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1.
Eur J Hum Genet ; 2021 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-33437034

RESUMO

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.

2.
J Community Genet ; 2020 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-32880035

RESUMO

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.

3.
United European Gastroenterol J ; 8(8): 865-877, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32703081

RESUMO

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.

4.
Br J Cancer ; 122(12): 1865-1871, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32307443

RESUMO

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).

5.
Fam Cancer ; 19(1): 65-76, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31773425

RESUMO

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.

7.
NPJ Breast Cancer ; 5: 38, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31700994

RESUMO

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.

8.
Br J Cancer ; 121(2): 180-192, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31213659

RESUMO

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.


Assuntos
Estatura , Índice de Massa Corporal , Genes BRCA1 , Genes BRCA2 , Heterozigoto , Análise da Randomização Mendeliana , Mutação , Neoplasias Ovarianas/etiologia , Adulto , Idoso , Feminino , Humanos , Menopausa , Pessoa de Meia-Idade , Neoplasias Ovarianas/genética , Modelos de Riscos Proporcionais
9.
Hum Mutat ; 40(9): 1557-1578, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31131967

RESUMO

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.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Biologia Computacional/métodos , Mutação de Sentido Incorreto , Neoplasias/diagnóstico , Processamento Alternativo , Detecção Precoce de Câncer , Feminino , Predisposição Genética para Doença , Humanos , Funções Verossimilhança , Masculino , Herança Multifatorial , Neoplasias/genética
10.
J Genet Couns ; 28(3): 533-542, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30629779

RESUMO

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.


Assuntos
Técnicas de Apoio para a Decisão , Predisposição Genética para Doença , Neoplasias/genética , Sistemas On-Line , Participação do Paciente , Reprodução , Adulto , Feminino , Humanos , Masculino , Países Baixos , Parceiros Sexuais
11.
J Natl Cancer Inst ; 111(4): 350-364, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30312457

RESUMO

BACKGROUND: BRCA1/2 mutations confer high lifetime risk of breast cancer, although other factors may modify this risk. Whether height or body mass index (BMI) modifies breast cancer risk in BRCA1/2 mutation carriers remains unclear. METHODS: We used Mendelian randomization approaches to evaluate the association of height and BMI on breast cancer risk, using data from the Consortium of Investigators of Modifiers of BRCA1/2 with 14 676 BRCA1 and 7912 BRCA2 mutation carriers, including 11 451 cases of breast cancer. We created a height genetic score using 586 height-associated variants and a BMI genetic score using 93 BMI-associated variants. We examined both observed and genetically determined height and BMI with breast cancer risk using weighted Cox models. All statistical tests were two-sided. RESULTS: Observed height was positively associated with breast cancer risk (HR = 1.09 per 10 cm increase, 95% confidence interval [CI] = 1.0 to 1.17; P = 1.17). Height genetic score was positively associated with breast cancer, although this was not statistically significant (per 10 cm increase in genetically predicted height, HR = 1.04, 95% CI = 0.93 to 1.17; P = .47). Observed BMI was inversely associated with breast cancer risk (per 5 kg/m2 increase, HR = 0.94, 95% CI = 0.90 to 0.98; P = .007). BMI genetic score was also inversely associated with breast cancer risk (per 5 kg/m2 increase in genetically predicted BMI, HR = 0.87, 95% CI = 0.76 to 0.98; P = .02). BMI was primarily associated with premenopausal breast cancer. CONCLUSION: Height is associated with overall breast cancer and BMI is associated with premenopausal breast cancer in BRCA1/2 mutation carriers. Incorporating height and BMI, particularly genetic score, into risk assessment may improve cancer management.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Estatura , Índice de Massa Corporal , Neoplasias da Mama/etiologia , Análise da Randomização Mendeliana , Mutação , Adulto , Neoplasias da Mama/patologia , Feminino , Predisposição Genética para Doença , Humanos , Polimorfismo de Nucleotídeo Único , Prognóstico , Fatores de Risco
12.
J Community Genet ; 10(2): 303-312, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30430454

RESUMO

Multigene panel testing is mainly used to improve identification of genetic causes in families with characteristics fitting multiple possible cancer syndromes. This technique may yield uncertainty, for example when variants of unknown significance are identified. This study explores counsellors' and counselees' experiences with uncertainty, and how they discuss uncertainties and decide about multigene panel testing. Six focus groups were conducted including 38 counsellors. Twelve counselees who had received genetic counselling about a multigene panel test were interviewed. The focus group sessions and interviews were audio-recorded and transcribed verbatim. Transcripts were analysed inductively by two independent coders and data were examined to obtain a comprehensive list of themes. Counsellors identified several uncertainties, e.g. finding a variant of unknown significance, or detecting an unsolicited finding. Most difficulty was experienced in deciding what uncertain information to communicate to counselees and how to do so. The extent and manner of providing uncertain information differed between centres and between counsellors. Counsellors attached more value to counselees' preferences in decision making compared to less extended tests. Counselees experienced difficulty in recalling which uncertainties had been discussed during genetic counselling. They primarily reported to have experienced uncertainty about their own and their relatives' risk of developing cancer. Counselees felt they had had a say in the decision. This study showed that counsellors need more guidance on whether and how to convey uncertainty. Undesirable practice variation in the communication of uncertainty may be prevented by determining what information should minimally be discussed to enable informed decision making.

13.
Fam Cancer ; 18(1): 137-146, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29846879

RESUMO

An online decision aid to support persons having a genetic predisposition to cancer and their partners during reproductive decision-making was developed. A two-phase usability test was conducted among 12 couples (N = 22; 2 persons participated without their partner) at risk for hereditary cancer and 15 health care providers. Couples and health care providers expressed similar suggestions for improvements, and evaluated the modified decision aid as acceptable, easy to use, and comprehensible. The final decision aid was pilot tested (N = 16) with paired sample t tests comparing main outcomes (decisional conflict, knowledge, realistic expectations regarding the reproductive options and decision self-efficacy) before (T0), immediately (T1) and 2 weeks after (T2) use of the decision aid. Pilot testing indicated decreased decisional conflict scores, increased knowledge, and improved realistic expectations regarding the reproductive options, at T1 and T2. No effect was found for couples' decision self-efficacy. The positive findings during usability testing were thus reflected in the pilot study. The decision aid will be further evaluated in a nationwide pretest-posttest study to facilitate implementation in the onco-genetic counselling setting. Ultimately, it is expected that the decision aid will enable end-users to make an informed decision.


Assuntos
Tomada de Decisões , Técnicas de Apoio para a Decisão , Predisposição Genética para Doença , Síndromes Neoplásicas Hereditárias/genética , Reprodução/genética , Adulto , Feminino , Aconselhamento Genético/métodos , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Internet , Masculino , Projetos Piloto
14.
Patient Educ Couns ; 101(12): 2083-2089, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30082116

RESUMO

OBJECTIVE: Persons seeking cancer genetic counseling mainly aim to obtain information and certainty about their medical situation. However, the information that counselees receive often involves many uncertainties. To develop strategies to enable optimal communication about uncertainties, the spectrum of uncertainty expressed within cancer genetic counseling needs to be established. This study aimed to gain insight into the uncertainties verbally expressed by counselors and counselees. METHODS: Twenty-five consultations were audiotaped, transcribed and qualitatively analyzed. A coding scheme identifying all uncertainties was developed parallel to the coding of the transcripts. RESULTS: Several uncertainties were identified varying in their source (i.e. the cause of uncertainty) and the issues involved (i.e. the topic to which uncertainty pertained). The main sources of uncertainty were the unpredictability of the future and a lack of knowledge. Counselees also expressed uncertainty related to the amount and complexity of the information. Counselors expressed uncertainties mainly related to scientific issues, whereas counselees' uncertainty mainly related to personal and practical issues. CONCLUSION: A wide range of uncertainties was expressed by both groups. Counselors differ from counselees in the degree and types of uncertainty they express. PRACTICE IMPLICATIONS: Counselors should address scientific uncertainties during genetic counseling to increase awareness and understanding in counselees.


Assuntos
Comunicação , Conselheiros , Aconselhamento Genético/psicologia , Testes Genéticos , Neoplasias/psicologia , Incerteza , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Satisfação do Paciente , Pesquisa Qualitativa , Encaminhamento e Consulta , Gravação em Fita , Adulto Jovem
15.
Patient Educ Couns ; 101(9): 1611-1619, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29789176

RESUMO

OBJECTIVE: In hereditary and familial cancer, counselees are requested to inform their at-risk relatives. We developed an intervention to support counselees in this task. METHODS: A randomized controlled trial was conducted aimed at improving cancer genetic counselees' i) knowledge, ii) motivation to disclose information, and ii) self-efficacy in this regard. Eligible participants were randomized to telephonic counseling (n = 148), or standard care (n = 157) and assessed at baseline, 1 week post-intervention, and 4 months after study enrolment. RESULTS: No between-group differences were found in participants' knowledge, motivation, and self-efficacy. Knowledge concerning which second-degree relatives to inform was lower compared to first-degree relatives. About 60% of the participants was of the opinion that they needed to inform more relatives than stated in their summary letter and only about 50% were correctly aware of which information to disclose. Of note, at baseline, almost 80% of the participants had already correctly informed their at-risk relatives. CONCLUSIONS: Since, unexpectedly, counselees already informed most of their relatives before the intervention was offered, efficacy of the intervention could not convincingly be determined. Counselees' knowledge about whom to inform about what is suboptimal. PRACTICE IMPLICATIONS: Future interventions should target a more homogeneous sample and address counselees' understanding and recall.


Assuntos
Comunicação , Família/psicologia , Aconselhamento Genético/métodos , Predisposição Genética para Doença , Conhecimentos, Atitudes e Prática em Saúde , Neoplasias/genética , Pacientes/psicologia , Revelação da Verdade , Adulto , Feminino , Aconselhamento Genético/psicologia , Humanos , Masculino , Pessoa de Meia-Idade , Motivação , Neoplasias/psicologia , Fatores de Risco , Autoeficácia , Telefone
16.
Hum Mutat ; 39(5): 593-620, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29446198

RESUMO

The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Internacionalidade , Mutação/genética , Bases de Dados Genéticas , Família , Geografia , Humanos
17.
J Med Genet ; 55(10): 669-674, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29330337

RESUMO

BACKGROUND: In approximately 10% of all gastric cancer (GC) cases, a heritable cause is suspected. A subset of these cases have a causative germline CDH1 mutation; however, in most cases the cause remains unknown. Our objective was to assess to what extent these remaining cases may be explained by germline mutations in the novel candidate GC predisposing genes CTNNA1, MAP3K6 or MYD88. METHODS: We sequenced a large cohort of unexplained young and/or familial patients with GC (n=286) without a CDH1germline mutation for germline variants affecting CTNNA1, MAP3K6 and MYD88 using a targeted next-generation sequencing approach based on single-molecule molecular inversion probes. RESULTS: Predicted deleterious germline variants were not encountered in MYD88, but recurrently observed in CTNNA1 (n=2) and MAP3K6 (n=3) in our cohort of patients with GC. In contrast to deleterious variants in CTNNA1, deleterious variants in MAP3K6 also occur frequently in the general population. CONCLUSIONS: Based on our results MAP3K6 should no longer be considered a GC predisposition gene, whereas deleterious CTNNA1 variants are confirmed as an infrequent cause of GC susceptibility. Biallelic MYD88 germline mutations are at most a very rare cause of GC susceptibility as no additional cases were identified.


Assuntos
Antígenos CD/genética , Caderinas/genética , MAP Quinase Quinase Quinases/genética , Fator 88 de Diferenciação Mieloide/genética , Neoplasias Gástricas/genética , alfa Catenina/genética , Adulto , Idoso , Estudos de Coortes , Europa (Continente) , Feminino , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência de DNA , Adulto Jovem
18.
Dis Colon Rectum ; 61(1): 58-66, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29215473

RESUMO

BACKGROUND: Patients with genetic adenomatous polyposis syndromes have an increased risk for duodenal cancer, and clear surveillance recommendations exist for this group. However, limited data are available on the duodenal phenotype of patients with multiple colorectal adenomas (10-99) without a germline APC or MUTYH mutation. OBJECTIVE: We aimed to assess the frequency, extent, and progression of duodenal adenomas in patients with multiple colorectal adenomas without a germline APC or MUTYH mutation. DESIGN: This was an historical cohort study. SETTINGS: This study was undertaken at 2 polyposis registries: the Academic Medical Center in the Netherlands, and St. Mark's Hospital in the United Kingdom. PATIENTS: We collected data on all patients with 10 to 99 colorectal adenomas and absent APC and MUTYH mutations, who underwent ≥1 esophagogastroduodenoscopy. MAIN OUTCOME MEASURES: The frequency, extent, and progression of duodenal adenomas were measured. Demographic and endoscopic data were collected, described, and compared between patients with and without duodenal adenomas. RESULTS: Eighty-three patients were identified, of which 8 (9.6%) had duodenal adenomas, detected at a median of 58 years (range, 45-75 y). Duodenal adenomas were detected in 6 of 8 patients at first esophagogastroduodenoscopy. At diagnosis, all 8 patients had Spigelman stage I or II disease. Two of 5 patients with duodenal adenomas who underwent follow-up esophagogastroduodenoscopies increased to stage III disease. The other 3 remained stable. No one developed duodenal cancer. No differences in demographic and endoscopic data were found between patients with and without duodenal adenomas. LIMITATIONS: This study was limited by its retrospective design, selection bias, and small sample size. CONCLUSIONS: Duodenal adenomas are found in a minority of patients with multiple colorectal adenomas without a germline APC or MUTYH mutation, at an average age of 58 years, and, at diagnosis, disease severity is mild. These results are a first step in unraveling the duodenal phenotype of these patients, which is needed to provide appropriate upper GI screening and surveillance recommendations. See Video Abstract at http://links.lww.com/DCR/A357.


Assuntos
Polipose Adenomatosa do Colo/genética , DNA Glicosilases/genética , Neoplasias Duodenais/genética , Genes APC/fisiologia , Adenoma/epidemiologia , Adenoma/genética , Polipose Adenomatosa do Colo/epidemiologia , Idoso , Neoplasias Duodenais/epidemiologia , Feminino , Mutação em Linhagem Germinativa , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Sistema de Registros , Estudos Retrospectivos , Reino Unido/epidemiologia
19.
JMIR Med Educ ; 3(2): e24, 2017 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-29254907

RESUMO

BACKGROUND: Nongenetic health providers may lack the relevant knowledge, experience, and communication skills to adequately detect familial colorectal cancer (CRC), despite a positive attitude toward the assessment of history of cancer in a family. Specific training may enable them to more optimally refer patients to genetic counseling. OBJECTIVE: The aim of this study was to develop an e-learning module for gastroenterologists and surgeons (in training) aimed at improving attitudes, knowledge, and comprehension of communication skills, and to assess the feasibility of the e-learning module for continued medical education of these specialists. METHODS: A focus group helped to inform the development of a training framework. The e-learning module was then developed, followed by a feasibility test among a group of surgeons-in-training (3rd- and 4th-year residents) and then among gastroenterologists, using pre- and posttest questionnaires. RESULTS: A total of 124 surgeons-in-training and 14 gastroenterologists participated. The e-learning was positively received (7.5 on a scale of 1 to 10). Between pre- and posttest, attitude increased significantly on 6 out of the 10 items. Mean test score showed that knowledge and comprehension of communication skills improved significantly from 49% to 72% correct at pretest to 67% to 87% correct at posttest. CONCLUSIONS: This study shows the feasibility of a problem-based e-learning module to help surgeons-in-training and gastroenterologists in recognizing a hereditary predisposition in patients with CRC. The e-learning led to improvements in attitude toward the assessment of cancer family history, knowledge on criteria for referral to genetic counseling for CRC, and comprehension of communication skills.

20.
Nat Genet ; 49(12): 1767-1778, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29058716

RESUMO

Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10-8 with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.


Assuntos
Proteína BRCA1/genética , Neoplasias da Mama/genética , Predisposição Genética para Doença/genética , Mutação , Polimorfismo de Nucleotídeo Único , Neoplasias da Mama/etnologia , Neoplasias da Mama/metabolismo , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença/etnologia , Estudo de Associação Genômica Ampla/métodos , Heterozigoto , Humanos , Receptores Estrogênicos/metabolismo , Fatores de Risco
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