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1.
JMIR Res Protoc ; 10(1): e24414, 2021 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-33480862

RESUMO

BACKGROUND: BRCA1/2 mutation carriers are recommended to undergo risk-reducing salpingo-oophorectomy (RRSO) at 35 to 45 years of age. RRSO substantially decreases ovarian cancer risk, but at the cost of immediate menopause. Knowledge about the potential adverse effects of premenopausal RRSO, such as increased risk of cardiovascular disease, osteoporosis, cognitive dysfunction, and reduced health-related quality of life (HRQoL), is limited. OBJECTIVE: The aim of this study is to assess the long-term health effects of premenopausal RRSO on cardiovascular disease, bone health, cognitive functioning, urological complaints, sexual functioning, and HRQoL in women with high familial risk of breast or ovarian cancer. METHODS: We will conduct a multicenter cross-sectional study with prospective follow-up, nested in a nationwide cohort of women at high familial risk of breast or ovarian cancer. A total of 500 women who have undergone RRSO before 45 years of age, with a follow-up period of at least 10 years, will be compared with 250 women (frequency matched on current age) who have not undergone RRSO or who have undergone RRSO at over 55 years of age. Participants will complete an online questionnaire on lifestyle, medical history, cardiovascular risk factors, osteoporosis, cognitive function, urological complaints, and HRQoL. A full cardiovascular assessment and assessment of bone mineral density will be performed. Blood samples will be obtained for marker analysis. Cognitive functioning will be assessed objectively with an online neuropsychological test battery. RESULTS: This study was approved by the institutional review board in July 2018. In February 2019, we included our first participant. As of November 2020, we had enrolled 364 participants in our study. CONCLUSIONS: Knowledge from this study will contribute to counseling women with a high familial risk of breast/ovarian cancer about the long-term health effects of premenopausal RRSO. The results can also be used to offer health recommendations after RRSO. TRIAL REGISTRATION: ClinicalTrials.gov NCT03835793; https://clinicaltrials.gov/ct2/show/NCT03835793. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/24414.

2.
Cancer Epidemiol Biomarkers Prev ; 28(6): 1010-1014, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30824524

RESUMO

BACKGROUND: PMS2-associated Lynch syndrome is characterized by a relatively low colorectal cancer penetrance compared with other Lynch syndromes. However, age at colorectal cancer diagnosis varies widely, and a strong genetic anticipation effect has been suggested for PMS2 families. In this study, we examined proposed genetic anticipation in a sample of 152 European PMS2 families. METHODS: The 152 families (637 family members) that were eligible for analysis were mainly clinically ascertained via clinical genetics centers. We used weighted Cox-type random effects model, adjusted by birth cohort and sex, to estimate the generational effect on the age of onset of colorectal cancer. Probands and young birth cohorts were excluded from the analyses. Weights represented mutation probabilities based on kinship coefficients, thus avoiding testing bias. RESULTS: Family data across three generations, including 123 colorectal cancers, were analyzed. When compared with the first generation, the crude HR for anticipation was 2.242 [95% confidence interval (CI), 1.162-4.328] for the second generation and 2.644 (95% CI, 1.082-6.464) for the third generation. However, after correction for birth cohort and sex, the effect vanished [HR = 1.302 (95% CI, 0.648-2.619) and HR = 1.074 (95% CI, 0.406-2.842) for second and third generations, respectively]. CONCLUSIONS: Our study did not confirm previous reports of genetic anticipation in PMS2-associated Lynch syndrome. Birth-cohort effect seems the most likely explanation for observed younger colorectal cancer diagnosis in subsequent generations, particularly because there is currently no commonly accepted biological mechanism that could explain genetic anticipation in Lynch syndrome. IMPACT: This new model for studying genetic anticipation provides a standard for rigorous analysis of families with dominantly inherited cancer predisposition.


Assuntos
Antecipação Genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Mutação , Idade de Início , Idoso , Efeito de Coortes , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Reparo de Erro de Pareamento de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Países Baixos/epidemiologia , Linhagem , Penetrância , Modelos de Riscos Proporcionais
3.
Br J Cancer ; 119: 357-363, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29937543

RESUMO

BACKGROUND: The effect of in vitro fertilisation (IVF) on breast cancer risk for BRCA1/2 mutation carriers is rarely examined. As carriers may increasingly undergo IVF as part of preimplantation genetic diagnosis (PGD), we examined the impact of ovarian stimulation for IVF on breast cancer risk in BRCA1/2 mutation carriers. METHODS: The study population consisted of 1550 BRCA1 and 964 BRCA2 mutation carriers, derived from the nationwide HEBON study and the nationwide PGD registry. Questionnaires, clinical records and linkages with the Netherlands Cancer Registry were used to collect data on IVF exposure, risk-reducing surgeries and cancer diagnosis, respectively. Time-dependent Cox regression analyses were conducted, stratified for birth cohort and adjusted for subfertility. RESULTS: Of the 2514 BRCA1/2 mutation carriers, 3% (n = 76) were exposed to ovarian stimulation for IVF. In total, 938 BRCA1/2 mutation carriers (37.3%) were diagnosed with breast cancer. IVF exposure was not associated with risk of breast cancer (HR: 0.79, 95% CI: 0.46-1.36). Similar results were found for the subgroups of subfertile women (n = 232; HR: 0.73, 95% CI: 0.39-1.37) and BRCA1 mutation carriers (HR: 1.12, 95% CI: 0.60-2.09). In addition, age at and recency of first IVF treatment were not associated with breast cancer risk. CONCLUSION: No evidence was found for an association between ovarian stimulation for IVF and breast cancer risk in BRCA1/2 mutation carriers.


Assuntos
Neoplasias da Mama/etiologia , Fertilização In Vitro/efeitos adversos , Genes BRCA1 , Genes BRCA2 , Heterozigoto , Mutação , Indução da Ovulação , Adulto , Idoso , Neoplasias da Mama/genética , Feminino , Humanos , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Risco
4.
J Med Genet ; 55(10): 669-674, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29330337

RESUMO

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


Assuntos
Antígenos CD/genética , Caderinas/genética , MAP Quinase Quinase Quinases/genética , Fator 88 de Diferenciação Mieloide/genética , Neoplasias Gástricas/genética , alfa Catenina/genética , Adulto , Idoso , Estudos de Coortes , Europa (Continente) , Feminino , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência de DNA , Adulto Jovem
5.
JNCI Cancer Spectr ; 2(2): pky023, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31360853

RESUMO

Background: For BRCA1 and BRCA2 mutation carriers, the association between oral contraceptive preparation (OCP) use and breast cancer (BC) risk is still unclear. Methods: Breast camcer risk associations were estimated from OCP data on 6030 BRCA1 and 3809 BRCA2 mutation carriers using age-dependent Cox regression, stratified by study and birth cohort. Prospective, left-truncated retrospective and full-cohort retrospective analyses were performed. Results: For BRCA1 mutation carriers, OCP use was not associated with BC risk in prospective analyses (hazard ratio [HR] = 1.08, 95% confidence interval [CI] = 0.75 to 1.56), but in the left-truncated and full-cohort retrospective analyses, risks were increased by 26% (95% CI = 6% to 51%) and 39% (95% CI = 23% to 58%), respectively. For BRCA2 mutation carriers, OCP use was associated with BC risk in prospective analyses (HR = 1.75, 95% CI = 1.03 to 2.97), but retrospective analyses were inconsistent (left-truncated: HR = 1.06, 95% CI = 0.85 to 1.33; full cohort: HR = 1.52, 95% CI = 1.28 to 1.81). There was evidence of increasing risk with duration of use, especially before the first full-term pregnancy (BRCA1: both retrospective analyses, P < .001 and P = .001, respectively; BRCA2: full retrospective analysis, P = .002). Conclusions: Prospective analyses did not show that past use of OCP is associated with an increased BC risk for BRCA1 mutation carriers in young middle-aged women (40-50 years). For BRCA2 mutation carriers, a causal association is also not likely at those ages. Findings between retrospective and prospective analyses were inconsistent and could be due to survival bias or a true association for younger women who were underrepresented in the prospective cohort. Given the uncertain safety of long-term OCP use for BRCA1/2 mutation carriers, indications other than contraception should be avoided and nonhormonal contraceptive methods should be discussed.

6.
Eur J Hum Genet ; 25(11): 1246-1252, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28875981

RESUMO

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


Assuntos
Exoma , Predisposição Genética para Doença , Testes Genéticos/métodos , Mutação em Linhagem Germinativa , Neoplasias Gástricas/genética , Adulto , Idoso , Antígenos CD , Caderinas/genética , Detecção Precoce de Câncer/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência de DNA/métodos , Neoplasias Gástricas/diagnóstico
7.
Hum Mutat ; 38(2): 226-235, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27767231

RESUMO

With the recent introduction of Poly(ADP-ribose) polymerase inhibitors, a promising novel therapy has become available for ovarian carcinoma (OC) patients with inactivating BRCA1 or BRCA2 mutations in their tumor. To select patients who may benefit from these treatments, assessment of the mutation status of BRCA1 and BRCA2 in the tumor is required. For reliable evaluation of germline and somatic mutations in these genes in DNA derived from formalin-fixed, paraffin-embedded (FFPE) tissue, we have developed a single-molecule molecular inversion probe (smMIP)-based targeted next-generation sequencing (NGS) approach. Our smMIP-based NGS approach provides analysis of both strands of the open reading frame of BRCA1 and BRCA2, enabling the discrimination between real variants and formalin-induced artefacts. The single molecule tag enables compilation of unique reads leading to a high analytical sensitivity and enabling assessment of the reliability of mutation-negative results. Multiplex ligation-dependent probe amplification (MLPA) and Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) were used to detect exon deletions of BRCA1 and methylation of the BRCA1 promoter, respectively. Here, we show that this combined approach allows the rapid and reliable detection of both germline and somatic aberrations affecting BRCA1 and BRCA2 in DNA derived from FFPE OCs, enabling improved hereditary cancer risk assessment and clinical treatment of ovarian cancer patients.


Assuntos
Tomada de Decisão Clínica , Genes BRCA1 , Genes BRCA2 , Aconselhamento Genético , Neoplasias Ovarianas/genética , Alelos , Substituição de Aminoácidos , Variações do Número de Cópias de DNA , Análise Mutacional de DNA , Gerenciamento Clínico , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Testes Genéticos/métodos , Testes Genéticos/normas , Genótipo , Mutação em Linhagem Germinativa , Humanos , Perda de Heterozigosidade , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/terapia , Reprodutibilidade dos Testes
8.
PLoS One ; 11(6): e0157381, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27300758

RESUMO

BACKGROUND AND AIMS: Lynch Syndrome (LS) is caused by pathogenic germline variants in one of the mismatch repair (MMR) genes. However, up to 60% of MMR-deficient colorectal cancer cases are categorized as suspected Lynch Syndrome (sLS) because no pathogenic MMR germline variant can be identified, which leads to difficulties in clinical management. We therefore analyzed the genomic regions of 15 CRC susceptibility genes in leukocyte DNA of 34 unrelated sLS patients and 11 patients with MLH1 hypermethylated tumors with a clear family history. METHODS: Using targeted next-generation sequencing, we analyzed the entire non-repetitive genomic sequence, including intronic and regulatory sequences, of 15 CRC susceptibility genes. In addition, tumor DNA from 28 sLS patients was analyzed for somatic MMR variants. RESULTS: Of 1979 germline variants found in the leukocyte DNA of 34 sLS patients, one was a pathogenic variant (MLH1 c.1667+1delG). Leukocyte DNA of 11 patients with MLH1 hypermethylated tumors was negative for pathogenic germline variants in the tested CRC susceptibility genes and for germline MLH1 hypermethylation. Somatic DNA analysis of 28 sLS tumors identified eight (29%) cases with two pathogenic somatic variants, one with a VUS predicted to pathogenic and LOH, and nine cases (32%) with one pathogenic somatic variant (n = 8) or one VUS predicted to be pathogenic (n = 1). CONCLUSIONS: This is the first study in sLS patients to include the entire genomic sequence of CRC susceptibility genes. An underlying somatic or germline MMR gene defect was identified in ten of 34 sLS patients (29%). In the remaining sLS patients, the underlying genetic defect explaining the MMRdeficiency in their tumors might be found outside the genomic regions harboring the MMR and other known CRC susceptibility genes.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais/genética , Metilação de DNA , Reparo de Erro de Pareamento de DNA , Regulação Neoplásica da Expressão Gênica , Estudos de Coortes , Colo/metabolismo , Colo/patologia , Neoplasias Colorretais/patologia , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Mutação em Linhagem Germinativa , Humanos , Leucócitos/metabolismo , Leucócitos/patologia , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL/genética , Reto/metabolismo , Reto/patologia
9.
Cancer Epidemiol Biomarkers Prev ; 25(8): 1251-8, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27277847

RESUMO

BACKGROUND: Paternal transmission of a BRCA mutation has been reported to increase the risk of breast cancer in offspring more than when the mutation is maternally inherited. As this effect might be caused by referral bias, the aim of this study was to assess the parent-of-origin effect of the BRCA1/2 mutation on the breast cancer lifetime risk, when adjusted for referral bias. METHODS: A Dutch national cohort including 1,314 proven BRCA1/2 mutation carriers and covering 54,752 person years. Data were collected by family cancer clinics, via questionnaires and from the national Dutch Cancer Registry. The parent-of-origin effect was assessed using Cox regression analyses, both unadjusted and adjusted for referral bias. Referral bias was operationalized by number of relatives with cancer and by personal cancer history. RESULTS: The mutation was of paternal origin in 330 (42%, P < 0.001) BRCA1 and 222 (42%, P < 0.001) BRCA2 carriers. Paternal origin increased the risk of prevalent breast cancer for BRCA1 [HR, 1.54; 95% confidence interval (CI), 1.19-2.00] and BRCA2 carriers (HR, 1.40; 95% CI, 0.95-2.06). Adjusted for referral bias by several family history factors, these HRs ranged from 1.41 to 1.83 in BRCA1 carriers and 1.27 to 1.62 in BRCA2 carriers. Adjusted for referral bias by personal history, these HRs were 0.66 (95% CI, 0.25-1.71) and 1.14 (95% CI, 0.42-3.15), respectively. CONCLUSION: A parent-of-origin effect is present after correction for referral bias by family history, but correction for the personal cancer history made the effect disappear. IMPACT: There is no conclusive evidence regarding incorporating a BRCA1/2 parent-of-origin effect in breast cancer risk prediction models. Cancer Epidemiol Biomarkers Prev; 25(8); 1251-8. ©2016 AACR.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Genes BRCA1 , Genes BRCA2 , Mutação em Linhagem Germinativa , Herança Paterna/genética , Adulto , Feminino , Predisposição Genética para Doença , Testes Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Encaminhamento e Consulta , Fatores de Risco
10.
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
11.
Eur J Hum Genet ; 24(7): 1089-92, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26648449

RESUMO

Many suspected Lynch Syndrome (sLS) patients who lack mismatch repair (MMR) germline gene variants and MLH1 or MSH2 hypermethylation are currently explained by somatic MMR gene variants or, occasionally, by germline POLE variants. To further investigate unexplained sLS patients, we analyzed leukocyte and tumor DNA of 62 sLS patients using gene panel sequencing including the POLE, POLD1 and MMR genes. Forty tumors showed either one, two or more somatic MMR variants predicted to affect function. Nine sLS tumors showed a likely ultramutated phenotype and were found to carry germline (n=2) or somatic variants (n=7) in the POLE/POLD1 exonuclease domain (EDM). Six of these POLE/POLD1-EDM mutated tumors also carried somatic MMR variants. Our findings suggest that faulty proofreading may result in loss of MMR and thereby in microsatellite instability.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA , DNA Polimerase III/genética , DNA Polimerase II/genética , Adulto , Idoso , Domínio Catalítico , Evolução Clonal , Neoplasias Colorretais Hereditárias sem Polipose/patologia , DNA Polimerase II/química , DNA Polimerase III/química , Feminino , Instabilidade Genômica , Mutação em Linhagem Germinativa , Humanos , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL/genética , Proteína 2 Homóloga a MutS/genética , Proteínas de Ligação a Poli-ADP-Ribose
12.
Oncotarget ; 6(38): 41108-22, 2015 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-26517685

RESUMO

BACKGROUND: The risk to develop colorectal and endometrial cancers among subjects testing positive for a pathogenic Lynch syndrome mutation varies, making the risk prediction difficult. Genetic risk modifiers alter the risk conferred by inherited Lynch syndrome mutations, and their identification can improve genetic counseling. We aimed at identifying rare genetic modifiers of the risk of Lynch syndrome endometrial cancer. METHODS: A family based approach was used to assess the presence of genetic risk modifiers among 35 Lynch syndrome mutation carriers having either a poor clinical phenotype (early age of endometrial cancer diagnosis or multiple cancers) or a neutral clinical phenotype. Putative genetic risk modifiers were identified by Next Generation Sequencing among a panel of 154 genes involved in endometrial physiology and carcinogenesis. RESULTS: A simple pipeline, based on an allele frequency lower than 0.001 and on predicted non-conservative amino-acid substitutions returned 54 variants that were considered putative risk modifiers. The presence of two or more risk modifying variants in women carrying a pathogenic Lynch syndrome mutation was associated with a poor clinical phenotype. CONCLUSION: A gene-panel is proposed that comprehends genes that can carry variants with putative modifying effects on the risk of Lynch syndrome endometrial cancer. Validation in further studies is warranted before considering the possible use of this tool in genetic counseling.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias do Endométrio/genética , Estrogênios/metabolismo , Mutação em Linhagem Germinativa , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais Hereditárias sem Polipose/metabolismo , Neoplasias do Endométrio/metabolismo , Feminino , Frequência do Gene , Predisposição Genética para Doença/genética , Genótipo , Humanos , Imuno-Histoquímica/estatística & dados numéricos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Prognóstico , Modelos de Riscos Proporcionais , Fatores de Risco
13.
Gastroenterology ; 149(4): 897-906.e19, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26072394

RESUMO

BACKGROUND & AIMS: Germline mutations in the cadherin 1, type 1, E-cadherin gene (CDH1) cause a predisposition to gastric cancer. We evaluated the ability of the internationally accepted hereditary diffuse gastric cancer (HDGC) criteria to identify individuals with pathogenic mutations in CDH1, and assessed their outcomes. The criteria were as follows: families with 2 or more cases of gastric cancer, with at least 1 patient diagnosed with diffuse gastric cancer (DGC) before age 50; families with 3 or more cases of DGC; families with 1 DGC before the age of 40; and families with a history of DGC and lobular breast cancer, with 1 diagnosis before the age of 50. METHODS: We collected results of a CDH1 mutation analysis of 578 individuals from 499 families tested in The Netherlands between 1999 and 2014 (118 families met the HDGC criteria for testing and 236 did not; there were 145 families with incomplete data and/or availability of only first-degree relatives). Data were linked with family histories and findings from clinical and pathology analyses. The Kaplan-Meier method and Cox regression analysis were used to evaluate the overall survival of patients with and without CDH1 mutations. RESULTS: In a cohort study in The Netherlands, the HDGC criteria identified individuals with a germline CDH1 mutation with a positive predictive value of 14% and 89% sensitivity. There were 18 pathogenic CDH1 mutations in 499 families (4%); 16 of these mutations were detected in the 118 families who met the HDGC criteria for testing. One pathogenic CDH1 mutation was detected in the 236 families who did not meet HDGC criteria and 1 in the 145 families with incomplete data and/or availability of only first-degree relatives. No CDH1 mutations were found in the 67 families whose members developed intestinal-type gastric cancer, or in the 22 families whose families developed lobular breast cancer. Among patients who fulfilled the HDGC criteria and had pathogenic CDH1 mutations, 36% survived for 1 year and 4% survived for 5 years; among patients who fulfilled the HDGC criteria but did not carry pathogenic CDH1 mutations, 48% survived for 1 year and 13% survived for 5 years (P = .014 for comparative survival analysis between patients with and without a CDH1 mutation). CONCLUSIONS: All individuals with a CDH1 mutation had a personal or family history of diffuse gastric cancer. Patients with gastric cancer and germline CDH1 mutations had shorter survival times than patients who met the HDGC criteria but did not have CDH1 mutations.


Assuntos
Neoplasias da Mama/genética , Caderinas/genética , Carcinoma Lobular/genética , Mutação em Linhagem Germinativa , Síndromes Neoplásicas Hereditárias/genética , Neoplasias Gástricas/genética , Adulto , Idoso , Antígenos CD , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Carcinoma Lobular/mortalidade , Carcinoma Lobular/patologia , Carcinoma Lobular/terapia , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Hereditariedade , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Síndromes Neoplásicas Hereditárias/mortalidade , Síndromes Neoplásicas Hereditárias/patologia , Síndromes Neoplásicas Hereditárias/terapia , Países Baixos , Linhagem , Fenótipo , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Neoplasias Gástricas/terapia , Taxa de Sobrevida , Fatores de Tempo , Adulto Jovem
14.
Cancer Epidemiol Biomarkers Prev ; 24(1): 308-16, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25336561

RESUMO

BACKGROUND: BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In this study, we evaluated the putative role of variants in many candidate modifier genes. METHODS: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n = 3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach. RESULTS: The observed P values of association ranged between 0.005 and 1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. CONCLUSION: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. IMPACT: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies.


Assuntos
Neoplasias da Mama/genética , Genes BRCA1/fisiologia , Genes BRCA2/fisiologia , Neoplasias Ovarianas/genética , Adulto , Estudos de Coortes , Feminino , Humanos , Mutação , Polimorfismo de Nucleotídeo Único , Estudos Retrospectivos , Adulto Jovem
15.
Cancer Epidemiol Biomarkers Prev ; 23(11): 2482-91, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25103822

RESUMO

BACKGROUND: We aimed to quantify previously observed relatively high cancer risks in BRCA2 mutation carriers (BRCA2 carriers) older than 60 in the Northern Netherlands, and to analyze whether these could be explained by mutation spectrum or population background risk. METHODS: This consecutive cohort study included all known pathogenic BRCA1/2 carriers in the Northern Netherlands (N = 1,050). Carrier and general reference populations were: BRCA1/2 carriers in the rest of the Netherlands (N = 2,013) and the general population in both regions. Regional differences were assessed with HRs and ORs. HRs were adjusted for birth year and mutation spectrum. RESULTS: All BRCA1 carriers and BRCA2 carriers younger than 60 had a significantly lower breast cancer risk in the Northern Netherlands; HRs were 0.66 and 0.64, respectively. Above age 60, the breast cancer risk in BRCA2 carriers in the Northern Netherlands was higher than in the rest of the Netherlands [HR, 3.99; 95% confidence interval (CI), 1.11-14.35]. Adjustment for mutational spectrum changed the HRs for BRCA1, BRCA2 <60, and BRCA2 ≥60 years by -3%, +32%, and +11% to 0.75, 0.50, and 2.61, respectively. There was no difference in background breast cancer incidence between the two regions (OR, 1.03; 95% CI, 0.97-1.09). CONCLUSIONS: Differences in mutation spectrum only partly explain the regional differences in breast cancer risk in BRCA2 carriers, and for an even smaller part in BRCA1 carriers. IMPACT: The increased risk in BRCA2 carriers older than 60 may warrant extension of intensive breast screening beyond age 60.


Assuntos
Proteína BRCA2/genética , Neoplasias da Mama/genética , Neoplasias da Mama/epidemiologia , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Humanos , Mutação , Países Baixos , Fatores de Risco
16.
Int J Cancer ; 135(12): 2940-9, 2014 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-24789418

RESUMO

Annual MRI and mammography is recommended for BRCA1/2 mutation carriers to reduce breast cancer mortality. Less intensive screening is advised ≥60 years, although effectiveness is unknown. We identified BRCA1/2 mutation carriers without bilateral mastectomy before age 60 to determine for whom screening ≥60 is relevant, in the Rotterdam Family Cancer Clinic and HEBON: a nationwide prospective cohort study. Furthermore, we compared tumour stage at breast cancer diagnosis between different screening strategies in BRCA1/2 mutation carriers ≥60. Tumours >2 cm, positive lymph nodes, or distant metastases at detection were defined as "unfavourable." Of 548 BRCA1/2 mutation carriers ≥60 years in 2012, 395 (72%) did not have bilateral mastectomy before the age of 60. Of these 395, 224 (57%) had a history of breast or other invasive carcinoma. In 136 BRCA1/2 mutation carriers, we compared 148 breast cancers (including interval cancers) detected ≥60, of which 84 (57%) were first breast cancers. With biennial mammography 53% (30/57) of carcinomas were detected in unfavourable stage, compared to 21% (12/56) with annual mammography (adjusted odds ratio: 4·07, 95% confidence interval [1.79-9.28], p = 0.001). With biennial screening 40% of breast cancers were interval cancers, compared to 20% with annual screening (p = 0.016). Results remained significant for BRCA1 and BRCA2 mutation carriers, and first breast cancers separately. Over 70% of 60-year old BRCA1/2 mutation carriers remain at risk for breast cancer, of which half has prior cancers. When life expectancy is good, continuation of annual breast cancer screening of BRCA1/2 mutation carriers ≥60 is worthwhile.


Assuntos
Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Detecção Precoce de Câncer , Genes BRCA1 , Genes BRCA2 , Programas de Rastreamento , Idoso , Proteína BRCA1/genética , Proteína BRCA2/genética , Estudos de Coortes , Feminino , Humanos , Mamografia , Mastectomia , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica , Países Baixos , Estudos Prospectivos , Fatores de Risco
17.
J Med Genet ; 51(1): 55-60, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24253443

RESUMO

BACKGROUND: Colorectal adenomatous polyposis is associated with a high risk of colorectal cancer (CRC) and is frequently caused by germline mutations in APC or MUTYH. However, in about 20-30% of patients no underlying gene defect can be identified. In this study, we tested if recently identified CRC risk variants play a role in patients with >10 adenomas. METHODS: We analysed a total of 16 SNPs with a reported association with CRC in a cohort of 252 genetically unexplained index patients with >10 colorectal adenomas and 745 controls. In addition, we collected detailed clinical information from index patients and their first-degree relatives (FDRs). RESULTS: We found a statistically significant association with two of the variants tested: rs3802842 (at chromosome 11q23, OR=1.60, 95% CI 1.3 to 2.0) and rs4779584 (at chromosome 15q13, OR=1.50, 95% CI 1.2 to 1.9). The majority of index patients (84%) had between 10 and 100 adenomas and 15% had >100 adenomas. Only two index patients (1%), both with >100 adenomas, had FDRs with polyposis. Forty-one per cent of the index patients had one or more FDRs with CRC. CONCLUSIONS: These SNPs are the first common, low-penetrant variants reported to be associated with adenomatous polyposis not caused by a defect in the APC, MUTYH, POLD1 and POLE genes. Even though familial occurrence of polyposis was very rare, CRC was over-represented in FDRs of polyposis patients and, if confirmed, these relatives will therefore benefit from surveillance.


Assuntos
Polipose Adenomatosa do Colo/complicações , Polipose Adenomatosa do Colo/genética , Aberrações Cromossômicas , Cromossomos Humanos Par 11 , Cromossomos Humanos Par 15 , Neoplasias Colorretais/complicações , Neoplasias Colorretais/genética , Adolescente , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Alelos , Estudos de Casos e Controles , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Pessoa de Meia-Idade , Mutação , Razão de Chances , Fenótipo , Polimorfismo de Nucleotídeo Único , Risco , Adulto Jovem
18.
Fam Cancer ; 13(1): 57-63, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23934601

RESUMO

Patients with germline PTEN mutations are at high risk of developing benign and malignant tumours. We aimed to evaluate the cumulative risk of several types of cancer and of dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease, LDD). In addition, genotype-phenotype correlations in PTEN hamartoma tumour syndrome (PHTS) were assessed. Data on patients with PTEN mutations were collected from clinical genetic centres in Western Europe, Australia, and the USA. The cumulative risk of developing cancers of the breast, thyroid, endometrium, skin, kidneys, colorectum, and lungs, and also LDD was calculated by Kaplan-Meier methods. Associations between mutations and cancer were assessed by Chi square means. A total of 180 germline PTEN mutation carriers, 81 males (45%), from nine countries were included. The cumulative risk of developing any cancer and/or LDD at age 60 was 56% for males and 87% for females (p = 0.001). Females had significant higher risks of developing breast cancer, thyroid cancer, and LDD than males. The only genotype-phenotype correlation identified was a lower frequency of thyroid cancer in patients with missense mutations (p = 0.014). In conclusion, PHTS patients, particularly females, have a substantial risk of developing one or more tumours from a broad tumour spectrum. Major genotype-phenotype associations could not be identified.


Assuntos
Síndrome do Hamartoma Múltiplo/genética , Neoplasias/genética , PTEN Fosfo-Hidrolase/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Heterozigoto , Humanos , Lactente , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Síndrome , Neoplasias da Glândula Tireoide/genética , Adulto Jovem
19.
Cancer Epidemiol Biomarkers Prev ; 21(8): 1362-70, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22729394

RESUMO

BACKGROUND: We previously reported significant associations between genetic variants in insulin receptor substrate 1 (IRS1) and breast cancer risk in women carrying BRCA1 mutations. The objectives of this study were to investigate whether the IRS1 variants modified ovarian cancer risk and were associated with breast cancer risk in a larger cohort of BRCA1 and BRCA2 mutation carriers. METHODS: IRS1 rs1801123, rs1330645, and rs1801278 were genotyped in samples from 36 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analyzed by a retrospective cohort approach modeling the associations with breast and ovarian cancer risks simultaneously. Analyses were stratified by BRCA1 and BRCA2 status and mutation class in BRCA1 carriers. RESULTS: Rs1801278 (Gly972Arg) was associated with ovarian cancer risk for both BRCA1 (HR, 1.43; 95% confidence interval (CI), 1.06-1.92; P = 0.019) and BRCA2 mutation carriers (HR, 2.21; 95% CI, 1.39-3.52, P = 0.0008). For BRCA1 mutation carriers, the breast cancer risk was higher in carriers with class II mutations than class I mutations (class II HR, 1.86; 95% CI, 1.28-2.70; class I HR, 0.86; 95%CI, 0.69-1.09; P(difference), 0.0006). Rs13306465 was associated with ovarian cancer risk in BRCA1 class II mutation carriers (HR, 2.42; P = 0.03). CONCLUSION: The IRS1 Gly972Arg single-nucleotide polymorphism, which affects insulin-like growth factor and insulin signaling, modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers and breast cancer risk in BRCA1 class II mutation carriers. IMPACT: These findings may prove useful for risk prediction for breast and ovarian cancers in BRCA1 and BRCA2 mutation carriers.


Assuntos
Neoplasias da Mama/genética , Genes BRCA1 , Genes BRCA2 , Proteínas Substratos do Receptor de Insulina/genética , Neoplasias Ovarianas/genética , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Mutação , Polimorfismo de Nucleotídeo Único
20.
Clin Cancer Res ; 18(10): 2828-37, 2012 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-22452945

RESUMO

PURPOSE: Pheochromocytomas (PCC) and paragangliomas (PGL) are genetically heterogeneous neural crest-derived neoplasms. Recently we identified germline mutations in a new tumor suppressor susceptibility gene, MAX (MYC-associated factor X), which predisposes carriers to PCC. How MAX mutations contribute to PCC/PGL and associated phenotypes remain unclear. This study aimed to examine the prevalence and associated phenotypic features of germline and somatic MAX mutations in PCC/PGL. DESIGN: We sequenced MAX in 1,694 patients with PCC or PGL (without mutations in other major susceptibility genes) from 17 independent referral centers. We screened for large deletions/duplications in 1,535 patients using a multiplex PCR-based method. Somatic mutations were searched for in tumors from an additional 245 patients. The frequency and type of MAX mutation was assessed overall and by clinical characteristics. RESULTS: Sixteen MAX pathogenic mutations were identified in 23 index patients. All had adrenal tumors, including 13 bilateral or multiple PCCs within the same gland (P < 0.001), 15.8% developed additional tumors at thoracoabdominal sites, and 37% had familial antecedents. Age at diagnosis was lower (P = 0.001) in MAX mutation carriers compared with nonmutated cases. Two patients (10.5%) developed metastatic disease. A mutation affecting MAX was found in five tumors, four of them confirmed as somatic (1.65%). MAX tumors were characterized by substantial increases in normetanephrine, associated with normal or minor increases in metanephrine. CONCLUSIONS: Germline mutations in MAX are responsible for 1.12% of PCC/PGL in patients without evidence of other known mutations and should be considered in the genetic work-up of these patients.


Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Mutação em Linhagem Germinativa , Paraganglioma/genética , Feocromocitoma/genética , Adolescente , Neoplasias das Glândulas Suprarrenais/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
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