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1.
Artigo em Inglês | MEDLINE | ID: mdl-38967411

RESUMO

This study investigated the neurodevelopmental impact of pathogenic adenomatous polyposis coli (APC) gene variants in patients with familial adenomatous polyposis (FAP), a cancer predisposition syndrome. We hypothesized that certain pathogenic APC variants result in behavioral-cognitive challenges. We compared 66 FAP patients (cases) and 34 unaffected siblings (controls) to explore associations between APC variants and behavioral and cognitive challenges. Our findings indicate that FAP patients exhibited higher Social Responsiveness Scale (SRS) scores, suggesting a greater prevalence of autistic traits when compared to unaffected siblings (mean 53.8 vs. 47.4, Wilcoxon p = 0.018). The distribution of SRS scores in cases suggested a bimodal pattern, potentially linked to the location of the APC variant, with scores increasing from the 5' to 3' end of the gene (Pearson's r = 0.33, p = 0.022). While we observed a trend toward lower educational attainment in cases, this difference was not statistically significant. This study is the first to explore the connection between APC variant location and neurodevelopmental traits in FAP, expanding our understanding of the genotype-phenotype correlation. Our results emphasize the importance of clinical assessment for autistic traits in FAP patients, shedding light on the potential role of APC gene variants in these behavioral and cognitive challenges.

2.
Ann Surg Oncol ; 30(8): 5142-5149, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37237094

RESUMO

OBJECTIVE: In this study, we aimed to describe the clinical features, management, and outcomes of desmoid tumors (DTs) in familial adenomatous polyposis (FAP) patients at a high-volume sarcoma center. METHODS: Consecutive patients with FAP and DTs were identified from our institutional databases (1985-2021). Patient demographics, treatment, and outcomes were described. Categorical data were compared using Fisher's exact test, and Kaplan-Meier curves were used to estimate progression-free survival (PFS). RESULTS: Forty-five patients with 67 DTs were identified: 39 mesenteric or retroperitoneal (58.2%), 17 abdominal wall (25.4%), 4 extremity (6%), 4 breast (6%) and 3 back (4.4%). Severe DT symptoms were present in 12 patients (26.7%). Initial treatments per tumor were observation in 30 (44.8%) DTs, chemotherapy in 15 (22.4%) DTs, surgery in 10 (14.9%) DTs, and other systemic therapies in 10 (14.9%) DTs. The majority of DTs remained stable with observation or a single intervention (77.8%). Median PFS was 23.4 years (95% confidence interval 7.6-39.2). In the 12 severely symptomatic patients, four patients required more than two interventions for DT control. At a median follow-up of 6.0 years (range 0.7-35.8 years), 33 (73.3%) patients were alive with disease, 7 (15.6%) were alive without disease, and 5 (11.1%) died of other causes. No patients died of DT-related complications. CONCLUSIONS: The majority of DTs in FAP patients remained stable with observation or a single intervention. There were no DT-related deaths; however, 12 of 45 patients (26.7%) experienced significant tumor morbidity and required more interventions for disease control. Further studies on quality of life are required.


Assuntos
Polipose Adenomatosa do Colo , Fibromatose Agressiva , Humanos , Fibromatose Agressiva/patologia , Qualidade de Vida , Polipose Adenomatosa do Colo/complicações , Mesentério/patologia
3.
J Natl Cancer Inst ; 115(7): 778-787, 2023 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-36964717

RESUMO

BACKGROUND: Lynch syndrome (LS) screening guidelines originally recommended colonoscopy every 1 to 2 years, beginning between the ages of 20 and 25 years. Recent studies have questioned the benefits of these short screening intervals in preventing colorectal cancer (CRC). Our goal is to determine how colonoscopy screening intervals impact CRC in patients with LS. METHODS: We analyzed the demographics, screening practices, and outcomes of patients with LS identified through the clinic based Familial Gastrointestinal Cancer Registry at the Zane Cohen Centre, Sinai Health System, Toronto, Canada. RESULTS: A total of 429 patients with LS were identified with median follow-up of 9.2 years; 44 developed CRC. We found a positive trend between shorter screening intervals and the number of adenomas detected during colonoscopy. Any new adenoma detected at screening decreased 10-year CRC incidence by 11.3%. For MLH1 carriers, a screening interval of 1-2 years vs 2-3 years led to a 20-year cumulative CRC risk reduction of 28% and 14% in females and males, respectively. For MSH2 carriers, this risk reduction was 29% and 17%, respectively, and for male MSH6 carriers 18%. Individuals without any adenomas detected (53.4% of LS carriers) had an increased 20-year CRC risk of 25.7% and 57.2% for women and men, respectively, compared with those diagnosed with adenomas at screening. CONCLUSIONS: The recommended colonoscopy screening interval of 1-2 years is efficient at detecting adenomas and reducing CRC risk. The observation that 53.4% of LS patients never had an adenoma warrants further investigation about a possible adenoma-free pathway.


Assuntos
Adenoma , Neoplasias Colorretais Hereditárias sem Polipose , Neoplasias Colorretais , Humanos , Masculino , Feminino , Adulto Jovem , Adulto , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/prevenção & controle , Canadá/epidemiologia , Colonoscopia , Adenoma/diagnóstico , Adenoma/epidemiologia , Adenoma/prevenção & controle , Sistema de Registros
4.
NPJ Genom Med ; 6(1): 63, 2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34282142

RESUMO

Next-generation sequencing (NGS) technologies have facilitated multi-gene panel (MGP) testing to detect germline DNA variants in hereditary cancer patients. This sensitive technique can uncover unexpected, non-germline incidental findings indicative of mosaicism, clonal hematopoiesis (CH), or hematologic malignancies. A retrospective chart review was conducted to identify cases of incidental findings from NGS-MGP testing. Inclusion criteria included: 1) multiple pathogenic variants in the same patient; 2) pathogenic variants at a low allele fraction; and/or 3) the presence of pathogenic variants not consistent with family history. Secondary tissue analysis, complete blood count (CBC) and medical record review were conducted to further delineate the etiology of the pathogenic variants. Of 6060 NGS-MGP tests, 24 cases fulfilling our inclusion criteria were identified. Pathogenic variants were detected in TP53, ATM, CHEK2, BRCA1 and APC. 18/24 (75.0%) patients were classified as CH, 3/24 (12.5%) as mosaic, 2/24 (8.3%) related to a hematologic malignancy, and 1/24 (4.2%) as true germline. We describe a case-specific workflow to identify and interpret the nature of incidental findings on NGS-MGP. This workflow will provide oncology and genetic clinics a practical guide for the management and counselling of patients with unexpected NGS-MGP findings.

5.
J Med Genet ; 58(4): 275-283, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-32581083

RESUMO

BACKGROUND: Exome and genome sequencing have been demonstrated to increase diagnostic yield in paediatric populations, improving treatment options and providing risk information for relatives. There are limited studies examining the clinical utility of these tests in adults, who currently have limited access to this technology. METHODS: Patients from adult and cancer genetics clinics across Toronto, Ontario, Canada were recruited into a prospective cohort study evaluating the diagnostic utility of exome and genome sequencing in adults. Eligible patients were ≥18 years of age and suspected of having a hereditary disorder but had received previous uninformative genetic test results. In total, we examined the diagnostic utility of exome and genome sequencing in 47 probands and 34 of their relatives who consented to participate and underwent exome or genome sequencing. RESULTS: Overall, 17% (8/47) of probands had a pathogenic or likely pathogenic variant identified in a gene associated with their primary indication for testing. The diagnostic yield for patients with a cancer history was similar to the yield for patients with a non-cancer history (4/18 (22%) vs 4/29 (14%)). An additional 24 probands (51%) had an inconclusive result. Secondary findings were identified in 10 patients (21%); three had medically actionable results. CONCLUSIONS: This study lends evidence to the diagnostic utility of exome or genome sequencing in an undiagnosed adult population. The significant increase in diagnostic yield warrants the use of this technology. The identification and communication of secondary findings may provide added value when using this testing modality as a first-line test.


Assuntos
Sequenciamento do Exoma , Predisposição Genética para Doença , Doenças não Diagnosticadas/diagnóstico , Sequenciamento Completo do Genoma , Adolescente , Adulto , Idoso , Canadá/epidemiologia , Exoma/genética , Feminino , Testes Genéticos/tendências , Genoma Humano/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Doenças não Diagnosticadas/epidemiologia , Doenças não Diagnosticadas/genética , Adulto Jovem
6.
Prev Med Rep ; 20: 101189, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33117641

RESUMO

Family history (FH) of a first-degree relative with colorectal cancer (CRC) is associated with two to fourfold increased risk, yet screening uptake is suboptimal despite proven mortality reduction. We developed a FH-based CRC Risk Triage/Management tool for family physicians (FPs), and educational booklet for patients with CRC FH. This report describes physician referral and patient screening behavior 5 and 10 years post-educational intervention, and factors associated with screening. Longitudinal cohort study. FPs/patients in Ontario and Newfoundland, Canada were sent questionnaires at baseline (2005), 5 and 10 years (2015) following tool/booklet receipt. FPs were asked about CRC screening, patients about FH, screening type and timing. "Correct" screening was concordance with tool recommendations. Results reported for 29/121 (24%) FPs and 98/297 (33%) patients who completed all 3 questionnaires. Over 10 years 2/3 patients received the correct CRC screening test at appropriate timing (baseline 75%, 5-year 62%, 10-year 65%). About half reported their FP recommended CRC screening (5-year 51%, 10-year 63%). Fewer than half the patients correctly assessed their CRC risk (44%, 40%, 41%). Patients were less likely to have correct screening timing if female (RR 0.78; 95% CI 0.61, 0.99; p = 0.045). Patients were less likely to have both correct test and timing if moderate/high CRC risk (RR 0.66; 95% CI 0.47, 0.93; p = 0.017) and more likely if their physician recommended screening (RR1.69; 95% CI 1.15, 2.49; p = 0.007). Physician discussion of CRC risk and screening can positively impact patient screening behavior. Efforts are particularly needed for women and patients at moderate/high CRC risk.

7.
Eur J Hum Genet ; 28(9): 1178-1186, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32424322

RESUMO

There is growing impetus to include measures of personal utility, the nonmedical value of information, in addition to clinical utility in health technology assessment (HTA) of genomic tests such as genomic sequencing (GS). However, personal utility and clinical utility are challenging to define and measure. This study aimed to explore what drives patients' preferences for hypothetically learning medically actionable and non-medically actionable secondary findings (SF), capturing clinical and personal utility; this may inform development of measures to evaluate patient outcomes following return of SF. Semi-structured interviews were conducted with adults with a personal or family cancer history participating in a trial of a decision aid for selection of SF from genomic sequencing (GS) ( www.GenomicsADvISER.com ). Interviews were analyzed thematically using constant comparison. Preserving health-related and non-health-related quality of life was an overarching motivator for both learning and not learning SF. Some participants perceived that learning SF would help them "have a good quality of life" through informing actions to maintain physical health or leading to psychological benefits such as emotional preparation for disease. Other participants preferred not to learn SF because results "could ruin your quality of life," such as by causing negative psychological impacts. Measuring health-related and non-health-related quality of life may capture outcomes related to clinical and personal utility of GS and SF, which have previously been challenging to measure. Without appropriate measures, generating and synthesizing evidence to evaluate genomic technologies such as GS will continue to be a challenge, and will undervalue potential benefits of GS and SF.


Assuntos
Predisposição Genética para Doença/psicologia , Testes Genéticos , Achados Incidentais , Preferência do Paciente/psicologia , Qualidade de Vida , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência de DNA
8.
Artigo em Inglês | MEDLINE | ID: mdl-31423292

RESUMO

BACKGROUND: Lynch syndrome, a hereditary cancer syndrome, predisposes women to colorectal, endometrial, and ovarian cancer. Current guidelines recommend that women with Lynch syndrome undergo risk-reducing gynecological surgery to reduce their chances of developing endometrial or ovarian cancer. Little is known about how women with Lynch syndrome perceive gynecological cancer screening, or the psychosocial factors associated with screening attitudes and behaviour. METHODS: This study used a cross-sectional, quantitative design. Using self-report questionnaire data from a sample of women with Lynch syndrome (N = 50) who had not undergone risk-reducing surgery, the current study sought to: 1) describe the gynecological cancer screening behaviours of women with Lynch syndrome, as well participant-reported sources of information about Lynch syndrome; 2) examine the extent to which women believe gynecological cancer screening is effective and provides them with reassurance and; 3) assess to what extent relationships with one's family physician were associated with gynecological cancer screening, perceptions about screening, and health self-efficacy. Data were analyzed using descriptive statistics and Spearman rank-ordered correlations. RESULTS: Data analyses showed that transvaginal ultrasound was the most common screening behaviour (57%) followed by pelvic ultrasound (47%). Only 22% of participants underwent endometrial biopsy. Patient-physician relationships were related to greater health self-efficacy to manage Lynch syndrome and greater perceived effectiveness of gynecological screening. However, health self-efficacy and better patient-physician relationships were not associated with increased engagement in gynecological cancer screening. CONCLUSIONS: The data suggest that feeling efficacious about managing one's Lynch syndrome and screening is related to positive interactions and communication with one's family physician. While this is encouraging, future research should examine educating both family physicians and patients about current guidelines for Lynch syndrome gynecological screening recommendations.

9.
Cancer ; 125(13): 2272-2282, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-30861097

RESUMO

BACKGROUND: Having a first-degree relative (FDR) with colorectal cancer (CRC) is a significant risk factor for CRC. Counseling for FDRs regarding CRC risk factors and personalized risk is important to improve knowledge and screening compliance. METHODS: A 3-arm randomized controlled trial compared tailored in-person and telephone CRC counseling interventions with controls among FDRs who were not mutation carriers for known hereditary cancer syndromes, but who were considered to be at an increased risk based on family history. It was hypothesized that both telephone and in-person approaches would increase CRC knowledge, screening adherence, perceived risk accuracy, and psychosocial functioning compared with controls. The authors anticipated greater satisfaction with the in-person approach. CRC knowledge, risk perception, psychosocial functioning, and intention to screen were assessed at baseline and at 2-week and 2-month follow-ups (primary endpoint). RESULTS: A total of 278 FDRs (mean age, 47.4 years, standard deviation, 11.38 years) participated. At baseline, participants reported low to moderate CRC knowledge and overestimations of risk. Screening adherence was 73.7%. At 2 months, participants in the in-person arm and telephone arm demonstrated improvements in knowledge and perceived risk and were not found to be statistically different from each other. However, when comparing each intervention with controls, knowledge in the in-person arm was found to be statistically significantly higher, but the difference between the telephone and control arms was not. Cancer-related stress reduced over time in all groups. Intervention benefits were maintained at 1 year. Baseline screening intent/adherence were high, and therefore did not reach statistically significant improvement. CONCLUSIONS: Tailored in-person or telephone formats for providing CRC risk counseling, incorporating behavioral interventions, appear to improve knowledge and risk perceptions, with high client satisfaction.


Assuntos
Colonoscopia/métodos , Neoplasias Colorretais/diagnóstico , Aconselhamento/métodos , Detecção Precoce de Câncer/métodos , Família/psicologia , Telefone/estatística & dados numéricos , Neoplasias Colorretais/psicologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico
10.
J Genet Couns ; 28(3): 495-506, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30638287

RESUMO

This study examined the differences in perceptions of one's health and one's child's health between parents with Lynch syndrome (LS) characterized with high versus low health anxiety. Twenty-one parents completed semistructured telephone interviews about their perceptions of their own health and the health of their children. Qualitative content analysis using a template coding approach examined the differences between parents with high and low health anxiety. Findings revealed that the most prevalent difference emerged on perceptions of personal health, showing individuals with high health anxiety reported more extreme worries, were more hypervigilant about physical symptoms, experienced the emotional and psychological consequences of LS as more negative and severe, and engaged in more dysfunctional coping strategies than those with low health anxiety. Unexpectedly, with regards to perceptions of their children, parents in the high and low health anxiety groups exhibited similar worries. However, high health anxiety parents reported using dysfunctional coping about their children's health more frequently than those with low health anxiety. The findings suggest that health anxiety is of clinical significance for individuals with LS. Accurately identifying and treating health anxiety among this population may be one avenue to reduce the distress experienced by LS carriers.


Assuntos
Ansiedade/psicologia , Neoplasias Colorretais Hereditárias sem Polipose/psicologia , Pais/psicologia , Adaptação Psicológica , Adulto , Criança , Saúde da Criança , Emoções , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
11.
J Clin Oncol ; 37(6): 461-470, 2019 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-30608896

RESUMO

PURPOSE: Constitutional mismatch repair deficiency (CMMRD) is a highly penetrant cancer predisposition syndrome caused by biallelic mutations in mismatch repair (MMR) genes. As several cancer syndromes are clinically similar, accurate diagnosis is critical to cancer screening and treatment. As genetic diagnosis is confounded by 15 or more pseudogenes and variants of uncertain significance, a robust diagnostic assay is urgently needed. We sought to determine whether an assay that directly measures MMR activity could accurately diagnose CMMRD. PATIENTS AND METHODS: In vitro MMR activity was quantified using a 3'-nicked G-T mismatched DNA substrate, which requires MSH2-MSH6 and MLH1-PMS2 for repair. We quantified MMR activity from 20 Epstein-Barr virus-transformed lymphoblastoid cell lines from patients with confirmed CMMRD. We also tested 20 lymphoblastoid cell lines from patients who were suspected for CMMRD. We also characterized MMR activity from patients with neurofibromatosis type 1, Li-Fraumeni syndrome, polymerase proofreading-associated cancer syndrome, and Lynch syndrome. RESULTS: All CMMRD cell lines had low MMR activity (n = 20; mean, 4.14 ± 1.56%) relative to controls (n = 6; mean, 44.00 ± 8.65%; P < .001). Repair was restored by complementation with the missing protein, which confirmed MMR deficiency. All cases of patients with suspected CMMRD were accurately diagnosed. Individuals with Lynch syndrome (n = 28), neurofibromatosis type 1 (n = 5), Li-Fraumeni syndrome (n = 5), and polymerase proofreading-associated cancer syndrome (n = 3) had MMR activity that was comparable to controls. To accelerate testing, we measured MMR activity directly from fresh lymphocytes, which yielded results in 8 days. CONCLUSION: On the basis of the current data set, the in vitro G-T repair assay was able to diagnose CMMRD with 100% specificity and sensitivity. Rapid diagnosis before surgery in non-neoplastic tissues could speed proper therapeutic management.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Reparo de Erro de Pareamento de DNA , Enzimas Reparadoras do DNA/genética , Testes Genéticos , Mutação , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/metabolismo , Estudos de Casos e Controles , Linhagem Celular Tumoral , Neoplasias Colorretais/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Predisposição Genética para Doença , Humanos , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Endonuclease PMS2 de Reparo de Erro de Pareamento/metabolismo , Proteína 1 Homóloga a MutL/genética , Proteína 1 Homóloga a MutL/metabolismo , Proteína 2 Homóloga a MutS/genética , Proteína 2 Homóloga a MutS/metabolismo , Síndromes Neoplásicas Hereditárias/metabolismo , Fenótipo , Valor Preditivo dos Testes
12.
BMC Med Genomics ; 11(1): 65, 2018 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-30092803

RESUMO

BACKGROUND: Matched tumor-normal sequencing, applied in precision cancer medicine, can identify unidentified germline Medically Actionable Variants (gMAVS) in cancer predisposition genes. We report patient preferences for the return of additional germline results, and describe various gMAV scenarios delivered through a clinical genetics service. METHODS: Tumor profiling was offered to 1960 advanced cancer patients, of which 1556 underwent tumor-normal sequencing with multigene hotspot panels containing 20 cancer predisposition genes. All patients were provided with an IRB-approved consent for return of additional gMAVs. RESULTS: Of the whole cohort 94% of patients consented to be informed of additional germline results and 5% declined, with no statistically significant differences based on age, sex, race or prior genetic testing. Eight patients were found to have gMAVs in a cancer predisposition gene. Five had previously unidentified gMAVs: three in TP53 (only one fulfilled Chompret's Revised criteria for Li-Fraumeni Syndrome), one in SMARCB1 in the absence of schwannomatosis features and one a TP53 variant at low allele frequency suggesting an acquired event in blood. CONCLUSION: Interest in germline findings is high among patients who undergo tumor profiling. Disclosure of previously unidentified gMAVs present multiple challenges, thus supporting the involvement of a clinical genetics service in all tumor profiling programs.


Assuntos
Testes Genéticos , Mutação em Linhagem Germinativa , Sequenciamento de Nucleotídeos em Larga Escala , Neoplasias/genética , Neoplasias/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Predisposição Genética para Doença/genética , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
13.
BMJ Open ; 8(4): e021876, 2018 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-29700101

RESUMO

INTRODUCTION: Genome sequencing, a novel genetic diagnostic technology that analyses the billions of base pairs of DNA, promises to optimise healthcare through personalised diagnosis and treatment. However, implementation of genome sequencing faces challenges including the lack of consensus on disclosure of incidental results, gene changes unrelated to the disease under investigation, but of potential clinical significance to the patient and their provider. Current recommendations encourage clinicians to return medically actionable incidental results and stress the importance of education and informed consent. Given the shortage of genetics professionals and genomics expertise among healthcare providers, decision aids (DAs) can help fill a critical gap in the clinical delivery of genome sequencing. We aim to assess the effectiveness of an interactive DA developed for selection of incidental results. METHODS AND ANALYSIS: We will compare the DA in combination with a brief Q&A session with a genetic counsellor to genetic counselling alone in a mixed-methods randomised controlled trial. Patients who received negative standard cancer genetic results for their personal and family history of cancer and are thus eligible for sequencing will be recruited from cancer genetics clinics in Toronto. Our primary outcome is decisional conflict. Secondary outcomes are knowledge, satisfaction, preparation for decision-making, anxiety and length of session with the genetic counsellor. A subset of participants will complete a qualitative interview about preferences for incidental results. ETHICS AND DISSEMINATION: This study has been approved by research ethics boards of St. Michael's Hospital, Mount Sinai Hospital and Sunnybrook Health Sciences Centre. This research poses no significant risk to participants. This study evaluates the effectiveness of a novel patient-centred tool to support clinical delivery of incidental results. Results will be shared through national and international conferences, and at a stakeholder workshop to develop a consensus statement to optimise implementation of the DA in practice. TRIAL REGISTRATION NUMBER: NCT03244202; Pre-results.


Assuntos
Técnicas de Apoio para a Decisão , Aconselhamento Genético , Achados Incidentais , Adolescente , Adulto , Aconselhamento , Tomada de Decisões , Genômica , Humanos , Consentimento Livre e Esclarecido , Ensaios Clínicos Controlados Aleatórios como Assunto
14.
J Med Genet ; 54(11): 742-746, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28779004

RESUMO

BACKGROUND: Previous studies assessing breast cancer risk in families with Lynch syndrome (LS) have yielded conflicting results. Furthermore, conclusions are limited by small sample size and few breast cancer outcomes. This study assesses breast cancer risk in a large prospectively followed LS cohort. METHODS: Pedigrees of 325 unrelated families with LS within the Familial Gastrointestinal Cancer Registry in Canada were examined for breast cancer diagnoses. Standardised incidence ratios (SIR) and lifetime cumulative incidence calculations were used to compare the incidence of breast cancer in mutation carriers with the general population. RESULTS: Forty-one mutation carriers diagnosed with breast cancer belonging to 34 unrelated families were identified. Mean age at diagnosis was 54 years. The mutation distribution among the LS patients with breast cancer was statistically different from those without breast cancer (p=0.015), reflecting the predominance of MSH2 mutations among affected patients (74%). Eighty-eight per cent of LS families with breast cancer met Amsterdam criteria, compared with 49% of LS families without breast cancer (p=0.03). Lifetime cumulative incidence of breast cancer in female MSH2 mutation carriers in our cohort was 22% (p<0.001). The SIR for breast cancer of female MSH2 mutation carriers in our cohort was 3.11 (95% CI 1.95 to 4.71). CONCLUSIONS: An increased risk of breast cancer in MSH2 mutation carriers was demonstrated in a Canadian familial cancer registry. Women with breast cancer often had a personal and family history of multiple LS-related malignancies. These results suggest a potential role for intensified breast cancer surveillance among women with LS.


Assuntos
Neoplasias da Mama/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Proteína 2 Homóloga a MutS/genética , Canadá/epidemiologia , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Heterozigoto , Humanos , Incidência , Linhagem , Sistema de Registros
15.
Fam Med ; 49(6): 443-450, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28633170

RESUMO

BACKGROUND AND OBJECTIVE: Given the increasing discussions of the impact of genetic medicine within family medicine, it is important to determine the most effective way of teaching this material to family medicine residents (FMRs). The objective of this study was to evaluate and compare the impact of three methods of delivering primary care genetic content to FMRs. METHODS: Curriculum materials and assessment tools were created to teach and evaluate knowledge, skills, and attitudes around four core competencies in primary care genetics, with a focus on hereditary colorectal cancer (CRC). Participants were randomly allocated to four learning conditions: (1) no intervention (control), (2) web-based module outlining genetic concepts applied to CRC, (3) live presentation of the web-based material, (4) live presentation and subsequent standardized patient (SP) encounter. Three months later, all participants completed a written knowledge test, attitude survey, and a standardized patient-based performance assessment. RESULTS: Sixty FMRs completed the study. All three educational interventions resulted in significantly improved outcome measures in knowledge and skills but not attitudes, compared to control. There was no significant difference in outcomes between intervention groups. CONCLUSION: FMRs acquired knowledge and improved skills in genetic medicine with three educational methods. Resources such as faculty expertise in genetic medicine and cost should guide decisions on curricular development for this rapidly expanding field. This may be especially relevant for programs with distributed teaching sites.


Assuntos
Medicina de Família e Comunidade/educação , Genética , Internato e Residência , Atenção Primária à Saúde , Ensino , Avaliação Educacional , Conhecimentos, Atitudes e Prática em Saúde , Humanos
16.
J Genet Couns ; 26(4): 866-877, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28127677

RESUMO

Providers and patients encounter challenges related to the management of Variants of Unknown Significance (VUS). A VUS introduces new counseling dilemmas for the understanding and psychosocial impact of uncertain genetic test results. This descriptive study uses Mishel's theory of uncertainty in illness to explore the experience of individuals who have received a VUS as part of the genetic testing process. Semi-structured interviews were conducted with 27 adult individuals who received a VUS for Lynch syndrome mismatch repair genes between 2002 and 2013. The interviews were transcribed and analyzed. Most individuals recalled their result and perceived various types of uncertainty associated with their VUS. Half of the participants appraised their variant as a danger and implemented coping strategies to reduce the threat of developing cancer. Mobilizing strategies to reduce their risk included vigilant cancer surveillance, information seeking and notifying relatives. The majority of participants were unaware of the possibility of a VUS before receiving their result and expected reclassification over time. These results provide insight into the ways healthcare providers can support patients who receive VUS for Lynch syndrome. Findings also provide direction for future work that can further explicate the impact of receiving a VUS.


Assuntos
Adaptação Psicológica , Neoplasias Colorretais Hereditárias sem Polipose/genética , Testes Genéticos , Conhecimentos, Atitudes e Prática em Saúde , Incerteza , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
18.
Cancer ; 122(11): 1672-9, 2016 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-27019099

RESUMO

BACKGROUND: In November 2001, genetic testing for Lynch syndrome (LS) was introduced by the Ministry of Health and Long-Term Care (MOH) in Ontario for individuals at high risk for LS cancers according to either tumor immunohistochemistry staining or their family history. This article describes the outcomes of the program and makes recommendations for improving it and informing other public health care programs. METHODS: Subjects were referred for molecular testing of the mismatch repair (MMR) genes MutL homolog 1, MutS homolog 2, and MutS homolog 6 if they met 1 of 7 MOH criteria. Testing was conducted from January 2001 to March 2015 at the Molecular Diagnostic Laboratory of Mount Sinai Hospital in Toronto. RESULTS: A total of 1452 subjects were tested. Of the 662 subjects referred for testing because their tumor was immunodeficient for 1 or more of the MMR genes, 251 (37.9%) carried a germline mutation. In addition, 597 subjects were tested for a known family mutation, and 298 (49.9%) were positive; 189 of these 298 subjects (63.4%) were affected with cancer at the time of testing. An additional 193 subjects were referred because of a family history of LS, and 34 of these (17.6%) had a mutation identified. CONCLUSIONS: These results indicate that the provincial criteria are useful in identifying LS carriers after an MMR-deficient tumor is identified. Placing greater emphasis on testing unaffected relatives in families with a known mutation may identify more unaffected carriers and facilitate primary prevention in those individuals. Cancer 2016;122:1672-9. © 2016 American Cancer Society.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA , Testes Genéticos/métodos , Mutação em Linhagem Germinativa , Adolescente , Adulto , Idoso , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Proteínas de Ligação a DNA/genética , Saúde da Família , Feminino , Heterozigoto , Humanos , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL/genética , Proteína 2 Homóloga a MutS/genética , Ontário , Avaliação de Programas e Projetos de Saúde , Adulto Jovem
19.
Am J Gastroenterol ; 111(2): 275-84, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26729549

RESUMO

OBJECTIVES: Hereditary biallelic mismatch repair deficiency (BMMRD) is caused by biallelic mutations in the mismatch repair (MMR) genes and manifests features of neurofibromatosis type 1, gastrointestinal (GI) polyposis, and GI, brain, and hematological cancers. This is the first study to characterize the GI phenotype in BMMRD using both retrospective and prospective surveillance data. METHODS: The International BMMRD Consortium was created to collect information on BMMRD families referred from around the world. All patients had germline biallelic MMR mutations or lack of MMR protein staining in normal and tumor tissue. GI screening data were obtained through medical records with annual updates. RESULTS: Thirty-five individuals from seven countries were identified with BMMRD. GI data were available on 24 of 33 individuals (73%) of screening age, totaling 53 person-years. The youngest age of colonic adenomas was 7, and small bowel adenoma was 11. Eight patients had 19 colorectal adenocarcinomas (CRC; median age 16.7 years, range 8-25), and 11 of 18 (61%) CRC were distal to the splenic flexure. Eleven patients had 15 colorectal surgeries (median 14 years, range 9-25). Four patients had five small bowel adenocarcinomas (SBC; median 18 years, range 11-33). Two CRC and two SBC were detected during surveillance within 6-11 months and 9-16 months, respectively, of last consecutive endoscopy. No patient undergoing surveillance died of a GI malignancy. Familial clustering of GI cancer was observed. CONCLUSIONS: The prevalence and penetrance of GI neoplasia in children with BMMRD is high, with rapid development of carcinoma. Colorectal and small bowel surveillance should commence at ages 3-5 and 8 years, respectively.


Assuntos
Adenocarcinoma/cirurgia , Adenoma/cirurgia , Neoplasias Encefálicas/fisiopatologia , Neoplasias Colorretais/cirurgia , Intestino Delgado/cirurgia , Síndromes Neoplásicas Hereditárias/fisiopatologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Adenocarcinoma/etiologia , Adenocarcinoma/genética , Adenoma/etiologia , Adenoma/genética , Adenosina Trifosfatases/genética , Adolescente , Adulto , Alelos , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/etiologia , Neoplasias Encefálicas/genética , Criança , Pré-Escolar , Neoplasias Colorretais/complicações , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/fisiopatologia , Enzimas Reparadoras do DNA/genética , Proteínas de Ligação a DNA/genética , Feminino , Mutação em Linhagem Germinativa , Glioma/etiologia , Humanos , Neoplasias Intestinais/etiologia , Neoplasias Intestinais/genética , Neoplasias Intestinais/cirurgia , Neoplasias Renais/etiologia , Leucemia/etiologia , Linfoma/etiologia , Masculino , Melanoma/etiologia , Endonuclease PMS2 de Reparo de Erro de Pareamento , Proteína 1 Homóloga a MutL , Síndromes Neoplásicas Hereditárias/complicações , Síndromes Neoplásicas Hereditárias/genética , Proteínas Nucleares/genética , Fenótipo , Estudos Prospectivos , Estudos Retrospectivos , Tumor de Wilms/etiologia , Adulto Jovem
20.
J Behav Med ; 39(3): 420-8, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26762124

RESUMO

This study investigated the extent to which intolerance of uncertainty was associated with cancer worry interference, anxiety and depression among women with Lynch syndrome (LS), and whether having greater trust in one's physician moderated those relationships. Women with confirmed LS (N = 128) were recruited from a high-risk of cancer registry and completed a one-time self-report questionnaire. Women who reported greater intolerance of uncertainty and more trust in their physician reported less cancer worry interference compared to women who had greater intolerance of uncertainty and less trust in their physician, who reported the highest worry interference, b = -1.39, t(99) = -2.27, p = .03. No moderation effect of trust in physician was found for anxiety or depression. Trust in one's physician buffered the impact of high intolerance of uncertainty on cancer worry interference, underscoring the need for supportive provider-patient relationships, particularly for LS patients.


Assuntos
Ansiedade/psicologia , Neoplasias Colorretais Hereditárias sem Polipose/psicologia , Depressão/psicologia , Relações Médico-Paciente , Sistema de Registros , Confiança/psicologia , Incerteza , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Pessoa de Meia-Idade , Adulto Jovem
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