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1.
Am J Med Genet A ; : e63605, 2024 May 16.
Artículo en Inglés | MEDLINE | ID: mdl-38752492

RESUMEN

Germline SMAD4 pathogenic variants (PVs) cause juvenile polyposis syndrome (JPS), which is known for an increased risk of gastrointestinal juvenile polyps and gastrointestinal cancer. Many patients with SMAD4 PV also show signs of hereditary hemorrhagic telangiectasia (HHT) and some patients have aneurysms and dissections of the thoracic aorta. Here we describe two patients with a germline SMAD4 PV and a remarkable clinical presentation including multiple medium-sized arterial aneurysms. More data are needed to confirm whether the more extensive vascular phenotype and the other described features in our patients are indeed part of a broader JPS spectrum.

2.
Psychiatr Genet ; 34(2): 31-36, 2024 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-38441147

RESUMEN

Recent advancements in psychiatric genetics have sparked a lively debate on the opportunities and pitfalls of incorporating polygenic scores into clinical practice. Yet, several ethical concerns have been raised, casting doubt on whether further development and implementation of polygenic scores would be compatible with providing ethically responsible care. While these ethical issues warrant thoughtful consideration, it is equally important to recognize the unresolved need for guidance on heritability among patients and their families. Increasing the availability of genetic counseling services in psychiatry should be regarded as a first step toward meeting these needs. As a next step, future integration of novel genetic tools such as polygenic scores into genetic counseling may be a promising way to improve psychiatric counseling practice. By embedding the exploration of polygenic psychiatry into the supporting environment of genetic counseling, some of the previously identified ethical pitfalls may be prevented, and opportunities to bolster patient empowerment can be seized upon. To ensure an ethically responsible approach to psychiatric genetics, active collaboration with patients and their relatives is essential, accompanied by educational efforts to facilitate informed discussions between psychiatrists and patients.


Asunto(s)
Trastornos Mentales , Psiquiatría , Humanos , Trastornos Mentales/genética , Psiquiatras , Herencia Multifactorial/genética , Atención Dirigida al Paciente
4.
Gastrointest Endosc ; 97(1): 69-77.e1, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36029885

RESUMEN

BACKGROUND AND AIMS: Patients with familial adenomatous polyposis (FAP) undergo (procto)colectomy to prevent colorectal cancer from developing. Interestingly, after proctocolectomy with ileal pouch-anal anastomosis (IPAA), most patients develop adenomas in the pouch. This is not well described for patients with end ileostomy. We aimed to compare ileal adenoma development in patients with IPAA with those with end ileostomy. METHODS: This historical cohort study included FAP patients with IPAA or end ileostomy who underwent surveillance endoscopies between 2001 and 2021. Primary outcomes were the proportion of patients with ileal adenomas, location of adenomas, and proportion of patients undergoing surgical excision of pouch/end ileostomy. RESULTS: Overall, 144 patients with IPAA (n = 111) and end ileostomy (n = 33) were included. Five years after surgery, 15% of patients with IPAA had ileal adenomas versus 4% after ileostomy. At 10 years, these estimates were 48% versus 9% and at 20 years were 85% versus 43% (log-rank P < .001). Adenomas developed more often in the pouch body (95%) in the IPAA group and more often at the everted site of the ileostomy (77%) in the ileostomy group. Numbers for surgical excision of the pouch (n = 9) or ileostomy (n = 3) for polyposis or cancer were comparable. Taking into account potential confounders in a multivariable Cox regression analysis, having an IPAA was significantly associated with ileal adenoma development. CONCLUSIONS: After proctocolectomy, FAP patients with IPAA more often developed ileal adenomas than patients with end ileostomy. This could potentially affect long-term management, and patients with end ileostomy might benefit from less-frequent endoscopic surveillance.


Asunto(s)
Adenoma , Poliposis Adenomatosa del Colon , Reservorios Cólicos , Proctocolectomía Restauradora , Humanos , Proctocolectomía Restauradora/efectos adversos , Reservorios Cólicos/efectos adversos , Ileostomía , Estudios de Cohortes , Poliposis Adenomatosa del Colon/cirugía , Adenoma/epidemiología , Anastomosis Quirúrgica/efectos adversos
5.
Transl Psychiatry ; 12(1): 442, 2022 10 11.
Artículo en Inglés | MEDLINE | ID: mdl-36220808

RESUMEN

Genetic testing has evolved rapidly over recent years and new developments have the potential to provide insights that could improve the ability to diagnose, treat, and prevent diseases. Information obtained through genetic testing has proven useful in other specialties, such as cardiology and oncology. Nonetheless, a range of barriers impedes techniques, such as whole-exome or whole-genome sequencing, pharmacogenomics, and polygenic risk scoring, from being implemented in psychiatric practice. These barriers may be procedural (e.g., limitations in extrapolating results to the individual level), economic (e.g., perceived relatively elevated costs precluding insurance coverage), or related to clinicians' knowledge, attitudes, and practices (e.g., perceived unfavorable cost-effectiveness, insufficient understanding of probability statistics, and concerns regarding genetic counseling). Additionally, several ethical concerns may arise (e.g., increased stigma and discrimination through exclusion from health insurance). Here, we provide an overview of potential barriers for the implementation of genetic testing in psychiatry, as well as an in-depth discussion of strategies to address these challenges.


Asunto(s)
Pruebas Genéticas , Psiquiatría , Conocimientos, Actitudes y Práctica en Salud , Humanos , Herencia Multifactorial
6.
J Neurol Neurosurg Psychiatry ; 93(1): 93-100, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-33906932

RESUMEN

OBJECTIVES: The chromosome 9 open reading frame 72 gene (C9orf72) hexanucleotide repeat expansion (C9orf72RE) is the most common genetic cause of behavioural variant frontotemporal dementia (bvFTD). Since the onset of the C9orf72RE-associated disease is sometimes hard to define, we hypothesise that C9orf72RE may cause a lifelong neuropsychiatric vulnerability. The first aim of our study was to explore lifelong behavioural and personality characteristics in C9orf72RE. Second, we aimed to describe distinctive characteristics of C9orf72RE during disease course. METHODS: Out of 183 patients from the Amsterdam Dementia Cohort that underwent genetic testing between 2011 and 2018, 20 C9orf72RE bvFTD patients and 23 C9orf72RE negative bvFTD patients were included. Patients and their relatives were interviewed extensively to chart their biography. Data analysis was performed through a mixed-methods approach including qualitative and quantitative analyses. RESULTS: Education, type of professional career and number of intimate partners were not different between carriers and non-carriers. Carriers were more often described by their relatives as having 'fixed behavioural patterns in daily life' and with limited empathy already years before onset of bvFTD symptoms. In carriers, disease course was more often characterised by excessive buying and obsessive physical exercise than in non-carriers. CONCLUSION: This is the first study thoroughly exploring biographies of bvFTD patients with C9orf72RE, revealing that subtle personality traits may be present early in life. Our study suggests that C9orf72RE exerts a lifelong neuropsychiatric vulnerability. This may strengthen hypotheses of links between neurodevelopmental and neurodegenerative diseases. Moreover, the presence of a distinct C9orf72RE -associated syndrome within the FTD spectrum opens doors for investigation of vulnerable neuronal networks.


Asunto(s)
Proteína C9orf72 , Expansión de las Repeticiones de ADN , Demencia Frontotemporal/psicología , Adulto , Anciano , Anciano de 80 o más Años , Esclerosis Amiotrófica Lateral/genética , Progresión de la Enfermedad , Femenino , Demencia Frontotemporal/genética , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Mutación , Países Bajos
7.
Cell Rep ; 35(11): 109259, 2021 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-34133918

RESUMEN

Dysfunction of the endolysosomal-autophagy network is emerging as an important pathogenic process in Alzheimer's disease. Mutations in the sorting receptor-encoding gene SORL1 cause autosomal-dominant Alzheimer's disease, and SORL1 variants increase risk for late-onset AD. To understand the contribution of SORL1 mutations to AD pathogenesis, we analyze the effects of a SORL1 truncating mutation on SORL1 protein levels and endolysosome function in human neurons. We find that truncating mutation results in SORL1 haploinsufficiency and enlarged endosomes in human neurons. Analysis of isogenic SORL1 wild-type, heterozygous, and homozygous null neurons demonstrates that, whereas SORL1 haploinsufficiency results in endosome dysfunction, complete loss of SORL1 leads to additional defects in lysosome function and autophagy. Neuronal endolysosomal dysfunction caused by loss of SORL1 is relieved by extracellular antisense oligonucleotide-mediated reduction of APP protein, demonstrating that PSEN1, APP, and SORL1 act in a common pathway regulating the endolysosome system, which becomes dysfunctional in AD.


Asunto(s)
Precursor de Proteína beta-Amiloide/metabolismo , Autofagia , Endosomas/metabolismo , Proteínas Relacionadas con Receptor de LDL/deficiencia , Lisosomas/metabolismo , Proteínas de Transporte de Membrana/deficiencia , Neuronas/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Ácido Aspártico Endopeptidasas/metabolismo , Demencia/genética , Demencia/patología , Técnicas de Inactivación de Genes , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Proteínas Relacionadas con Receptor de LDL/genética , Proteínas Relacionadas con Receptor de LDL/metabolismo , Proteínas de Transporte de Membrana/genética , Proteínas de Transporte de Membrana/metabolismo , Oligonucleótidos Antisentido/administración & dosificación , Oligonucleótidos Antisentido/farmacología , Fenotipo , Unión Proteica
8.
Health Expect ; 24(4): 1025-1043, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34101951

RESUMEN

BACKGROUND: Health-care providers increasingly have to discuss uncertainty with patients. Awareness of uncertainty can affect patients variably, depending on how it is communicated. To date, no overview existed for health-care professionals on how to discuss uncertainty. OBJECTIVE: To generate an overview of available recommendations on how to communicate uncertainty with patients during clinical encounters. SEARCH STRATEGY: A scoping review was conducted. Four databases were searched following the PRISMA-ScR statement. Independent screening by two researchers was performed of titles and abstracts, and subsequently full texts. INCLUSION CRITERIA: Any (non-)empirical papers were included describing recommendations for any health-care provider on how to orally communicate uncertainty to patients. DATA EXTRACTION: Data on provided recommendations and their characteristics (eg, target group and strength of evidence base) were extracted. Recommendations were narratively synthesized into a comprehensible overview for clinical practice. RESULTS: Forty-seven publications were included. Recommendations were based on empirical findings in 23 publications. After narrative synthesis, 13 recommendations emerged pertaining to three overarching goals: (a) preparing for the discussion of uncertainty, (b) informing patients about uncertainty and (c) helping patients deal with uncertainty. DISCUSSION AND CONCLUSIONS: A variety of recommendations on how to orally communicate uncertainty are available, but most lack an evidence base. More substantial research is needed to assess the effects of the suggested communicative approaches. Until then, health-care providers may use our overview of communication strategies as a toolbox to optimize communication about uncertainty with patients. PATIENT OR PUBLIC CONTRIBUTION: Results were presented to stakeholders (physicians) to check and improve their practical applicability.


Asunto(s)
Comunicación , Médicos , Personal de Salud , Humanos , Incertidumbre
9.
Breast ; 58: 80-87, 2021 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-33933926

RESUMEN

BACKGROUND: There is an underuse of genetic testing in breast cancer patients with a lower level of education, limited health literacy or a migrant background. We aimed to study the effect of a health literacy training program for surgical oncologists and specialized nurses on disparities in referral to genetic testing. METHODS: We conducted a multicenter study in a quasi-experimental pre-post (intervention) design. The intervention consisted of an online module and a group training for surgical oncologists and specialized nurses in three regions in the Netherlands. Six months pre- and 12 months post intervention, clinical geneticists completed a checklist with socio-demographic characteristics including the level of health literacy of each referred patient. We conducted univariate and logistic regression analysis to evaluate the effect of the training program on disparities in referral to genetic testing. RESULTS: In total, 3179 checklists were completed, of which 1695 were from hospital referrals. No significant differences were found in educational level, level of health literacy and migrant background of patients referred for genetic testing by healthcare professionals working in trained hospitals before (n = 795) and after (n = 409) the intervention. The mean age of patients referred by healthcare professionals from trained hospitals was significantly lower after the intervention (52.0 vs. 49.8, P = 0.003). CONCLUSION: The results of our study suggest that the health literacy training program did not decrease disparities in referral to genetic testing. Future research in a more controlled design is needed to better understand how socio-demographic factors influence referral to breast cancer genetic testing and what other factors might contribute.


Asunto(s)
Neoplasias de la Mama , Alfabetización en Salud , Enfermeras y Enfermeros , Oncólogos , Neoplasias de la Mama/genética , Femenino , Pruebas Genéticas , Humanos , Derivación y Consulta
10.
Fam Cancer ; 20(4): 263-271, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-33686467

RESUMEN

Recognizing a tumor predisposition syndrome (TPS) in a child with cancer is of clinical relevance. Earlier we developed a screening tool to increase diagnostic accuracy and clinical efficiency of identifying TPSs in children with cancer. Here we report on the value of this tool in clinical practice. TuPS is a prospective, observational, multi-center study including children newly diagnosed with cancer from 2016 to 2019 in the Netherlands. Children in whom a TPS had been diagnosed before the cancer diagnosis were excluded. The screening tool consists of a checklist, 2D and 3D photographic series and digital assessment of these by a clinical geneticist. If a TPS was suspected, the patient was assessed positive and referred for routine genetic consultation. Primary aim was to assess the clinical value of this new screening tool. Of the 363 included patients, 57% (208/363) were assessed positive. In 15% of patients (32/208), the 2D photographic series with (n = 12) or without (n = 20) 3D photographs were decisive in the positive assessment. In 2% (4/208) of positive assessed patients, a TPS was diagnosed, and in an additional 2% (4/208) a germline variant of uncertain significance was found. Thirty-five negatively assessed patients were evaluated through routine genetic consultation as controls, in none a TPS was detected. Using the screening tool, 57% of the patients were assessed as suspected for having a TPS. No false negative results were identified in the negative control group in the clinical care setting. The observed prevalence of TPS was lower than expected, due to selection bias in the cohort.


Asunto(s)
Neoplasias , Niño , Detección Precoz del Cáncer , Humanos , Tamizaje Masivo , Neoplasias/diagnóstico , Neoplasias/genética , Estudios Prospectivos , Síndrome
11.
Eur J Hum Genet ; 29(5): 789-799, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33437034

RESUMEN

Uncertainty is increasingly discussed during genetic counseling due to innovative techniques, e.g., multigene panel testing. Discussions about uncertainty may impact counselees variably, depending on counselors' communication styles. Ideally, the discussion of uncertainty enables counselees to cope with uncertainty and make well-informed decisions about testing. We examined the impact of how counselors convey uncertainty and address counselees' uncertainty, and explored the role of individual characteristics. Therefore, a randomized controlled experiment using videos was conducted. Former counselees (N = 224) viewed one video depicting a genetic consultation about multigene panel testing. The extent of counselors' communication of uncertainty (comprehensive vs. the essence) and their response to counselees' uncertainty expressions (providing information vs. providing space for emotions vs. normalizing and counterbalancing uncertainty) were systematically manipulated. Individual characteristics, e.g., uncertainty tolerance, were assessed, as well as outcome variables (primary outcomes: feelings of uncertainty and information recall). No effects were found on primary outcomes. Participants were most satisfied when the essence was communicated, combined with providing information or providing space responses (p = 0.002). Comprehensive information resulted in less perceived steering toward testing (p = 0.005). Participants with lower uncertainty tolerance or higher trait anxiety were less confident about their understanding when receiving comprehensive information (p = 0.025). Participants seeking information experienced less uncertainty (p = 0.003), and trusted their counselor more (p = 0.028), when the counselor used information providing responses. In sum, the impact of discussing uncertainty primarily depends on individual characteristics. Practical guidelines should address how to tailor the discussion of uncertainty.


Asunto(s)
Asesoramiento Genético/métodos , Neoplasias/genética , Incertidumbre , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Asesoramiento Genético/psicología , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/diagnóstico , Satisfacción del Paciente , Revelación de la Verdad
12.
J Community Genet ; 12(1): 101-110, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-32880035

RESUMEN

Individuals having a genetic predisposition to cancer and their partners face challenging decisions regarding their wish to have children. This study aimed to determine the effects of an online decision aid to support couples in making an informed decision regarding their reproductive options. A nationwide pretest-posttest study was conducted in the Netherlands among 131 participants between November 2016 and May 2018. Couples were eligible for participation if one partner had a pathogenic variant predisposing for an autosomal dominant hereditary cancer syndrome. Participants completed a questionnaire before use (T0), and at 3 months (T3) after use of the decision aid to assess the primary outcome measure informed decision-making, and the secondary outcome measures decisional conflict, knowledge, realistic expectations, level of deliberation, and decision self-efficacy. T0-T3 comparisons show an overall positive effect for all outcome measures (all ps < 0.05; knowledge (ES = - 1.05), decisional conflict (ES = 0.99), participants' decision self-efficacy (ES = -0.55), level of deliberation (ES = - 0.50), and realistic expectations (ES = - 0.44). Informed decision-making increased over time and 58.0% of the participants made an informed reproductive decision at T3. The online decision aid seems to be an appropriate tool to complement standard reproductive counseling to support our target group in making an informed reproductive decision. Use of the decision aid may lessen the negative psychological impact of decision-making on couples' daily life and wellbeing.

13.
United European Gastroenterol J ; 8(8): 865-877, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32703081

RESUMEN

BACKGROUND: Individuals with a very high lifetime risk of developing pancreatic ductal adenocarcinoma; for example, hereditary pancreatitis and main-duct or mixed-type intraductal papillary mucinous neoplasm, may wish to discuss prophylactic total pancreatectomy but strategies to do so are lacking. OBJECTIVE: To develop a shared decision-making programme for prophylactic total pancreatectomy using decision tables. METHODS: Focus group meetings with patients were used to identify relevant questions. Systematic reviews were performed to answer these questions. RESULTS: The first tables included hereditary pancreatitis and main-duct or mixed-type intraductal papillary mucinous neoplasm. No studies focused on prophylactic total pancreatectomy in these groups. In 52 studies (3570 patients), major morbidity after total pancreatectomy was 25% and 30-day mortality was 6%. After minimally invasive total pancreatectomy (seven studies, 35 patients) this was, respectively, 13% and 0%. Exocrine insufficiency-related symptoms occurred in 33%. Quality of life after total pancreatectomy was slightly lower compared with the general population. CONCLUSION: The decision tables can be helpful for discussing prophylactic total pancreatectomy with individuals at high risk of pancreatic ductal adenocarcinoma.


Asunto(s)
Carcinoma Ductal Pancreático/prevención & control , Toma de Decisiones Conjunta , Técnicas de Apoyo para la Decisión , Pancreatectomía/efectos adversos , Procedimientos Quirúrgicos Profilácticos/efectos adversos , Carcinoma Ductal Pancreático/epidemiología , Progresión de la Enfermedad , Insuficiencia Pancreática Exocrina/epidemiología , Insuficiencia Pancreática Exocrina/etiología , Humanos , Pancreatectomía/métodos , Conductos Pancreáticos/patología , Neoplasias Pancreáticas/epidemiología , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/cirugía , Pancreatitis Crónica/epidemiología , Pancreatitis Crónica/patología , Pancreatitis Crónica/cirugía , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Procedimientos Quirúrgicos Profilácticos/métodos , Calidad de Vida , Medición de Riesgo/métodos , Resultado del Tratamiento
14.
Br J Cancer ; 122(12): 1865-1871, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32307443

RESUMEN

BACKGROUND: Faecal immunochemical testing (FIT) is suboptimal in detecting advanced neoplasia (AN). To increase the sensitivity and yield of a FIT-based screening programme, FIT could be combined with risk factors for AN. We evaluated the incremental yield of adding a family history questionnaire (FHQ) on colorectal cancer (CRC) and Lynch syndrome-associated tumours to the Dutch FIT-based screening programme. METHODS: Six thousand screen-naive individuals, aged 59-75 years, were invited to complete a FIT (FOB-Gold, cut-off 47 µg Hb/g faeces) and a validated online FHQ. Participants with a positive FIT and/or positive FHQ, confirmed after genetic counselling, were referred for colonoscopy. Yield of detecting AN per 1000 invitees for the combined strategy was compared with the FIT-only strategy. RESULTS: Of the 5979 invitees, 1952 (32.6%) completed the FIT only, 2379 (39.8%) completed both the FIT and FHQ and 95 (1.6%) completed the FHQ only. Addition of the FHQ to FIT-based screening resulted in one extra case of AN detected after 16 additional colonoscopies, resulting in a yield of 19.6 (95% CI, 16.4-23.5) for the combined strategy versus 19.5 (95% CI, 16.3-23.3) for the FIT-only strategy (p = 1.0). CONCLUSIONS: The addition of an FHQ to one round of FIT screening did not increase the detection of AN compared with FIT only (ClinicalTrials.gov NCT02698462).


Asunto(s)
Neoplasias Colorrectales/diagnóstico , Detección Precoz del Cáncer/métodos , Encuestas y Cuestionarios , Anciano , Colonoscopía , Heces/química , Femenino , Humanos , Masculino , Persona de Mediana Edad , Países Bajos , Sangre Oculta
16.
Fam Cancer ; 19(1): 65-76, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31773425

RESUMEN

Pre-test counseling about multigene panel testing involves many uncertainties. Ideally, counselees are informed about uncertainties in a way that enables them to make an informed decision about panel testing. It is presently unknown whether and how uncertainty is discussed during initial cancer genetic counseling. We therefore investigated whether and how counselors discuss and address uncertainty, and the extent of shared decision-making (SDM), and explored associations between counselors' communication and their characteristics in consultations on panel testing for cancer. For this purpose, consultations of counselors discussing a multigene panel with a simulated patient were videotaped. Simulated patients represented a counselee who had had multiple cancer types, according to a script. Before and afterwards, counselors completed a survey. Counselors' uncertainty expressions, initiating and the framing of expressions, and their verbal responses to scripted uncertainties of the simulated patient were coded by two researchers independently. Coding was done according to a pre-developed coding scheme using The Observer XT software for observational analysis. Additionally, the degree of SDM was assessed by two observers. Correlation and regression analyses were performed to assess associations of communicated uncertainties, responses and the extent of SDM, with counselors' background characteristics. In total, twenty-nine counselors, including clinical geneticists, genetic counselors, physician assistants-in-training, residents and interns, participated of whom working experience varied between 0 and 25 years. Counselors expressed uncertainties mainly regarding scientific topics (94%) and on their own initiative (95%). Most expressions were framed directly (77%), e.g. We don't know, and were emotionally neutral (59%; without a positive/negative value). Counselors mainly responded to uncertainties of the simulated patient by explicitly referring to the uncertainty (69%), without providing space for further disclosure (66%). More experienced counselors provided less space to further disclose uncertainty (p < 0.02), and clinical geneticists scored lower on SDM compared with other types of counselors (p < 0.03). Our findings that counselors mainly communicate scientific uncertainties and use space-reducing responses imply that the way counselors address counselees' personal uncertainties and concerns during initial cancer genetic counseling is suboptimal.


Asunto(s)
Consejeros/psicología , Toma de Decisiones Conjunta , Asesoramiento Genético , Pruebas Genéticas , Neoplasias/genética , Incertidumbre , Adulto , Comunicación , Estudios Transversales , Femenino , Predisposición Genética a la Enfermedad , Genética , Humanos , Masculino , Persona de Mediana Edad , Herencia Multifactorial , Países Bajos , Simulación de Paciente
17.
NPJ Breast Cancer ; 5: 38, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31700994

RESUMEN

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM -/- patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors.

18.
Br J Cancer ; 121(2): 180-192, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-31213659

RESUMEN

BACKGROUND: Height and body mass index (BMI) are associated with higher ovarian cancer risk in the general population, but whether such associations exist among BRCA1/2 mutation carriers is unknown. METHODS: We applied a Mendelian randomisation approach to examine height/BMI with ovarian cancer risk using the Consortium of Investigators for the Modifiers of BRCA1/2 (CIMBA) data set, comprising 14,676 BRCA1 and 7912 BRCA2 mutation carriers, with 2923 ovarian cancer cases. We created a height genetic score (height-GS) using 586 height-associated variants and a BMI genetic score (BMI-GS) using 93 BMI-associated variants. Associations were assessed using weighted Cox models. RESULTS: Observed height was not associated with ovarian cancer risk (hazard ratio [HR]: 1.07 per 10-cm increase in height, 95% confidence interval [CI]: 0.94-1.23). Height-GS showed similar results (HR = 1.02, 95% CI: 0.85-1.23). Higher BMI was significantly associated with increased risk in premenopausal women with HR = 1.25 (95% CI: 1.06-1.48) and HR = 1.59 (95% CI: 1.08-2.33) per 5-kg/m2 increase in observed and genetically determined BMI, respectively. No association was found for postmenopausal women. Interaction between menopausal status and BMI was significant (Pinteraction < 0.05). CONCLUSION: Our observation of a positive association between BMI and ovarian cancer risk in premenopausal BRCA1/2 mutation carriers is consistent with findings in the general population.


Asunto(s)
Estatura , Índice de Masa Corporal , Genes BRCA1 , Genes BRCA2 , Heterocigoto , Análisis de la Aleatorización Mendeliana , Mutación , Neoplasias Ováricas/etiología , Adulto , Anciano , Femenino , Humanos , Menopausia , Persona de Mediana Edad , Neoplasias Ováricas/genética , Modelos de Riesgos Proporcionales
19.
Hum Mutat ; 40(9): 1557-1578, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31131967

RESUMEN

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification.


Asunto(s)
Proteína BRCA1/genética , Proteína BRCA2/genética , Biología Computacional/métodos , Mutación Missense , Neoplasias/diagnóstico , Empalme Alternativo , Detección Precoz del Cáncer , Femenino , Predisposición Genética a la Enfermedad , Humanos , Funciones de Verosimilitud , Masculino , Herencia Multifactorial , Neoplasias/genética
20.
J Genet Couns ; 28(3): 533-542, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30629779

RESUMEN

A nationwide pretest-posttest study was conducted in all clinical genetic centres in the Netherlands, to evaluate the effects of an online decision aid to support persons who have a genetic predisposition to cancer and their partners in making an informed decision regarding reproductive options. Main outcomes (decisional conflict, knowledge, realistic expectations, level of deliberation, and decision self-efficacy) were measured before use (T0), immediately after use (T1), and at 2 weeks (T2) after use of the decision aid. Paired sample t tests were used to compute differences between the first and subsequent measurements. T0-T1 and T0-T2 comparisons indicate a significant reduction in mean decisional conflict scores with stronger effects for participants with high baseline decisional conflict. Furthermore, use of the decision aid resulted in increased knowledge levels and improved realistic expectations. Level of deliberation only increased for participants with lower baseline levels of deliberation. Decision self-efficacy increased for those with low baseline scores, whereas those with high baseline scores showed a reduction at T2. It can be concluded that use of the decision aid resulted in several positive outcomes indicative of informed decision-making. The decision aid is an appropriate and highly appreciated tool to be used in addition to reproductive counseling.


Asunto(s)
Técnicas de Apoyo para la Decisión , Predisposición Genética a la Enfermedad , Neoplasias/genética , Sistemas en Línea , Participación del Paciente , Reproducción , Adulto , Femenino , Humanos , Masculino , Países Bajos , Parejas Sexuales
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