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1.
Cancer ; 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33320347

RESUMO

BACKGROUND: Little is known about the psychological outcomes of germline multigene panel testing, particularly among diverse patients and those with moderate-risk pathogenic variants (PVs). METHODS: Study participants (N = 1264) were counseled and tested with a 25- or 28-gene panel and completed a 3-month postresult survey including the Multidimensional Impact of Cancer Risk Assessment (MICRA). RESULTS: The mean age was 52 years, 80% were female, and 70% had cancer; 45% were non-Hispanic White, 37% were Hispanic, 10% were Asian, 3% were Black, and 5% had another race/ethnicity. Approximately 28% had a high school education or less, and 23% were non-English-speaking. The genetic test results were as follows: 7% had a high-risk PV, 6% had a moderate-risk PV, 35% had a variant of uncertain significance (VUS), and 52% were negative. Most participants (92%) had a total MICRA score ≤ 38, which corresponded to a mean response of "never," "rarely," or only "sometimes" reacting negatively to results. A multivariate analysis found that mean total MICRA scores were significantly higher (more uncertainty/distress) among high- and moderate-risk PV carriers (29.7 and 24.8, respectively) than those with a VUS or negative results (17.4 and 16.1, respectively). Having cancer or less education was associated with a significantly higher total MICRA score; race/ethnicity was not associated with the total MICRA score. High- and moderate-risk PV carriers did not differ significantly from one another in the total MICRA score, uncertainty, distress, or positive experiences. CONCLUSIONS: In a diverse population undergoing genetic counseling and multigene panel testing for hereditary cancer risk, the psychological response corresponded to test results and showed low distress and uncertainty. Further studies are needed to assess patient understanding and subsequent cancer screening among patients from diverse backgrounds. LAY SUMMARY: Multigene panel tests for hereditary cancer have become widespread despite concerns about adverse psychological reactions among carriers of moderate-risk pathogenic variants (mutations) and among carriers of variants of uncertain significance. This large study of an ethnically and economically diverse cohort of patients undergoing panel testing found that 92% "never," "rarely," or only "sometimes" reacted negatively to results. Somewhat higher uncertainty and distress were identified among carriers of high- and moderate-risk pathogenic variants, and lower levels were identified among those with a variant of uncertain significance or a negative result. Although the psychological response corresponded to risk, reactions to testing were favorable, regardless of results.

2.
Gynecol Oncol ; 159(3): 869-876, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33032822

RESUMO

OBJECTIVE: Pathogenic variations in the homologous recombination (HR) gene, BRCA1 interacting protein C-terminal helicase 1 (BRIP1) increase the risk for ovarian cancer. PARP inhibitors (PARPi) exert a synthetic lethal effect in BRCA-mutated ovarian cancers. Effective HR requires cooperation between BRCA1 and BRIP1; therefore, BRIP1-incompetancy may predict vulnerability to synthetic lethality. Here we investigated the response of ovarian epithelial cells with defective BRIP1 function to PARPi, and compared these cells to those lacking BRCA1 activity. METHODS: We engineered Chinese Hamster ovarian (CHO) epithelial cells to express deficient BRIP1 or BRCA1, and exposed them to olaparib with or without carboplatin or cisplatin. We assessed cellular proliferation and survival; we calculated inhibitory concentrations and combination and reduction drug indices. RESULTS: BRIP1 and BRCA1 inactivation impedes HR activity, decreases cellular proliferation and compromises DNA damage recovery. Platinum agent exposure impairs cellular survival. Olaparib exposure alone decreases cell viability in BRCA1-deficient cells, although has no effect on BRIP1-deficient cells. Combining carboplatin or cisplatin with olaparib synergistically attenuates cellular survival, consistent with synthetic lethality. CONCLUSIONS: BRIP1-deficient ovarian epithelial cells exhibit defective HR, resulting in synthetic lethality when exposed to a platinum agent/PARPi combination. PARPi alone had no effect; this lack of effect may result from distinguishing molecular properties of BRIP1and/or consequences of genomic background. Our study identifies altered BRIP1 as a target for precision medicine-based therapies for ovarian cancers. This investigation supports consideration of the use of a platinum agent/PARPi combination in ovarian cancers depending upon genetic profile and genomic background.

3.
J Clin Oncol ; 38(7): 674-685, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31841383

RESUMO

PURPOSE: To estimate age-specific relative and absolute cancer risks of breast cancer and to estimate risks of ovarian, pancreatic, male breast, prostate, and colorectal cancers associated with germline PALB2 pathogenic variants (PVs) because these risks have not been extensively characterized. METHODS: We analyzed data from 524 families with PALB2 PVs from 21 countries. Complex segregation analysis was used to estimate relative risks (RRs; relative to country-specific population incidences) and absolute risks of cancers. The models allowed for residual familial aggregation of breast and ovarian cancer and were adjusted for the family-specific ascertainment schemes. RESULTS: We found associations between PALB2 PVs and risk of female breast cancer (RR, 7.18; 95% CI, 5.82 to 8.85; P = 6.5 × 10-76), ovarian cancer (RR, 2.91; 95% CI, 1.40 to 6.04; P = 4.1 × 10-3), pancreatic cancer (RR, 2.37; 95% CI, 1.24 to 4.50; P = 8.7 × 10-3), and male breast cancer (RR, 7.34; 95% CI, 1.28 to 42.18; P = 2.6 × 10-2). There was no evidence for increased risks of prostate or colorectal cancer. The breast cancer RRs declined with age (P for trend = 2.0 × 10-3). After adjusting for family ascertainment, breast cancer risk estimates on the basis of multiple case families were similar to the estimates from families ascertained through population-based studies (P for difference = .41). On the basis of the combined data, the estimated risks to age 80 years were 53% (95% CI, 44% to 63%) for female breast cancer, 5% (95% CI, 2% to 10%) for ovarian cancer, 2%-3% (95% CI females, 1% to 4%; 95% CI males, 2% to 5%) for pancreatic cancer, and 1% (95% CI, 0.2% to 5%) for male breast cancer. CONCLUSION: These results confirm PALB2 as a major breast cancer susceptibility gene and establish substantial associations between germline PALB2 PVs and ovarian, pancreatic, and male breast cancers. These findings will facilitate incorporation of PALB2 into risk prediction models and optimize the clinical cancer risk management of PALB2 PV carriers.

4.
J Natl Cancer Inst ; 110(10): 1059-1066, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-29618041

RESUMO

Background: In germline genetic testing, variants from understudied ancestries have been disproportionately classified as being of uncertain significance. We hypothesized that the rate of variant reclassification likewise differs by ancestry. Methods: Nonbenign variants in actionable genes were collected from consenting subjects undergoing genetic testing at two Southern California sites from September 1996 through December 2016. Variant reclassifications were recorded as they were received, until February 2017 or reclassification to benign. Excluding duplicate variants (same ancestry, laboratory, classification), generalized linear models for the hereditary breast cancer genes (BRCA1/2) and other variants investigated whether rate of reclassification differed for seven categories of ancestry compared with non-Hispanic European. Models took into account laboratory, year, gene, sex, and current classification (handled as a time-dependent covariate) and were adjusted for multiple hypothesis testing. Results: Among 1483 nonbenign variants, 693 (46.7%) involved BRCA1/2. Overall, 268 (18.1%) variants were reclassified at least once. Few (9.7%) reclassified variants underwent a net upgrade in pathogenicity. For BRCA1/2 variants, reclassification rates varied by ancestry and increased over time, more steeply for ancestries with lower initial rates (African, Ashkenazi, Chinese) than for ancestries whose initial rates were high (Middle Eastern) or similar to non-Hispanic European (non-Chinese Asian, Native American, Hispanic). In contrast, reclassification rates of non-BRCA1/2 variants did not vary over time but were elevated for most minority ancestries except non-Chinese Asian and Native American. Conclusions: For nonbenign variants in cancer-related genes, the rates at which reclassifications are issued vary by ancestry in ways that differ between BRCA1/2 and other genes.


Assuntos
Predisposição Genética para Doença , Variação Genética , Neoplasias/genética , Grupos Étnicos/genética , Estudos de Associação Genética , Humanos , Estimativa de Kaplan-Meier , Neoplasias/diagnóstico , Neoplasias/mortalidade , Grupos Populacionais/genética , Estudos Prospectivos
5.
NPJ Genom Med ; 3: 7, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29479477

RESUMO

Clinical testing of BRCA1 and BRCA2 began over 20 years ago. With the expiration and overturning of the BRCA patents, limitations on which laboratories could offer commercial testing were lifted. These legal changes occurred approximately the same time as the widespread adoption of massively parallel sequencing (MPS) technologies. Little is known about how these changes impacted laboratory practices for detecting genetic alterations in hereditary breast and ovarian cancer genes. Therefore, we sought to examine current laboratory genetic testing practices for BRCA1/BRCA2. We employed an online survey of 65 questions covering four areas: laboratory characteristics, details on technological methods, variant classification, and client-support information. Eight United States (US) laboratories and 78 non-US laboratories completed the survey. Most laboratories (93%; 80/86) used MPS platforms to identify variants. Laboratories differed widely on: (1) technologies used for large rearrangement detection; (2) criteria for minimum read depths; (3) non-coding regions sequenced; (4) variant classification criteria and approaches; (5) testing volume ranging from 2 to 2.5 × 105 tests annually; and (6) deposition of variants into public databases. These data may be useful for national and international agencies to set recommendations for quality standards for BRCA1/BRCA2 clinical testing. These standards could also be applied to testing of other disease genes.

6.
Cancer Genet ; 209(4): 130-7, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26908360

RESUMO

This study aims to assess multi-gene panel testing in an ethnically diverse clinical cancer genetics practice. We conducted a retrospective study of individuals with a personal or family history of cancer undergoing clinically indicated multi-gene panel tests of 6-110 genes, from six commercial laboratories. The 475 patients in the study included 228 Hispanics (47.6%), 166 non-Hispanic Whites (35.4%), 55 Asians (11.6%), 19 Blacks (4.0%), and seven others (1.5%). Panel testing found that 15.6% (74/475) of patients carried deleterious mutations for a total of 79 mutations identified. This included 7.4% (35/475) of patients who had a mutation identified that would not have been tested with a gene-by-gene approach. The identification of a panel-added mutation impacted clinical management for most of cases (69%, 24/35), and genetic testing was recommended for the first degree relatives of nearly all of them (91%, 32/35). Variants of uncertain significance (VUSs) were identified in a higher proportion of tests performed in ethnic minorities. Multi-gene panel testing increases the yield of mutations detected and adds to the capability of providing individualized cancer risk assessment. VUSs represent an interpretive challenge due to less data available outside of White, non-Hispanic populations. Further studies are necessary to expand understanding of the implementation and utilization of panels across broad clinical settings and patient populations.


Assuntos
Mutação , Neoplasias/etnologia , Neoplasias/genética , Estudos de Coortes , Feminino , Predisposição Genética para Doença/etnologia , Predisposição Genética para Doença/genética , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Medição de Risco
7.
Cancer Genet ; 209(3): 75-81, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26774355

RESUMO

Germline mutations in the tumor suppressor gene, BRCA-1 associated protein (BAP1), underlie a tumor predisposition syndrome characterized by increased risk for numerous cancers including uveal melanoma, melanocytic tumors and mesothelioma, among others. In the present study we report the identification of a novel germline BAP1 mutation, c.1777C>T, which produces a truncated BAP1 protein product and segregates with cancer. Family members with this mutation demonstrated a primary clinical phenotype of autosomal dominant, early-onset melanocytic neoplasms with immunohistochemistry (IHC) of these tumors demonstrating lack of BAP1 protein expression. In addition, family members harboring the BAP1 c.1777C>T germline mutation developed other neoplastic disease including thyroid cancer. IHC analysis of the thyroid cancer, as well, demonstrated loss of BAP1 protein expression. Our investigation identifies a new BAP1 mutation, further highlights the relevance of BAP1 as a clinically important tumor suppressor gene, and broadens the range of cancers associated with BAP1 inactivation. Further study will be required to understand the full scope of BAP1-associated neoplastic disease.


Assuntos
Mutação em Linhagem Germinativa , Nevo Pigmentado/genética , Neoplasias Cutâneas/genética , Neoplasias da Glândula Tireoide/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Feminino , Humanos , Pessoa de Meia-Idade , Proteínas Supressoras de Tumor/análise , Ubiquitina Tiolesterase/análise
8.
Genet Test Mol Biomarkers ; 19(12): 657-65, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26539620

RESUMO

BACKGROUND: Advances in next-generation sequencing (NGS) technologies are driving a shift from single-gene to multigene panel testing for clinical genetic cancer risk assessment (GCRA). This study explored perceptions, experiences, and challenges with NGS testing for GCRA among U.S. community-based clinicians. METHODS: Surveys delivered at initial and 8-month time points, and 12-month tracking of cases presented in a multidisciplinary web-based case conference series, were conducted with GCRA providers who participated in a 235-member nationwide community of practice. RESULTS: The proportion of respondents ordering panel tests rose from 29% at initial survey (27/94) to 44% (46/107) within 8 months. Respondents reported significantly less confidence about interpreting and counseling about NGS compared with single-gene test results (p < 0.0001 for all comparisons). The most cited reasons for not ordering NGS tests included concerns about clinical utility, interpreting and communicating results, and lack of knowledge/skills. Multigene panels were used in 204/668 cases presented during 2013, yielding 37 (18%) deleterious (7% in low/moderate-penetrance genes), 88 (43%) with ≥1 variant of uncertain significance, 77 (38%) uninformative negative, and 2 (1%) inconclusive results. CONCLUSIONS: Despite concerns about utility and ability to interpret/counsel about NGS results, a rapidly increasing uptake of NGS testing among community clinicians was documented. Challenges identified in case discussions point to the need for ongoing education, practice-based support, and opportunities to partner in research that contributes to characterization of lesser known genes.


Assuntos
Serviços de Saúde Comunitária , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Neoplasias , Educação de Pacientes como Assunto , Inquéritos e Questionários , Feminino , Humanos , Masculino , Neoplasias/diagnóstico , Neoplasias/genética
9.
Mol Diagn Ther ; 17(1): 31-47, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23355100

RESUMO

Prevalent as an acquired abnormality in cancer, the role of tumor protein p53 (TP53) as a germline mutation continues to evolve. The clinical impact of a germline TP53 mutation is often dramatic and affects the full life course, with a propensity to develop rare tumors in childhood and multiple common cancers of unexpectedly early onset in adulthood. In this article, we review the clinical relevance of germline mutations in the TP53 tumor suppressor gene to current healthcare practice, including the optimal ways to identify patients with Li-Fraumeni syndrome (LFS), to recognize the core cancers associated with LFS, and to develop strategies for early detection of LFS-associated tumors. Several TP53-targeted approaches to improve outcomes in LFS patients are also reviewed. A case report is used to highlight special TP53 testing dilemmas and unique challenges associated with genetic testing decisions in the current age of rapidly advancing genomic technologies.


Assuntos
Testes Genéticos/métodos , Síndrome de Li-Fraumeni/diagnóstico , Proteína Supressora de Tumor p53/análise , Neoplasias do Córtex Suprarrenal/genética , Neoplasias Encefálicas/genética , Neoplasias da Mama/genética , Feminino , Genes p53 , Estudos de Associação Genética/métodos , Mutação em Linhagem Germinativa , Humanos , Síndrome de Li-Fraumeni/genética , Linhagem , Sarcoma/genética , Proteína Supressora de Tumor p53/genética
10.
J Cancer Educ ; 27(3): 467-77, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22610836

RESUMO

This paper describes the use of action research in a patient conference to provide updated hereditary cancer information, explore patient and family member needs and experiences related to genetic cancer risk assessment (GCRA), elicit feedback on how to improve the GCRA process, and inform future research efforts. Invitees completed GCRA at City of Hope or collaborating facilities and had a BRCA mutation or a strong personal or family history of breast cancer. Action research activities were facilitated by surveys, round table discussions, and reflection time to engage participants, faculty, and researchers in multiple cycles of reciprocal feedback. The multimodal action research design effectively engaged conference participants to share their experiences, needs, and ideas for improvements to the GCRA process. Participants indicated that they highly valued the information and resources provided and desired similar future conferences. The use of action research in a patient conference is an innovative and effective approach to provide health education, elicit experiences, identify and help address needs of high-risk patients and their family members, and generate research hypotheses. Insights gained yielded valuable feedback to inform clinical care, future health services research, and continuing medical education activities. These methods may also be effective in other practice settings.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/psicologia , Congressos como Assunto/organização & administração , Predisposição Genética para Doença/psicologia , Pesquisa sobre Serviços de Saúde/organização & administração , Família , Feminino , Genes BRCA1 , Genes BRCA2 , Aconselhamento Genético/organização & administração , Humanos , Determinação de Necessidades de Cuidados de Saúde , Avaliação de Programas e Projetos de Saúde , Medição de Risco
11.
J Genet Couns ; 21(2): 151-61, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22134580

RESUMO

Updated from their original publication in 2004, these cancer genetic counseling recommendations describe the medical, psychosocial, and ethical ramifications of counseling at-risk individuals through genetic cancer risk assessment with or without genetic testing. They were developed by members of the Practice Issues Subcommittee of the National Society of Genetic Counselors Familial Cancer Risk Counseling Special Interest Group. The information contained in this document is derived from extensive review of the current literature on cancer genetic risk assessment and counseling as well as the personal expertise of genetic counselors specializing in cancer genetics. The recommendations are intended to provide information about the process of genetic counseling and risk assessment for hereditary cancer disorders rather than specific information about individual syndromes. Essential components include the intake, cancer risk assessment, genetic testing for an inherited cancer syndrome, informed consent, disclosure of genetic test results, and psychosocial assessment. These recommendations should not be construed as dictating an exclusive course of management, nor does use of such recommendations guarantee a particular outcome. These recommendations do not displace a health care provider's professional judgment based on the clinical circumstances of a client.


Assuntos
Aconselhamento Genético , Testes Genéticos , Neoplasias/genética , Medição de Risco , Predisposição Genética para Doença , Humanos , Recursos Humanos
12.
CA Cancer J Clin ; 61(5): 327-59, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21858794

RESUMO

Scientific and technologic advances are revolutionizing our approach to genetic cancer risk assessment, cancer screening and prevention, and targeted therapy, fulfilling the promise of personalized medicine. In this monograph, we review the evolution of scientific discovery in cancer genetics and genomics, and describe current approaches, benefits, and barriers to the translation of this information to the practice of preventive medicine. Summaries of known hereditary cancer syndromes and highly penetrant genes are provided and contrasted with recently discovered genomic variants associated with modest increases in cancer risk. We describe the scope of knowledge, tools, and expertise required for the translation of complex genetic and genomic test information into clinical practice. The challenges of genomic counseling include the need for genetics and genomics professional education and multidisciplinary team training, the need for evidence-based information regarding the clinical utility of testing for genomic variants, the potential dangers posed by premature marketing of first-generation genomic profiles, and the need for new clinical models to improve access to and responsible communication of complex disease risk information. We conclude that given the experiences and lessons learned in the genetics era, the multidisciplinary model of genetic cancer risk assessment and management will serve as a solid foundation to support the integration of personalized genomic information into the practice of cancer medicine.


Assuntos
Genômica/métodos , Neoplasias/genética , Medicina de Precisão/métodos , Medição de Risco , Predisposição Genética para Doença , Testes Genéticos , Humanos
13.
Genet Med ; 13(9): 832-40, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21629123

RESUMO

PURPOSE: To assess the impact of a multimodal interdisciplinary course on genetic cancer risk assessment and research collaboration for community-based clinicians. Clinicians are increasingly requested to conduct genetic cancer risk assessment, but many are inadequately prepared to provide these services. METHODS: A prospective analysis of 131 participants (48 physicians, 41 advanced-practice nurses, and 42 genetic counselors) from community settings across the United States. The course was delivered in three phases: distance didactic learning, face-to-face training, and 12 months of web-based professional development activities to support integration of skills into practice. Cancer genetics knowledge, skills, professional self-efficacy, and practice changes were measured at baseline, immediate, and 14 months postcourse. RESULTS: Knowledge, skills, and self-efficacy scores were significantly different between practice disciplines; however, postscores increased significantly overall and for each discipline (P < 0.001). Fourteen-month practice outcomes reflect significant increases in provision of genetic cancer risk assessment services (P = 0.018), dissemination of cancer prevention information (P = 0.005) and high-risk screening recommendations (P = 0.004) to patients, patient enrollment in research (P = 0.013), and educational outreach about genetic cancer risk assessment (P = 0.003). CONCLUSIONS: Results support the efficacy of the multimodal course as a tool to develop a genetically literate workforce. Sustained alumni participation in web-based professional development activities has evolved into a distance-mediated community of practice in clinical cancer genetics, modeling the lifelong learning goals envisioned by leading continuing medical education stakeholders.


Assuntos
Educação Médica Continuada , Aconselhamento Genético/métodos , Medicina de Precisão/métodos , Aconselhamento Genético/tendências , Testes Genéticos/métodos , Pesquisas sobre Serviços de Saúde , Humanos , Neoplasias/diagnóstico , Neoplasias/genética , Estudos Prospectivos , Medição de Risco , Fatores de Risco
14.
J Genet Couns ; 20(3): 294-307, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21369831

RESUMO

BRCA+ breast cancer patients face high risk for a second breast cancer and ovarian cancer. Helping these women decide among risk-reducing options requires effectively conveying complex, emotionally-laden, information. To support their decision-making needs, we developed a web-based decision aid (DA) as an adjunct to genetic counseling. Phase 1 used focus groups to determine decision-making needs. These findings and the Ottawa Decision Support Framework guided the DA development. Phase 2 involved nine focus groups of four stakeholder types (BRCA+ breast cancer patients, breast cancer advocates, and genetics and oncology professionals) to evaluate the DA's decision-making utility, information content, visual display, and implementation. Overall, feedback was very favorable about the DA, especially a values and preferences ranking-exercise and an output page displaying personalized responses. Stakeholders were divided as to whether the DA should be offered at-home versus only in a clinical setting. This well-received DA will be further tested to determine accessibility and effectiveness.


Assuntos
Neoplasias da Mama/psicologia , Técnicas de Apoio para a Decisão , Genes BRCA1 , Genes BRCA2 , Triagem de Portadores Genéticos , Neoplasias da Mama/genética , Neoplasias da Mama/cirurgia , Feminino , Grupos Focais , Aconselhamento Genético , Humanos , Mastectomia , Ovariectomia , Comportamento de Redução do Risco
15.
Hum Mutat ; 32(4): 407-14, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21309036

RESUMO

Recently, we identified 3' end deletions in the EPCAM gene as a novel cause of Lynch syndrome. These truncating EPCAM deletions cause allele-specific epigenetic silencing of the neighboring DNA mismatch repair gene MSH2 in tissues expressing EPCAM. Here we screened a cohort of unexplained Lynch-like families for the presence of EPCAM deletions. We identified 27 novel independent MSH2-deficient families from multiple geographical origins with varying deletions all encompassing the 3' end of EPCAM, but leaving the MSH2 gene intact. Within The Netherlands and Germany, EPCAM deletions appeared to represent at least 2.8% and 1.1% of the confirmed Lynch syndrome families, respectively. MSH2 promoter methylation was observed in epithelial tissues of all deletion carriers tested, thus confirming silencing of MSH2 as the causative defect. In a total of 45 families, 19 different deletions were found, all including the last two exons and the transcription termination signal of EPCAM. All deletions appeared to originate from Alu-repeat mediated recombination events. In 17 cases regions of microhomology around the breakpoints were found, suggesting nonallelic homologous recombination as the most likely mechanism. We conclude that 3' end EPCAM deletions are a recurrent cause of Lynch syndrome, which should be implemented in routine Lynch syndrome diagnostics.


Assuntos
Antígenos de Neoplasias/genética , Moléculas de Adesão Celular/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Variação Genética , Mutação em Linhagem Germinativa/genética , Deleção de Sequência/genética , Antígenos de Neoplasias/metabolismo , Sequência de Bases , Moléculas de Adesão Celular/metabolismo , Metilação de DNA , Molécula de Adesão da Célula Epitelial , Modelos Genéticos , Dados de Sequência Molecular , Proteína 2 Homóloga a MutS/genética , Proteína 2 Homóloga a MutS/metabolismo , Países Baixos , Regiões Promotoras Genéticas , Recidiva
16.
Lancet Oncol ; 12(1): 49-55, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21145788

RESUMO

BACKGROUND: Lynch syndrome is caused by germline mutations in MSH2, MLH1, MSH6, and PMS2 mismatch-repair genes and leads to a high risk of colorectal and endometrial cancer. We previously showed that constitutional 3' end deletions of EPCAM can cause Lynch syndrome through epigenetic silencing of MSH2 in EPCAM-expressing tissues, resulting in tissue-specific MSH2 deficiency. We aim to establish the risk of cancer associated with such EPCAM deletions. METHODS: We obtained clinical data for 194 carriers of a 3' end EPCAM deletion from 41 families known to us at the Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands and compared cancer risk with data from a previously described cohort of 473 carriers from 91 families with mutations in MLH1, MSH2, MSH6, or a combined EPCAM-MSH2 deletion. FINDINGS: 93 of the 194 EPCAM deletion carriers were diagnosed with colorectal cancer; three of the 92 women with EPCAM deletions were diagnosed with endometrial cancer. Carriers of an EPCAM deletion had a 75% (95% CI 65-85) cumulative risk of colorectal cancer before the age of 70 years (mean age at diagnosis 43 years [SD 12]), which did not differ significantly from that of carriers of combined EPCAM-MSH2 deletion (69% [95% CI 47-91], p=0·8609) or mutations in MSH2 (77% [64-90], p=0·5892) or MLH1 (79% [68-90], p=0·5492), but was higher than noted for carriers of MSH6 mutation (50% [38-62], p<0·0001). By contrast, women with EPCAM deletions had a 12% [0-27] cumulative risk of endometrial cancer, which was lower than was that noted for carriers of a combined EPCAM-MSH2 deletion (55% [20-90], p<0·0001) or of a mutation in MSH2 (51% [33-69], p=0·0006) or MSH6 (34% [20-48], p=0·0309), but did not differ significantly from that noted for MLH1 (33% [15-51], p=0·1193) mutation carriers. This risk seems to be restricted to deletions that extend close to the MSH2 gene promoter. Of 194 carriers of an EPCAM deletion, three had duodenal cancer and four had pancreatic cancer. INTERPRETATION: EPCAM deletion carriers have a high risk of colorectal cancer; only those with deletions extending close to the MSH2 promoter have an increased risk of endometrial cancer. These results underscore the effect of mosaic MSH2 deficiency, leading to variable cancer risks, and could form the basis of an optimised protocol for the recognition and targeted prevention of cancer in EPCAM deletion carriers.


Assuntos
Antígenos de Neoplasias/genética , Moléculas de Adesão Celular/genética , Neoplasias Colorretais/genética , Neoplasias do Endométrio/genética , Deleção de Sequência , Adolescente , Adulto , Idoso , Estudos de Coortes , Neoplasias Colorretais/etiologia , Neoplasias do Endométrio/etiologia , Molécula de Adesão da Célula Epitelial , Feminino , Deleção de Genes , Humanos , Masculino , Pessoa de Meia-Idade , Proteína 2 Homóloga a MutS/genética , Regiões Promotoras Genéticas , Risco
17.
Patient Educ Couns ; 83(1): 92-8, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20554149

RESUMO

OBJECTIVE: Health literacy and numeracy are necessary to understand health information and to make informed medical decisions. This study explored the relationships among health literacy, numeracy, and ability to accurately interpret graphical representations of breast cancer risk. METHODS: Participants (N=120) were recruited from the Facing Our Risk of Cancer Empowered (FORCE) membership. Health literacy and numeracy were assessed. Participants interpreted graphs depicting breast cancer risk, made hypothetical treatment decisions, and rated preference of graphs. RESULTS: Most participants were Caucasian (98%) and had completed at least one year of college (93%). Fifty-two percent had breast cancer, 86% had a family history of breast cancer, and 57% had a deleterious BRCA gene mutation. Mean health literacy score was 65/66; mean numeracy score was 4/6; and mean graphicacy score was 9/12. Education and numeracy were significantly associated with accurate graph interpretation (r=0.42, p<0.001 and r=0.65, p<0.001, respectively). However, after adjusting for numeracy in multivariate linear regression, education added little to the prediction of graphicacy (r(2)=0.41 versus 0.42, respectively). CONCLUSION: In our highly health-literate population, numeracy was predictive of graphicacy. PRACTICE IMPLICATIONS: Effective risk communication strategies should consider the impact of numeracy on graphicacy and patient understanding.


Assuntos
Neoplasias da Mama/epidemiologia , Comunicação , Letramento em Saúde , Matemática , Medição de Risco , Adulto , Idoso , Recursos Audiovisuais , Compreensão , Tomada de Decisões , Feminino , Humanos , Pessoa de Meia-Idade , Educação de Pacientes como Assunto/métodos , Preferência do Paciente , Probabilidade , Psicometria , Fatores Socioeconômicos , Inquéritos e Questionários , Adulto Jovem
18.
Genet Med ; 11(10): 735-41, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19661809

RESUMO

PURPOSE: To assess primary care providers' communication about breast cancer risk. METHODS: We evaluated 86 primary care providers' communication of risk using unannounced standardized (simulated) patients. Physicians were randomly assigned to receive one of three cases: (1) moderate risk case (n = 25), presenting with a breast lump and mother with postmenopausal breast cancer; (2) high-risk (maternal side) case (n = 28), presenting with concern about breast cancer risk; and (3) high-risk (paternal side) case (n = 33), presenting with an unrelated problem. After the appointment, three qualitative parameters were assessed by standardized patients on a 3-point scale (3 = highest satisfaction, 1 = lowest): whether the physician took adequate time; acknowledged her concerns; and offered reassurance. RESULTS: Mean satisfaction with physician communication was higher for the moderate risk case (2.92) than for the high-risk paternal case (2.25) or high-risk maternal case (2.42) (P < 0.0001). The score was not influenced by session length, medical specialty, or physician gender. CONCLUSION: Physicians more consistently provided a moderate risk standardized patients with reassurance and support compared with the high-risk cases. Primary care physicians may be more unprepared or uneasy addressing the issues raised by more complex scenarios and may benefit from training in the assessment and communication of breast cancer risk.


Assuntos
Neoplasias da Mama/diagnóstico , Comunicação , Simulação de Paciente , Relações Médico-Paciente , Médicos de Família , Adulto , Neoplasias da Mama/genética , Neoplasias da Mama/psicologia , Feminino , Aconselhamento Genético/normas , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Satisfação do Paciente , Linhagem , Risco
19.
JAMA ; 297(23): 2587-95, 2007 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-17579227

RESUMO

CONTEXT: An autosomal dominant pattern of hereditary breast cancer may be masked by small family size or transmission through males given sex-limited expression. OBJECTIVE: To determine if BRCA gene mutations are more prevalent among single cases of early onset breast cancer in families with limited vs adequate family structure than would be predicted by currently available probability models. DESIGN, SETTING, AND PARTICIPANTS: A total of 1543 women seen at US high-risk clinics for genetic cancer risk assessment and BRCA gene testing were enrolled in a prospective registry study between April 1997 and February 2007. Three hundred six of these women had breast cancer before age 50 years and no first- or second-degree relatives with breast or ovarian cancers. MAIN OUTCOME MEASURE: The main outcome measure was whether family structure, assessed from multigenerational pedigrees, predicts BRCA gene mutation status. Limited family structure was defined as fewer than 2 first- or second-degree female relatives surviving beyond age 45 years in either lineage. Family structure effect and mutation probability by the Couch, Myriad, and BRCAPRO models were assessed with stepwise multiple logistic regression. Model sensitivity and specificity were determined and receiver operating characteristic curves were generated. RESULTS: Family structure was limited in 153 cases (50%). BRCA gene mutations were detected in 13.7% of participants with limited vs 5.2% with adequate family structure. Family structure was a significant predictor of mutation status (odds ratio, 2.8; 95% confidence interval, 1.19-6.73; P = .02). Although none of the models performed well, receiver operating characteristic analysis indicated that modification of BRCAPRO output by a corrective probability index accounting for family structure was the most accurate BRCA gene mutation status predictor (area under the curve, 0.72; 95% confidence interval, 0.63-0.81; P<.001) for single cases of breast cancer. CONCLUSIONS: Family structure can affect the accuracy of mutation probability models. Genetic testing guidelines may need to be more inclusive for single cases of breast cancer when the family structure is limited and probability models need to be recreated using limited family history as an actual variable.


Assuntos
Neoplasias da Mama/genética , Genes BRCA1 , Genes BRCA2 , Mutação , Adulto , Idade de Início , Neoplasias da Mama/epidemiologia , Características da Família , Feminino , Genes Dominantes , Predisposição Genética para Doença , Testes Genéticos , Humanos , Pessoa de Meia-Idade , Modelos Genéticos , Linhagem , Probabilidade , Sistema de Registros , Medição de Risco
20.
Am J Med Genet A ; 143A(6): 564-9, 2007 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-17318844

RESUMO

Genetic information is used increasingly in health care. Some experts have argued that genetic information is qualitatively different from other medical information and, therefore, raises unique social issues. This view, called "genetic exceptionalism," has importantly influenced recent policy efforts. Others have argued that genetic information is like other medical information and that treating it differently may actually result in unintended disparities. Little is known about how the general public views genetic information. To identify opinions about implications of genetic and other medical information among the general population, we conducted a series of focus groups in Seattle, WA. Participants were women and men between ages 18 and 74, living within 30 miles of Seattle and members of the Group Health Cooperative. A structured discussion guide was used to ensure coverage of all predetermined topics. Sessions lasted approximately 2 hr; were audio taped and transcribed. The transcripts formed the basis of the current analysis. Key findings included the theme that genetic information was much like other medical information and that all sensitive medical information should be well protected. Personal choice (i.e., the right to choose whether to know health risk information and to control who else knows) was reported to be of crucial importance. Participants had an understanding of the tensions involved in protecting privacy versus sharing medical information to help another person. These data may guide future research and policy concerning the use and protection of medical information, including genetic information.


Assuntos
Confidencialidade/ética , Grupos Focais , Privacidade Genética/ética , Sistemas Pré-Pagos de Saúde/normas , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Informática Médica/ética , Informática Médica/tendências , Pessoa de Meia-Idade
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