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1.
Eur J Hum Genet ; 29(5): 789-799, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33437034

RESUMO

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


Assuntos
Aconselhamento Genético/métodos , Neoplasias/genética , Incerteza , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Aconselhamento Genético/psicologia , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/diagnóstico , Satisfação do Paciente , Revelação da Verdade
2.
Fam Cancer ; 19(1): 65-76, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31773425

RESUMO

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


Assuntos
Conselheiros/psicologia , Tomada de Decisão Compartilhada , Aconselhamento Genético , Testes Genéticos , Neoplasias/genética , Incerteza , Adulto , Comunicação , Estudos Transversais , Feminino , Predisposição Genética para Doença , Genética , Humanos , Masculino , Pessoa de Meia-Idade , Herança Multifatorial , Países Baixos , Simulação de Paciente
3.
J Med Genet ; 57(5): 308-315, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31784484

RESUMO

BACKGROUND: Inactivating mutations in the MLH1 DNA mismatch repair (MMR) gene underlie 42% of Lynch syndrome (LS) cases. LS is a cancer predisposition causing early onset colorectal and endometrial cancer. Nonsense and frameshift alterations unambiguously cause LS. The phenotype of missense mutations that only alter a single amino acid is often unclear. These variants of uncertain significance (VUS) hinder LS diagnosis and family screening and therefore functional tests are urgently needed. We developed a functional test for MLH1 VUS termed 'oligonucleotide-directed mutation screening' (ODMS). METHODS: The MLH1 variant was introduced by oligonucleotide-directed gene modification in mouse embryonic stem cells that were subsequently exposed to the guanine analogue 6-thioguanine to determine whether the variant abrogated MMR. RESUTS: In a proof-of-principle analysis, we demonstrate that ODMS can distinguish pathogenic and non-pathogenic MLH1 variants with a sensitivity of >95% and a specificity of >91%. We subsequently applied the screen to 51 MLH1 VUS and identified 31 pathogenic variants. CONCLUSION: ODMS is a reliable tool to identify pathogenic MLH1 variants. Implementation in clinical diagnostics will improve clinical care of patients with suspected LS and their relatives.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Predisposição Genética para Doença , Testes Genéticos , Proteína 1 Homóloga a MutL/genética , Animais , Códon sem Sentido/genética , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Modelos Animais de Doenças , Mutação da Fase de Leitura/genética , Variação Genética/genética , Humanos , Camundongos , Células-Tronco Embrionárias Murinas/metabolismo , Mutagênese Sítio-Dirigida , Mutação de Sentido Incorreto/genética
4.
J Surg Oncol ; 116(8): 1029-1039, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28703900

RESUMO

BACKGROUND: Rapid genetic counseling and testing (RGCT) in newly diagnosed high-risk breast cancer (BC) patients may influence surgical treatment decisions. To successfully integrate RGCT in practice, knowledge of professionals', and patients' attitudes toward RGCT is essential. METHODS: Between 2008 and 2010, we performed a randomized clinical trial evaluating the impact of RGCT. Attitudes toward and experience with RGCT were assessed in 265 patients (at diagnosis, 6- and 12-month follow-up) and 29 medical professionals (before and after the recruitment period). RESULTS: At 6-month follow-up, more patients who had been offered RGCT felt they had been actively involved in treatment decision-making than patients who had been offered usual care (67% vs 48%, P = 0.06). Patients who received DNA-test results before primary surgery reported more often that RGCT influenced treatment decisions than those who received results afterwards (P < 0.01). Eighty-seven percent felt that genetic counseling and testing (GCT) should preferably take place between diagnosis and surgery. Most professionals (72%) agreed that RGCT should be routinely offered to eligible patients. Most patients (74%) and professionals (85%) considered surgeons the most appropriate source for referral. CONCLUSIONS: RGCT is viewed as helpful for newly diagnosed high-risk BC patients in choosing their primary surgery and should be offered routinely by surgeons.


Assuntos
Atitude do Pessoal de Saúde , Neoplasias da Mama/genética , Aconselhamento Genético , Testes Genéticos , Adulto , Idoso , Neoplasias da Mama/terapia , Tomada de Decisões , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Encaminhamento e Consulta
5.
Genet Med ; 19(5): 599-603, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-27711073

RESUMO

PURPOSE: CHEK2*1100delC is a founder variant in European populations that confers a two- to threefold increased risk of breast cancer (BC). Epidemiologic and family studies have suggested that the risk associated with CHEK2*1100delC is modified by other genetic factors in a multiplicative fashion. We have investigated this empirically using data from the Breast Cancer Association Consortium (BCAC). METHODS: Using genotype data from 39,139 (624 1100delC carriers) BC patients and 40,063 (224) healthy controls from 32 BCAC studies, we analyzed the combined risk effects of CHEK2*1100delC and 77 common variants in terms of a polygenic risk score (PRS) and pairwise interaction. RESULTS: The PRS conferred odds ratios (OR) of 1.59 (95% CI: 1.21-2.09) per standard deviation for BC for CHEK2*1100delC carriers and 1.58 (1.55-1.62) for noncarriers. No evidence of deviation from the multiplicative model was found. The OR for the highest quintile of the PRS was 2.03 (0.86-4.78) for CHEK2*1100delC carriers, placing them in the high risk category according to UK NICE guidelines. The OR for the lowest quintile was 0.52 (0.16-1.74), indicating a lifetime risk close to the population average. CONCLUSION: Our results confirm the multiplicative nature of risk effects conferred by CHEK2*1100delC and the common susceptibility variants. Furthermore, the PRS could identify carriers at a high lifetime risk for clinical actions.Genet Med advance online publication 06 October 2016.


Assuntos
Neoplasias da Mama/genética , Quinase do Ponto de Checagem 2/genética , Deleção de Sequência , Feminino , Genes Modificadores , Predisposição Genética para Doença , Humanos , Razão de Chances , Penetrância
6.
J Med Genet ; 53(12): 800-811, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27595995

RESUMO

BACKGROUND: The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study. METHODS: We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant. RESULTS: For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10-5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10-8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants. CONCLUSIONS: This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Neoplasias da Mama/metabolismo , Quinase do Ponto de Checagem 2/genética , Predisposição Genética para Doença , Mutação , Proteínas Nucleares/genética , Neoplasias da Próstata/metabolismo , Proteínas Supressoras de Tumor/genética , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Estudos de Casos e Controles , Proteína do Grupo de Complementação N da Anemia de Fanconi , Feminino , Estudos de Associação Genética , Humanos , Masculino , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/genética , Risco
7.
Hum Mutat ; 37(11): 1162-1179, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27435373

RESUMO

Monoallelic PMS2 germline mutations cause 5%-15% of Lynch syndrome, a midlife cancer predisposition, whereas biallelic PMS2 mutations cause approximately 60% of constitutional mismatch repair deficiency (CMMRD), a rare childhood cancer syndrome. Recently improved DNA- and RNA-based strategies are applied to overcome problematic PMS2 mutation analysis due to the presence of pseudogenes and frequent gene conversion events. Here, we determined PMS2 mutation detection yield and mutation spectrum in a nationwide cohort of 396 probands. Furthermore, we studied concordance between tumor IHC/MSI (immunohistochemistry/microsatellite instability) profile and mutation carrier state. Overall, we found 52 different pathogenic PMS2 variants explaining 121 Lynch syndrome and nine CMMRD patients. In vitro mismatch repair assays suggested pathogenicity for three missense variants. Ninety-one PMS2 mutation carriers (70%) showed isolated loss of PMS2 in their tumors, for 31 (24%) no or inconclusive IHC was available, and eight carriers (6%) showed discordant IHC (presence of PMS2 or loss of both MLH1 and PMS2). Ten cases with isolated PMS2 loss (10%; 10/97) harbored MLH1 mutations. We confirmed that recently improved mutation analysis provides a high yield of PMS2 mutations in patients with isolated loss of PMS2 expression. Application of universal tumor prescreening methods will however miss some PMS2 germline mutation carriers.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais/genética , Análise Mutacional de DNA/métodos , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Síndromes Neoplásicas Hereditárias/genética , Neoplasias Encefálicas/metabolismo , Estudos de Coortes , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais Hereditárias sem Polipose/metabolismo , Predisposição Genética para Doença , Variação Genética , Mutação em Linhagem Germinativa , Humanos , Instabilidade de Microssatélites , Endonuclease PMS2 de Reparo de Erro de Pareamento/metabolismo , Síndromes Neoplásicas Hereditárias/metabolismo , Países Baixos
8.
Sci Rep ; 6: 30026, 2016 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-27424772

RESUMO

The HOXB13 p.G84E mutation has been firmly established as a prostate cancer susceptibility allele. Although HOXB13 also plays a role in breast tumor progression, the association of HOXB13 p.G84E with breast cancer risk is less evident. Therefore, we comprehensively interrogated the entire HOXB13 coding sequence for mutations in 1,250 non-BRCA1/2 familial breast cancer cases and 800 controls. We identified two predicted deleterious missense mutations, p.G84E and p.R217C, that were recurrent among breast cancer cases and further evaluated their association with breast cancer risk in a larger study. Taken together, 4,520 familial non-BRCA1/2 breast cancer cases and 3,127 controls were genotyped including the cases and controls of the whole gene screen. The concordance rate for the genotyping assays compared with Sanger sequencing was 100%. The prostate cancer risk allele p.G84E was identified in 18 (0.56%) of 3,187 cases and 16 (0.70%) of 2,300 controls (OR = 0.81, 95% CI = 0.41-1.59, P = 0.54). Additionally, p.R217C was identified in 10 (0.31%) of 3,208 cases and 2 (0.087%) of 2,288 controls (OR = 3.57, 95% CI = 0.76-33.57, P = 0.14). These results imply that none of the recurrent HOXB13 mutations in the Dutch population are associated with breast cancer risk, although it may be worthwhile to evaluate p.R217C in a larger study.


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença , Proteínas de Homeodomínio/genética , Neoplasias da Próstata/genética , Neoplasias da Mama/epidemiologia , Estudos de Casos e Controles , Feminino , Genótipo , Mutação em Linhagem Germinativa/genética , Humanos , Masculino , Mutação de Sentido Incorreto/genética , Países Baixos/epidemiologia , Risco
9.
Menopause ; 23(8): 903-10, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27326821

RESUMO

OBJECTIVE: It has been hypothesized that BRCA1/2 mutation carriers have an earlier age at natural menopause (ANM), although to date findings are inconclusive. This study assessed the influence of BRCA mutation status on ANM, and aimed to explore the reasons of inconsistency in the literature. METHODS: Cross-sectional assessment from an ongoing nationwide cohort study among members of BRCA1/2 mutated families. Information was obtained by a standardized questionnaire. Kaplan-Meier curves were constructed, and Cox regression was used to assess the association between BRCA1/2 mutation status and ANM. Adjustments were made for birth cohort, family, smoking, use of hormonal contraceptives, and parity. RESULTS: A total of 1,208 BRCA1/2 mutation carriers and 2,211 proven noncarriers were included. Overall, no association was found between BRCA1/2 mutation status and ANM (adjusted hazard ratio [HR] = 1.06 [95% CI, 0.87-1.30]). We examined if the null finding was due to informative censoring by uptake of risk-reducing salpingo-oophorectomy. Indeed, within the oldest birth cohort, in which the percentage of surgical menopause events was lowest and comparable between carriers and noncarriers, the HR for earlier natural menopause in carriers was 1.45 (95% CI, 1.09-1.94). The second oldest birth cohort, however, demonstrated a decreased HR (0.67 [95% CI, 0.46-0.98]), and thus no trend over birth cohorts was found. CONCLUSIONS: Various types of selection bias hamper the comparison of ANM between BRCA1/2 mutation carriers and noncarriers, genetically tested in the clinic.


Assuntos
Envelhecimento/genética , Genes BRCA1 , Genes BRCA2 , Heterozigoto , Menopausa/genética , Mutação , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Análise de Regressão , Adulto Jovem
10.
Proc Natl Acad Sci U S A ; 113(15): 4128-33, 2016 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-26951660

RESUMO

Single-stranded DNA oligonucleotides can achieve targeted base-pair substitution with modest efficiency but high precision. We show that "oligo targeting" can be used effectively to study missense mutations in DNA mismatch repair (MMR) genes. Inherited inactivating mutations in DNA MMR genes are causative for the cancer predisposition Lynch syndrome (LS). Although overtly deleterious mutations in MMR genes can clearly be ascribed as the cause of LS, the functional implications of missense mutations are often unclear. We developed a genetic screen to determine the pathogenicity of these variants of uncertain significance (VUS), focusing on mutator S homolog 2 (MSH2). VUS were introduced into the endogenous Msh2 gene of mouse embryonic stem cells by oligo targeting. Subsequent selection for MMR-deficient cells using the guanine analog 6-thioguanine allowed the detection of MMR-abrogating VUS. The screen was able to distinguish weak and strong pathogenic variants from polymorphisms and was used to investigate 59 Msh2 VUS. Nineteen of the 59 VUS were identified as pathogenic. Functional assays revealed that 14 of the 19 detected variants fully abrogated MMR activity and that five of the detected variants attenuated MMR activity. Implementation of the screen in clinical practice allows proper counseling of mutation carriers and treatment of their tumors.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA , Proteína 2 Homóloga a MutS/genética , Mutagênese , Oligonucleotídeos/genética , Humanos
11.
Genet Med ; 18(2): 137-44, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25905441

RESUMO

PURPOSE: Female breast cancer patients carrying a BRCA1/2 mutation have an increased risk of second primary breast cancer. Rapid genetic counseling and testing (RGCT) before surgery may influence choice of primary surgical treatment. In this article, we report on the psychosocial impact of RGCT. METHODS: Newly diagnosed breast cancer patients at risk for carrying a BRCA1/2 mutation were randomized to an intervention group (offer of RGCT) or a usual care control group (ratio 2:1). Psychosocial impact and quality of life were assessed with the Impact of Events Scale, Hospital Anxiety and Depression Scale, Cancer Worry Scale, and the EORTC QLQ-C30 and QLQ-BR23. Assessments took place at study entry and at 6- and 12-month follow-up visits. RESULTS: Between 2008 and 2010, 265 patients were recruited into the study. Completeness of follow-up data was more than 90%. Of the 178 women in the intervention group, 177 had genetic counseling, of whom 71 (40%) had rapid DNA testing and 59 (33%) received test results before surgery. Intention-to-treat and per-protocol analyses showed no statistically significant differences between groups over time in any of the psychosocial outcomes. CONCLUSIONS: In this study, RGCT in newly diagnosed breast cancer patients did not have any measurable adverse psychosocial effects.


Assuntos
Neoplasias da Mama/psicologia , Aconselhamento Genético/psicologia , Testes Genéticos , Adulto , Idoso , Neoplasias da Mama/diagnóstico , Feminino , Genes BRCA1 , Genes BRCA2 , Humanos , Pessoa de Meia-Idade , Fatores de Tempo , Adulto Jovem
12.
J Natl Cancer Inst ; 107(5)2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25855707

RESUMO

BACKGROUND: Data for multiple common susceptibility alleles for breast cancer may be combined to identify women at different levels of breast cancer risk. Such stratification could guide preventive and screening strategies. However, empirical evidence for genetic risk stratification is lacking. METHODS: We investigated the value of using 77 breast cancer-associated single nucleotide polymorphisms (SNPs) for risk stratification, in a study of 33 673 breast cancer cases and 33 381 control women of European origin. We tested all possible pair-wise multiplicative interactions and constructed a 77-SNP polygenic risk score (PRS) for breast cancer overall and by estrogen receptor (ER) status. Absolute risks of breast cancer by PRS were derived from relative risk estimates and UK incidence and mortality rates. RESULTS: There was no strong evidence for departure from a multiplicative model for any SNP pair. Women in the highest 1% of the PRS had a three-fold increased risk of developing breast cancer compared with women in the middle quintile (odds ratio [OR] = 3.36, 95% confidence interval [CI] = 2.95 to 3.83). The ORs for ER-positive and ER-negative disease were 3.73 (95% CI = 3.24 to 4.30) and 2.80 (95% CI = 2.26 to 3.46), respectively. Lifetime risk of breast cancer for women in the lowest and highest quintiles of the PRS were 5.2% and 16.6% for a woman without family history, and 8.6% and 24.4% for a woman with a first-degree family history of breast cancer. CONCLUSIONS: The PRS stratifies breast cancer risk in women both with and without a family history of breast cancer. The observed level of risk discrimination could inform targeted screening and prevention strategies. Further discrimination may be achievable through combining the PRS with lifestyle/environmental factors, although these were not considered in this report.


Assuntos
Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Perfilação da Expressão Gênica , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Biomarcadores Tumorais/análise , Neoplasias da Mama/química , Europa (Continente)/epidemiologia , Feminino , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Genótipo , Humanos , Pessoa de Meia-Idade , Razão de Chances , Valor Preditivo dos Testes , Receptores de Estrogênio/análise , Medição de Risco , Fatores de Risco
13.
Eur J Hum Genet ; 23(5): 588-95, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25138101

RESUMO

In this study, we evaluated the diagnostic value of the Dutch Clinical Genetic Center (CGC) referral guidelines for BRCA1/2 mutation testing in 903 early breast cancer patients, unselected for family history, diagnosed in a cancer hospital before the age of 50 years in 1974-2002; most prevalent Dutch pathogenic BRCA1/2 mutations had been analyzed on coded DNA in a research setting. Forty-nine (5.4%) of the patients were proven to be BRCA1/2 mutation carriers. We found that 78% and 69% of BRCA1 and BRCA2 mutation carriers identified met the criteria for referral to the CGC based on age, family history and synchronous multiple tumors; reflected by a combined sensitivity of 75.5% and specificity of 63.2%. More than half of the BRCA1 mutation carriers, that is, 58% had a triple-negative tumor. The highest AUC was obtained by shifting the age at diagnosis threshold criterion from 40 to 35 years and by adding a 'triple-negative breast cancer' criterion with an age threshold of 45 years; the specificity increased to 71.2%, whereas the sensitivity remained the same; that is, a referral of fewer patients will lead to the identification of at least the same number of BRCA1/2 mutation carriers. Two-thirds of the BRCA1/2 mutation carriers identified in this research setting had been referred for counseling and testing. Our results indicate that, awaiting a possibly more extended mutation screening of all breast cancer patients, the triple-negative status of a breast cancer should be added to the CGC referral criteria.


Assuntos
Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Genes BRCA1 , Genes BRCA2 , Testes Genéticos , Encaminhamento e Consulta , Adulto , Biomarcadores Tumorais , Neoplasias da Mama/epidemiologia , Feminino , Mutação em Linhagem Germinativa , Heterozigoto , Humanos , Pessoa de Meia-Idade , Mutação , Estadiamento de Neoplasias , Países Baixos/epidemiologia , Reprodutibilidade dos Testes , Estudos Retrospectivos , Sensibilidade e Especificidade , Adulto Jovem
14.
J Med Genet ; 51(4): 245-53, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24501230

RESUMO

BACKGROUND: Lynch syndrome, an autosomal-dominant disorder characterised by high colorectal and endometrial cancer risks, is caused by inherited mutations in DNA mismatch repair (MMR) genes. Mutations fully abrogating gene function are unambiguously disease causing. However, missense mutations often have unknown functional implications, hampering genetic counselling. We have applied a novel approach to study three MSH2 unclassified variants (UVs) found in Dutch families with suspected Lynch syndrome. METHODS: The three mutations were recreated in the endogenous Msh2 gene in mouse embryonic stem cells by oligonucleotide-directed gene modification. The effect of the UVs on MMR activity was then tested using a set of functional assays interrogating the main MMR functions. RESULTS: We recreated and functionally tested three MSH2 UVs: MSH2-Y165D (c.493T>G), MSH2-Q690E (c.2068C>G) and MSH2-M813V (c.2437A>G). We observed reduced levels of MSH2-Y165D and MSH2-Q690E but not MSH2-M813V proteins. MSH2-M813V was able to support all MMR functions similar to wild-type MSH2, whereas MSH2-Y165D and MSH2-Q690E showed partial defects. CONCLUSIONS: Based on the results from our functional assays, we conclude that the MSH2-M813V variant is not disease causing. The MSH2-Y165D and MSH2-Q690E variants affect MMR function and are therefore likely the underlying cause of familial cancer predisposition. Since the MMR defect is partial, these variants may represent low penetrance alleles.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA/genética , Proteína 2 Homóloga a MutS/genética , Mutação/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Substituição de Aminoácidos/genética , Animais , Sequência de Bases , Linhagem Celular , Códon/genética , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Simulação por Computador , Análise Mutacional de DNA , Células-Tronco Embrionárias/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Pessoa de Meia-Idade , Dados de Sequência Molecular , Linhagem
15.
J Med Genet ; 51(2): 98-107, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24285858

RESUMO

BACKGROUND: BRCA1 or BRCA2 mutations confer increased risks of breast and ovarian cancer, but risks have been found to vary across studies and populations. METHODS: We ascertained pedigree data of 582 BRCA1 and 176 BRCA2 families and studied the variation in breast and ovarian cancer risks using a modified segregation analysis model. RESULTS: The average cumulative breast cancer risk by age 70 years was estimated to be 45% (95% CI 36 to 52%) for BRCA1 and 27% (95% CI 14 to 38%) for BRCA2 mutation carriers. The corresponding cumulative risks for ovarian cancer were 31% (95% CI 17 to 43%) for BRCA1 and 6% (95% CI 2 to 11%) for BRCA2 mutation carriers. In BRCA1 families, breast cancer relative risk (RR) increased with more recent birth cohort (p heterogeneity = 0.0006) and stronger family histories of breast cancer (p heterogeneity < 0.001). For BRCA1, our data suggest a significant association between the location of the mutation and the ratio of breast to ovarian cancer (p<0.001). By contrast, in BRCA2 families, no evidence was found for risk heterogeneity by birth cohort, family history or mutation location. CONCLUSIONS: BRCA1 mutation carriers conferred lower overall breast and ovarian cancer risks than reported so far, while the estimates of BRCA2 mutations were among the lowest. The low estimates for BRCA1 might be due to older birth cohorts, a moderate family history, or founder mutations located within specific regions of the gene. These results are important for a more accurate counselling of BRCA1/2 mutation carriers.


Assuntos
Efeito Fundador , Genes BRCA1 , Genes BRCA2 , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Adulto , Distribuição por Idade , Idade de Início , Idoso , Estudos de Coortes , Feminino , Síndrome Hereditária de Câncer de Mama e Ovário/epidemiologia , Humanos , Pessoa de Meia-Idade , Mutação , Países Baixos/epidemiologia , Linhagem , Risco , Adulto Jovem
16.
Am J Hum Genet ; 92(4): 489-503, 2013 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-23540573

RESUMO

Analysis of 4,405 variants in 89,050 European subjects from 41 case-control studies identified three independent association signals for estrogen-receptor-positive tumors at 11q13. The strongest signal maps to a transcriptional enhancer element in which the G allele of the best candidate causative variant rs554219 increases risk of breast cancer, reduces both binding of ELK4 transcription factor and luciferase activity in reporter assays, and may be associated with low cyclin D1 protein levels in tumors. Another candidate variant, rs78540526, lies in the same enhancer element. Risk association signal 2, rs75915166, creates a GATA3 binding site within a silencer element. Chromatin conformation studies demonstrate that these enhancer and silencer elements interact with each other and with their likely target gene, CCND1.


Assuntos
Neoplasias da Mama/genética , Cromossomos Humanos Par 11/genética , Ciclina D1/genética , Elementos Facilitadores Genéticos/genética , Polimorfismo de Nucleotídeo Único/genética , Sítios de Ligação , Estudos de Casos e Controles , Linhagem Celular Tumoral , Cromatina/química , Cromatina/genética , Imunoprecipitação da Cromatina , Ciclina D1/metabolismo , Ensaio de Desvio de Mobilidade Eletroforética , Feminino , Fator de Transcrição GATA3/antagonistas & inibidores , Fator de Transcrição GATA3/genética , Fator de Transcrição GATA3/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Luciferases/metabolismo , Regiões Promotoras Genéticas/genética , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Elementos Silenciadores Transcricionais/genética , Proteínas Elk-4 do Domínio ets/antagonistas & inibidores , Proteínas Elk-4 do Domínio ets/genética , Proteínas Elk-4 do Domínio ets/metabolismo
17.
Eur J Cancer ; 49(8): 1993-9, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23415889

RESUMO

AIM: The CHEK2∗1100delC mutation confers a relative risk of two for breast cancer (BC) in the general population. This study aims to explore the excess cancer risk due to the CHEK2∗1100delC mutation within a familial non-BRCA1/2 breast cancer setting. PATIENTS AND METHODS: Cancer incidences were compared between first degree relatives of 107 familial breast cancer patients positive for the CHEK2∗1100delC mutation (CHEK2 positive families) and first degree relatives of 314 familial breast cancer patients without the CHEK2∗1100delC mutation (CHEK2 negative families). All families were derived from the same pool of familial non-BRCA1/2 breast cancer families (n=2554). Medical information of 2188 first degree relatives of these families was analysed for cancer risk. CHEK2∗1100delC status of relatives was unknown. RESULTS: Increased breast cancer risk (hazard ratio (HR) 2.0 (95% confidence interval (CI): 1.4-2.7), p<0.001) was observed in sisters of CHEK2∗1100delC positive index cases compared to sisters of CHEK2∗1100delC negative index cases. HR was 1.6 (95% CI: 1.0-2.4) for mothers of CHEK2 positive versus negative index cases (p=0.041). For second primary breast cancers HR was increased in CHEK2∗1100delC positive index cases (HR 2.1, 95% CI: 1.3-3.3, p=0.003) and their sisters (HR 2.6, 95% CI: 1.1-6.1, p=0.025). CONCLUSION: There is an excess breast cancer risk in first degree relatives of CHEK2∗1100delC positive non-BRCA1/2 familial breast cancer patients compared to non-CHEK2∗1100delC familial breast cancer relatives. Genotyping for the CHEK2∗1100delC mutation in a familial breast cancer setting contributes to optimal clinical surveillance in countries in which this mutation is prevalent. Carriers and female relatives are eligible for stringent breast surveillance programs.


Assuntos
Neoplasias da Mama/genética , Família , Predisposição Genética para Doença/genética , Mutação , Proteínas Serina-Treonina Quinases/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Quinase do Ponto de Checagem 2 , Saúde da Família , Feminino , Genótipo , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Linhagem , Fatores de Risco , Deleção de Sequência , Irmãos
18.
Patient Educ Couns ; 89(1): 89-95, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22543000

RESUMO

OBJECTIVE: Female breast cancer patients carrying a BRCA1/2-mutation have an increased risk of second primary breast and ovarian tumors. Little is known about the psychological impact and treatment consequences of rapid genetic counseling and testing offered between breast cancer diagnosis and surgery. METHODS: Female breast cancer patients, who had received rapid genetic counseling (and optional testing) (RGC(T)) at The Netherlands Cancer Institute between 2004 and 2008, received a questionnaire in 2009. RESULTS: BRCA-mutations were found in 10 of the 26 participants. Six mutation-carriers (60%) had an immediate bilateral mastectomy, compared with 25% of those without a mutation. Five patients (19%) reported having frequent worries about cancer recurrence; none indicated that such worries impaired daily functioning. Six patients had clinically relevant levels of breast cancer-specific distress at the time of assessment. CONCLUSION: These results suggest that RGC(T) in high-risk breast cancer patients may influence surgical treatment, without causing long-term psychosocial distress in the majority. PRACTICE IMPLICATIONS: These results are important, since rapid genetic counseling and testing are expected to be offered to newly diagnosed breast cancer patients with increasing frequency in order to inform these women and their surgeons about the possible familial/hereditary nature of their disease before deciding on treatment.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/psicologia , Tomada de Decisões , Aconselhamento Genético/métodos , Mastectomia/psicologia , Adaptação Psicológica , Adulto , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/cirurgia , Feminino , Genes BRCA2 , Aconselhamento Genético/psicologia , Predisposição Genética para Doença , Testes Genéticos/estatística & dados numéricos , Humanos , Pessoa de Meia-Idade , Mutação/genética , Países Baixos , Preferência do Paciente , Satisfação do Paciente , Projetos Piloto , Fatores de Risco , Fatores Socioeconômicos , Estresse Psicológico , Inquéritos e Questionários , Resultado do Tratamento , Adulto Jovem
19.
Breast Cancer Res ; 14(1): R33, 2012 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-22348646

RESUMO

INTRODUCTION: Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 (ZNF365), rs704010 (ZMIZ1), rs2380205 (10p15), rs614367 (11q13), rs1292011 (12q24), rs10771399 (12p11 near PTHLH) and rs865686 (9q31.2). METHODS: To evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12,599 BRCA1 and 7,132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework. RESULTS: Only SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele hazard ratio (HR) = 0.87, 95% CI: 0.81 to 0.94, P-trend = 3 × 10-4). The association was restricted to mutations proven or predicted to lead to absence of protein expression (HR = 0.82, 95% CI: 0.74 to 0.90, P-trend = 3.1 × 10-5, P-difference = 0.03). Four SNPs were associated with the risk of breast cancer for BRCA2 mutation carriers: rs10995190, P-trend = 0.015; rs1011970, P-trend = 0.048; rs865686, 2df-P = 0.007; rs1292011 2df-P = 0.03. rs10771399 (PTHLH) was predominantly associated with estrogen receptor (ER)-negative breast cancer for BRCA1 mutation carriers (HR = 0.81, 95% CI: 0.74 to 0.90, P-trend = 4 × 10-5) and there was marginal evidence of association with ER-negative breast cancer for BRCA2 mutation carriers (HR = 0.78, 95% CI: 0.62 to 1.00, P-trend = 0.049). CONCLUSIONS: The present findings, in combination with previously identified modifiers of risk, will ultimately lead to more accurate risk prediction and an improved understanding of the disease etiology in BRCA1 and BRCA2 mutation carriers.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 9/genética , Proteínas de Ligação a DNA/genética , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Heterozigoto , Fatores de Transcrição/genética , Adulto , Idoso , Feminino , Estudos de Associação Genética , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco
20.
Nat Genet ; 44(3): 312-8, 2012 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-22267197

RESUMO

Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for ∼8% of the heritability of the disease. We attempted to replicate 72 promising associations from two independent genome-wide association studies (GWAS) in ∼70,000 cases and ∼68,000 controls from 41 case-control studies and 9 breast cancer GWAS. We identified three new breast cancer risk loci at 12p11 (rs10771399; P = 2.7 × 10(-35)), 12q24 (rs1292011; P = 4.3 × 10(-19)) and 21q21 (rs2823093; P = 1.1 × 10(-12)). rs10771399 was associated with similar relative risks for both estrogen receptor (ER)-negative and ER-positive breast cancer, whereas the other two loci were associated only with ER-positive disease. Two of the loci lie in regions that contain strong plausible candidate genes: PTHLH (12p11) has a crucial role in mammary gland development and the establishment of bone metastasis in breast cancer, and NRIP1 (21q21) encodes an ER cofactor and has a role in the regulation of breast cancer cell growth.


Assuntos
Neoplasias da Mama/genética , Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 21/genética , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Modelos Logísticos , Polimorfismo de Nucleotídeo Único/genética , Análise de Componente Principal , População Branca/genética
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