Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 54
Filtrar
1.
Br J Cancer ; 121(2): 180-192, 2019 Jul.
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.

2.
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.

3.
J Genet Couns ; 28(3): 533-542, 2019 Jun.
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.

4.
J Community Genet ; 2018 Nov 14.
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.

5.
J Natl Cancer Inst ; 2018 10 12.
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.

6.
Patient Educ Couns ; 101(12): 2083-2089, 2018 Dec.
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.

7.
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.

8.
Fam Cancer ; 2018 May 30.
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.

9.
Hum Mutat ; 39(5): 593-620, 2018 May.
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.

10.
J Med Genet ; 55(10): 669-674, 2018 Oct.
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.

11.
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
12.
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.

13.
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
14.
Eur J Hum Genet ; 25(11): 1246-1252, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28875981

RESUMO

Recognition of individuals with a genetic predisposition to gastric cancer (GC) enables preventive measures. However, the underlying cause of genetic susceptibility to gastric cancer remains largely unexplained. We performed germline whole-exome sequencing on leukocyte DNA of 54 patients from 53 families with genetically unexplained diffuse-type and intestinal-type GC to identify novel GC-predisposing candidate genes. As young age at diagnosis and familial clustering are hallmarks of genetic tumor susceptibility, we selected patients that were diagnosed below the age of 35, patients from families with two cases of GC at or below age 60 and patients from families with three GC cases at or below age 70. All included individuals were tested negative for germline CDH1 mutations before or during the study. Variants that were possibly deleterious according to in silico predictions were filtered using several independent approaches that were based on gene function and gene mutation burden in controls. Despite a rigorous search, no obvious candidate GC predisposition genes were identified. This negative result stresses the importance of future research studies in large, homogeneous cohorts.


Assuntos
Exoma , Predisposição Genética para Doença , Testes Genéticos/métodos , Mutação em Linhagem Germinativa , Neoplasias Gástricas/genética , Adulto , Idoso , Antígenos CD , Caderinas/genética , Detecção Precoce de Câncer/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência de DNA/métodos , Neoplasias Gástricas/diagnóstico
15.
Dis Colon Rectum ; 60(10): 1057-1064, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28891849

RESUMO

BACKGROUND: The reported proportion of patients with familial adenomatous polyposis who have adrenal lesions varies between 7% and 13% compared with 4% in the general population; the prevalence of adrenal lesions in patients with attenuated familial adenomatous polyposis and MUTYH-associated polyposis is unknown. Data on the clinical relevance and clinical course are limited. OBJECTIVE: We aimed to report on the frequency, characteristics, and progression of adrenal lesions in polyposis patients. DESIGN: This was a historical cohort study. SETTINGS: The study was performed at the Academic Medical Center, Amsterdam. PATIENTS: All of the patients with familial adenomatous polyposis, attenuated familial adenomatous polyposis, and MUTYH-associated polyposis were included. Medical charts and imaging reports were analyzed for data on adrenal lesions. A radiologist reassessed all of the images. Patients had not routinely been screened for adrenal lesions. MAIN OUTCOME MEASURES: The frequency, characteristics, and progression of adrenal lesions in patients with polyposis who underwent abdominal imaging were assessed. Findings were compared with a reference. RESULTS: A total of 39 adrenal lesions were identified in 23 (26%) of 90 patients with familial adenomatous polyposis, 2 (18%) of 11 with attenuated familial adenomatous polyposis, and 5 (24%) of 21 with MUTYH-associated polyposis. Mean age at time of detection was 50.7 years (range, 17.1-83.3 y). Median lesion size at baseline was 1.4 cm (range, 1.0-5.0 cm) versus 1.7 cm (range, 1.0-5.7 cm) after a median of 3.5 years (range, 1.0-11.4 y). Two patients were diagnosed with a hyperfunctioning lesion, and 4 underwent adrenalectomy: 3 lesions appeared benign, and 1 was oncocytic of uncertain malignant potential. The OR for detecting at least 1 lesion in a patient with polyposis versus reference was 6.2 (95% CI, 3.2-12.3), with no significant differences in ORs among the 3 syndromes. LIMITATIONS: The study was limited by its retrospective design. CONCLUSIONS: Adrenal lesions are frequent in patients with polyposis who undergo abdominal imaging. They appear to follow a benign and slowly progressive course and are mostly nonhyperfunctioning. See Abstract Video at http://links.lww.com/DCR/A323.


Assuntos
Neoplasias das Glândulas Suprarrenais , Glândulas Suprarrenais/diagnóstico por imagem , DNA Glicosilases/genética , Polipose Adenomatosa do Colo/epidemiologia , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/patologia , Polipose Adenomatosa do Colo/cirurgia , Neoplasias das Glândulas Suprarrenais/epidemiologia , Neoplasias das Glândulas Suprarrenais/patologia , Neoplasias das Glândulas Suprarrenais/fisiopatologia , Neoplasias das Glândulas Suprarrenais/cirurgia , Adrenalectomia/estatística & dados numéricos , Adulto , Colectomia/métodos , Colectomia/estatística & dados numéricos , Feminino , Humanos , Imagem por Ressonância Magnética/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/estatística & dados numéricos , Estudos Retrospectivos , Estatística como Assunto
16.
Eur J Cancer ; 80: 48-54, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28544908

RESUMO

INTRODUCTION: Recognising a tumour predisposition syndrome (TPS) in childhood cancer patients is of major clinical relevance. The presence of a TPS may be suggested by the type of tumour in the child. We present an overview of 23 childhood tumours that in themselves should be a reason to refer a child for genetic consultation. METHODS: We performed a PubMed search to review the incidence of TPSs in children for 85 tumour types listed in the International Classification of Childhood Cancer third edition (ICCC-3). The results were discussed during a national consensus meeting with representative clinical geneticists from all six academic paediatric oncology centres in The Netherlands. A TPS incidence of 5% or more was considered a high probability and therefore in itself a reason for referral to a clinical geneticist. RESULTS: The literature search resulted in data on the incidence of a TPS in 26 tumours. For 23/26 tumour types, a TPS incidence of 5% or higher was reported. In addition, during the consensus meeting the experts agreed that children with any carcinoma should always be referred for clinical genetic consultation as well, as it may point to a TPS. CONCLUSION: We present an overview of 23 paediatric tumours with a high probability of a TPS; this will facilitate paediatric oncologists to decide which patients should be referred for genetic consultation merely based on type of tumour.


Assuntos
Aconselhamento Genético , Predisposição Genética para Doença , Síndromes Neoplásicas Hereditárias/epidemiologia , Criança , Humanos , Incidência , Encaminhamento e Consulta
17.
Nat Genet ; 49(5): 680-691, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28346442

RESUMO

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.


Assuntos
Loci Gênicos/genética , Predisposição Genética para Doença/genética , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Ovarianas/genética , Alelos , Proteína BRCA1/genética , Proteína BRCA2/genética , Carcinoma Epitelial do Ovário , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Metanálise como Assunto , Mutação , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/patologia , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Proteínas de Ligação a Telômeros/genética
18.
Cancer Res ; 77(11): 2789-2799, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28283652

RESUMO

Breast cancer risks conferred by many germline missense variants in the BRCA1 and BRCA2 genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk were investigated through a breast cancer case-control study using genotyping data from 38 studies of predominantly European ancestry (41,890 cases and 41,607 controls) and nine studies of Asian ancestry (6,269 cases and 6,624 controls). The BRCA2 c.9104A>C, p.Tyr3035Ser (OR = 2.52; P = 0.04), and BRCA1 c.5096G>A, p.Arg1699Gln (OR = 4.29; P = 0.009) variant were associated with moderately increased risks of breast cancer among Europeans, whereas BRCA2 c.7522G>A, p.Gly2508Ser (OR = 2.68; P = 0.004), and c.8187G>T, p.Lys2729Asn (OR = 1.4; P = 0.004) were associated with moderate and low risks of breast cancer among Asians. Functional characterization of the BRCA2 variants using four quantitative assays showed reduced BRCA2 activity for p.Tyr3035Ser compared with wild-type. Overall, our results show how BRCA2 missense variants that influence protein function can confer clinically relevant, moderately increased risks of breast cancer, with potential implications for risk management guidelines in women with these specific variants. Cancer Res; 77(11); 2789-99. ©2017 AACR.


Assuntos
Proteína BRCA2/genética , Neoplasias da Mama/genética , Idoso , Substituição de Aminoácidos , Animais , Estudos de Casos e Controles , Feminino , Genótipo , Mutação em Linhagem Germinativa , Humanos , Camundongos , Mutação de Sentido Incorreto , Risco
19.
BMJ Open ; 7(1): e013237, 2017 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-28110285

RESUMO

INTRODUCTION: Recognising a tumour predisposition syndrome (TPS) in patients with childhood cancer is of significant clinical relevance, as it affects treatment, prognosis and facilitates genetic counselling. Previous studies revealed that only half of the known TPSs are recognised during standard paediatric cancer care. In current medical practice it is impossible to refer every patient with childhood cancer to a clinical geneticist, due to limited capacity for routine genetic consultation. Therefore, we have developed a screening instrument to identify patients with childhood cancer with a high probability of having a TPS. The aim of this study is to validate the clinical screening instrument for TPS in patients with childhood cancer. METHODS AND ANALYSIS: This study is a prospective nationwide cohort study including all newly diagnosed patients with childhood cancer in the Netherlands. The screening instrument consists of a checklist, two- and three-dimensional photographic series of the patient. 2 independent clinical geneticists will assess the content of the screening instrument. If a TPS is suspected based on the instrument data and thus further evaluation is indicated, the patient will be invited for full genetic consultation. A negative control group consists of 20% of the patients in whom a TPS is not suspected based on the instrument; they will be randomly invited for full genetic consultation. Primary outcome measurement will be sensitivity of the instrument. ETHICS AND DISSEMINATION: The Medical Ethical Committee of the Academic Medical Centre stated that the Medical Research Involving Human Subjects Act does not apply to this study and that official approval of this study by the Committee was not required. The results will be offered for publication in peer-reviewed journals and presented at International Conferences on Oncology and Clinical Genetics. The clinical data gathered in this study will be available for all participating centres. TRIAL REGISTRATION NUMBER: NTR5605.


Assuntos
Doenças Genéticas Inatas/diagnóstico , Programas de Rastreamento/métodos , Neoplasias/genética , Adolescente , Lista de Checagem , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Recém-Nascido , Masculino , Neoplasias/etiologia , Países Baixos , Fotografação , Estudos Prospectivos , Projetos de Pesquisa , Síndrome
20.
Pancreas ; 46(1): 28-34, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27846136

RESUMO

OBJECTIVES: The aim of this study was to compare the prevalence of cystic pancreatic lesions and their natural behavior in 2 distinct high-risk groups for developing pancreatic ductal adenocarcinoma (PDAC): (1) carriers of a mutation that predisposes to PDAC and (2) individuals without a known gene mutation but with a family history of PDAC (familial pancreatic cancer [FPC]). METHODS: Pancreatic surveillance by annual magnetic resonance imaging and endoscopic ultrasound was performed in individuals with an estimated lifetime risk of developing PDAC of 10% or greater. Progression of a lesion was defined as growth 4 mm or greater or the development of worrisome features. RESULTS: We included 186 individuals: 98 mutation carriers and 88 FPC individuals (mean follow-up, 51 months). Individuals with FPC were significantly more likely than mutation carriers to have a pancreatic cyst 10 mm or greater (16% vs 5%, P = 0.045). Pancreatic cysts detected in mutation carriers, however, were significantly more likely to progress than those in FPC individuals (16% vs 2%, P = 0.050). CONCLUSIONS: This study provides evidence that the prevalence and growth characteristics of pancreatic cysts differ between distinct high-risk groups: individuals with FPC have a higher prevalence of pancreatic cysts 10 mm or greater, whereas cysts in mutation carriers are more likely to progress. These observations may help to develop more optimally tailored surveillance strategies in specific high-risk populations.


Assuntos
Carcinoma Ductal Pancreático/diagnóstico , Detecção Precoce de Câncer/métodos , Cisto Pancreático/diagnóstico , Neoplasias Pancreáticas/diagnóstico , Adulto , Idoso , Proteína BRCA2/genética , Carcinoma Ductal Pancreático/epidemiologia , Carcinoma Ductal Pancreático/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Países Baixos/epidemiologia , Cisto Pancreático/epidemiologia , Cisto Pancreático/genética , Neoplasias Pancreáticas/epidemiologia , Neoplasias Pancreáticas/genética , Prevalência , Estudos Prospectivos , Medição de Risco/métodos , Medição de Risco/estatística & dados numéricos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA