.5 mm (range 3.3-20.5 mm) in the lateral direction, 8.6 mm (range 2.7-21.6 mm) in the ventrodorsal direction, and 8.2 mm (range 2.5-19.7 mm) in the craniocaudal direction. As was anticipated, the volume encompassing all measured 3D positions of the stent represented only a fraction of the whole heart volume in all patients, i.e., less than 0.6%. CONCLUSIONS: ECG-gated MSCT allowed the measurement of the volume encompassing multiphase 3D positions of coronary artery stents during the cardiac cycle. This volume, a measure of the cardiac motion effect on coronary artery stent position during the cardiac cycle, represents a moving gross target for stereotactic external beam radiation therapy.