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1.
BMC Med Res Methodol ; 21(1): 7, 2021 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-33407157

RESUMO

BACKGROUND: Although human longevity tends to cluster within families, genetic studies on longevity have had limited success in identifying longevity loci. One of the main causes of this limited success is the selection of participants. Studies generally include sporadically long-lived individuals, i.e. individuals with the longevity phenotype but without a genetic predisposition for longevity. The inclusion of these individuals causes phenotype heterogeneity which results in power reduction and bias. A way to avoid sporadically long-lived individuals and reduce sample heterogeneity is to include family history of longevity as selection criterion using a longevity family score. A main challenge when developing family scores are the large differences in family size, because of real differences in sibship sizes or because of missing data. METHODS: We discussed the statistical properties of two existing longevity family scores: the Family Longevity Selection Score (FLoSS) and the Longevity Relatives Count (LRC) score and we evaluated their performance dealing with differential family size. We proposed a new longevity family score, the mLRC score, an extension of the LRC based on random effects modeling, which is robust for family size and missing values. The performance of the new mLRC as selection tool was evaluated in an intensive simulation study and illustrated in a large real dataset, the Historical Sample of the Netherlands (HSN). RESULTS: Empirical scores such as the FLOSS and LRC cannot properly deal with differential family size and missing data. Our simulation study showed that mLRC is not affected by family size and provides more accurate selections of long-lived families. The analysis of 1105 sibships of the Historical Sample of the Netherlands showed that the selection of long-lived individuals based on the mLRC score predicts excess survival in the validation set better than the selection based on the LRC score . CONCLUSIONS: Model-based score systems such as the mLRC score help to reduce heterogeneity in the selection of long-lived families. The power of future studies into the genetics of longevity can likely be improved and their bias reduced, by selecting long-lived cases using the mLRC.

2.
Int J Mol Sci ; 21(23)2020 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-33287451

RESUMO

Different methodological approaches are available to assess DNA methylation biomarkers. In this study, we evaluated two sodium bisulfite conversion-dependent methods, namely pyrosequencing and methylation-specific qPCR (MS-qPCR), with the aim of measuring the closeness of agreement of methylation values between these two methods and its effect when setting a cut-off. Methylation of tumor suppressor gene p16/INK4A was evaluated in 80 lung cancer patients from which cytological lymph node samples were obtained. Cluster analyses were used to establish methylated and unmethylated groups for each method. Agreement and concordance between pyrosequencing and MS-qPCR was evaluated with Pearson's correlation, Bland-Altman, Cohen's kappa index and ROC curve analyses. Based on these analyses, cut-offs were derived for MS-qPCR. An acceptable correlation (Pearson's R2 = 0.738) was found between pyrosequencing (PYRmean) and MS-qPCR (NMP; normalized methylation percentage), providing similar clinical results when categorizing data as binary using cluster analysis. Compared to pyrosequencing, MS-qPCR tended to underestimate methylation for values between 0 and 15%, while for methylation >30% overestimation was observed. The estimated cut-off for MS-qPCR data based on cluster analysis, kappa-index agreement and ROC curve analysis were much lower than that derived from pyrosequencing. In conclusion, our results indicate that independently of the approach used for estimating the cut-off, the methylation percentage obtained through MS-qPCR is lower than that calculated for pyrosequencing. These differences in data and therefore in the cut-off should be examined when using methylation biomarkers in the clinical practice.

3.
J Med Genet ; 2020 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-32994281

RESUMO

BACKGROUND: Familial clustering of melanoma suggests a shared genetic predisposition among family members, but only 10%-40% of familial cases carry a pathogenic variant in a known high-risk melanoma susceptibility gene. We investigated whether a melanoma-specific Polygenic Risk Score (PRS) is associated with melanoma risk in patients with genetically unexplained familial melanoma. METHODS: Dutch familial melanoma cases (n=418) were genotyped for 46 SNPs previously identified as independently associated with melanoma risk. The 46-SNP PRS was calculated and standardised to 3423 healthy controls (sPRS) and the association between PRS and melanoma risk was modelled using logistic regression. Within the case series, possible differences were further explored by investigating the PRS in relation to (1) the number of primary melanomas in a patient and (2) the extent of familial clustering of melanoma. RESULTS: The PRS was significantly associated with melanoma risk, with a per-SD OR of 2.12 (95% CI 1.90 to 2.35, p<0.001), corresponding to a 5.70-fold increased risk (95% CI 3.93 to 8.28) when comparing the top 90th to the middle 40-60th PRS percentiles. The mean PRS was significantly higher in cases with multiple primary melanomas than in cases with a single melanoma (sPRS 1.17 vs 0.71, p=0.001). Conversely, cases from high-density melanoma families had a lower (but non-significant) mean PRS than cases from low-density families (sPRS 0.60 vs 0.94, p=0.204). CONCLUSION: Our work underlines the significance of a PRS in determining melanoma susceptibility and encourages further exploration of the diagnostic value of a PRS in genetically unexplained melanoma families.

4.
Genet Med ; 22(11): 1803-1811, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32624571

RESUMO

PURPOSE: We evaluated the performance of the recently extended Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA version 5) in a Dutch prospective cohort, using a polygenic risk score (PRS) based on 313 breast cancer (BC)-associated variants (PRS313) and other, nongenetic risk factors. METHODS: Since 1989, 6522 women without BC aged 45 or older of European descent have been included in the Rotterdam Study. The PRS313 was calculated per 1 SD in controls from the Breast Cancer Association Consortium (BCAC). Cox regression analysis was performed to estimate the association between the PRS313 and incident BC risk. Cumulative 10-year risks were calculated with BOADICEA including different sets of variables (age, risk factors and PRS313). C-statistics were used to evaluate discriminative ability. RESULTS: In total, 320 women developed BC. The PRS313 was significantly associated with BC (hazard ratio [HR] per SD of 1.56, 95% confidence interval [CI] [1.40-1.73]). Using 10-year risk estimates including age and the PRS313, other risk factors improved the discriminatory ability of the BOADICEA model marginally, from a C-statistic of 0.636 to 0.653. CONCLUSIONS: The effect size of the PRS313 is highly reproducible in the Dutch population. Our results validate the BOADICEA v5 model for BC risk assessment in the Dutch general population.

5.
J Med Genet ; 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32482799

RESUMO

BACKGROUND: Pathogenic variants in the CDKN2A gene are generally associated with the development of melanoma and pancreatic ductal adenocarcinoma (PDAC), but specific genotype-phenotype correlations might exist and the extent of PDAC risk is not well established for many variants. METHODS: Using the Dutch national familial melanoma database, we identified all families with a pathogenic CDKN2A variant and investigated the occurrence of PDAC within these families. We also estimated the standardised incidence ratio and lifetime PDAC risk for carriers of a highly prevalent variant in these families. RESULTS: We identified 172 families in which 649 individuals carried 15 different pathogenic variants. The most prevalent variant was the founder mutation c.225_243del (p16-Leiden, 484 proven carriers). Second most prevalent was c.67G>C (55 proven carriers). PDAC developed in 95 of 163 families (58%, including 373 of 629 proven carriers) harbouring a variant with an effect on the p16INK4a protein, whereas PDAC did not occur in the 9 families (20 proven carriers) with a variant affecting only p14ARF. In the c.67G>C families, PDAC occurred in 12 of the 251 (5%) persons at risk. The standardised incidence ratio was 19.1 (95% CI 8.3 to 33.6) and the cumulative PDAC incidence at age 75 years (lifetime risk) was 19% (95% CI 7.5% to 30.1%). CONCLUSIONS: Our results support the notion that pathogenic CDKN2A variants affecting the p16INK4a protein, including c.67G>C, are associated with increased PDAC risk and carriers of such variants should be offered pancreatic cancer surveillance. There is no clinical evidence that impairment of only the p14ARF protein leads to an increased PDAC risk.

6.
Aging Cell ; 19(6): e13139, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32352215

RESUMO

Loci associated with longevity are likely to harbor genes coding for key players of molecular pathways involved in a lifelong decreased mortality and decreased/compressed morbidity. However, identifying such loci is challenging. One of the most plausible reasons is the uncertainty in defining long-lived cases with the heritable longevity trait among long-living phenocopies. To avoid phenocopies, family selection scores have been constructed, but these have not yet been adopted as state of the art in longevity research. Here, we aim to identify individuals with the heritable longevity trait by using current insights and a novel family score based on these insights. We use a unique dataset connecting living study participants to their deceased ancestors covering 37,825 persons from 1,326 five-generational families, living between 1788 and 2019. Our main finding suggests that longevity is transmitted for at least two subsequent generations only when at least 20% of all relatives are long-lived. This proves the importance of family data to avoid phenocopies in genetic studies.

7.
Lab Invest ; 100(9): 1252-1261, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32341520

RESUMO

Myxoid liposarcoma (MLS) is the second most common subtype of liposarcoma, accounting for ~6% of all sarcomas. MLS is characterized by a pathognomonic FUS-DDIT3, or rarely EWSR1-DDIT3, gene fusion. The presence of ≥5% hypercellular round cell areas is associated with a worse prognosis for the patient and is considered high grade. The prognostic significance of areas with moderately increased cellularity (intermediate) is currently unknown. Here we have applied matrix-assisted laser desorption/ionization mass spectrometry imaging to analyze the spatial distribution of N-linked glycans on an MLS microarray in order to identify molecular markers for tumor progression. Comparison of the N-glycan profiles revealed that increased relative abundances of high-mannose type glycans were associated with tumor progression. Concomitantly, an increase of the average number of mannoses on high-mannose glycans was observed. Although overall levels of complex-type glycans decreased, an increase of tri- and tetra-antennary N-glycans was observed with morphological tumor progression and increased tumor histological grade. The high abundance of tri-antennary N-glycan species was also associated with poor disease-specific survival. These findings mirror recent observations in colorectal cancer, breast cancer, ovarian cancer, and cholangiocarcinoma, and are in line with a general role of high-mannose glycans and higher-antennary complex-type glycans in cancer progression.


Assuntos
Lipossarcoma Mixoide/metabolismo , Polissacarídeos/metabolismo , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Espectrometria de Massas em Tandem/métodos , Adulto , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Lipossarcoma Mixoide/genética , Lipossarcoma Mixoide/patologia , Masculino , Gradação de Tumores , Proteínas de Fusão Oncogênica/genética , Proteínas Repressoras/genética
8.
Stat Methods Med Res ; 29(8): 2344-2359, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31880204

RESUMO

Information on the age at onset distribution of the asymptomatic stage of a disease can be of paramount importance in early detection and timely management of that disease. However, accurately estimating this distribution is challenging, because the asymptomatic stage is difficult to recognize for the patient and is often detected as an incidental finding or in case of recommended screening; the age at onset is often interval-censored. In this paper, we propose a method for the estimation of the age at onset distribution of the asymptomatic stage of a genetic disease based on ascertained pedigree data that take into account the way the data are ascertained to overcome selection bias. Simulation studies show that the estimates seem to be asymptotically unbiased. Our work is motivated by the analysis of data on facioscapulohumeral muscular dystrophy, a genetic muscle disorder. In our application, carriers of the genetic causal variant are identified through genetic screening of the relatives of symptomatic carriers and their disease status is determined by a medical examination. The estimates reveal an early age at onset of the asymptomatic stage of facioscapulohumeral muscular dystrophy.

9.
Clin Gastroenterol Hepatol ; 17(13): 2657-2667.e9, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31525516

RESUMO

BACKGROUND & AIMS: Guidelines recommend that individuals with familial colorectal cancer undergo colonoscopy surveillance instead of average-risk screening. However, these recommendations vary widely. To substantiate appropriate surveillance strategies, precise and valid evidence-based risk estimates are needed for individuals with a family history of colorectal cancer (CRC). METHODS: We systematically searched MEDLINE, EMBASE, and Cochrane from inception to July 2018 for case-control and cohort studies investigating the effect of family history on CRC risk. We calculated summary estimates of pooled relative risks (RRs) using a random-effects model. Life tables were created to convert RR estimates into absolute risk estimates. RESULTS: We screened 4417 articles and identified 42 eligible case-control and 20 cohort studies. In case-control studies, the RR for CRC in patients with 1 first-degree relative (FDR with CRC) was 1.92 (95% CI, 1.53-2.41) and 1.37 (95% CI, 0.76-2.46) for cohort studies. For individuals with 2 or more FDRs with CRC, the RR was 2.81 in case-control studies (95% CI, 1.73-4.55) and 2.40 in cohort studies (95% CI, 1.76-3.28). For individuals having a FDR diagnosed with CRC at an age younger than 50 years, the RR for CRC in their FDRs was 3.57 in case-control studies (95% CI, 1.07-11.85) and 3.26 in cohort studies (95% CI, 2.82-3.77). The cumulative absolute risks for CRC at 85 years in Western Europe were 4.8% for persons with 1 FDR with CRC (95% CI, 2.7%-8.3%), 8.2% for individuals with 2 or more FDRs (95% CI, 6.1%-10.9%), and 11% for persons with a FDR diagnosed with CRC at an age younger than 50 years (95% CI, 9.5%-12.4%). CONCLUSIONS: In this systematic review and meta-analysis, we found that the RR of CRC among FDRs is lower than previously expected, especially based on cohort studies. Risk estimates are affected by the number of relatives with CRC and their age at diagnosis. Intensified colonoscopy surveillance strategies could be considered for high-risk groups. PROSPERO trial identification no: CRD42018103058.

10.
Cancers (Basel) ; 11(10)2019 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-31547177

RESUMO

The evaluation of mediastinal lymph nodes is critical for the correct staging of patients with lung cancer (LC). Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a minimally invasive technique for mediastinal staging, though unfortunately lymph node micrometastasis is often missed by cytological analysis. The aim of this study was to evaluate the predictive capacity of methylation biomarkers and provide a classification rule for predicting malignancy in false negative EBUS-TBNA samples. The study included 112 patients with a new or suspected diagnosis of LC that were referred to EBUS-TBNA. Methylation of p16/INK4a, MGMT, SHOX2, E-cadherin, DLEC1, and RASSF1A was quantified by nested methylation-specific qPCR in 218 EBUS-TBNA lymph node samples. Cross-validated linear regression models were evaluated to predict malignancy. According to EBUS-TBNA and final diagnosis, 90 samples were true positives for malignancy, 110 were true negatives, and 18 were false negatives. MGMT, SHOX2, and E-cadherin were the methylation markers that better predicted malignancy. The model including sex, age, short axis diameter and standard uptake value of adenopathy, and SHOX2 showed 82.7% cross-validated sensitivity and 82.4% specificity for the detection of malignant lymphadenopathies among negative cytology samples. Our results suggest that the predictive model approach proposed can complement EBUS-TBNA for mediastinal staging.

11.
J Med Genet ; 56(9): 581-589, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31186341

RESUMO

BACKGROUND: The currently known breast cancer-associated single nucleotide polymorphisms (SNPs) are presently not used to guide clinical management. We explored whether a genetic test that incorporates a SNP-based polygenic risk score (PRS) is clinically meaningful in non-BRCA1/2 high-risk breast cancer families. METHODS: 101 non-BRCA1/2 high-risk breast cancer families were included; 323 cases and 262 unaffected female relatives were genotyped. The 161-SNP PRS was calculated and standardised to 327 population controls (sPRS). Association analysis was performed using a Cox-type random effect regression model adjusted by family history. Updated individualised breast cancer lifetime risk scores were derived by combining the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm breast cancer lifetime risk with the effect of the sPRS. RESULTS: The mean sPRS for cases and their unaffected relatives was 0.70 (SD=0.9) and 0.53 (SD=0.9), respectively. A significant association was found between sPRS and breast cancer, HR=1.16, 95% CI 1.03 to 1.28, p=0.026. Addition of the sPRS to risk prediction based on family history alone changed screening recommendations in 11.5%, 14.7% and 19.8 % of the women according to breast screening guidelines from the USA (National Comprehensive Cancer Network), UK (National Institute for Health and Care Excellence and the Netherlands (Netherlands Comprehensive Cancer Organisation), respectively. CONCLUSION: Our results support the application of the PRS in risk prediction and clinical management of women from genetically unexplained breast cancer families.


Assuntos
Biomarcadores Tumorais , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Neoplasias da Mama/mortalidade , Neoplasias da Mama/terapia , Estudos de Casos e Controles , Tomada de Decisão Clínica , Gerenciamento Clínico , Genótipo , Humanos , Pessoa de Meia-Idade , Linhagem , Prognóstico , Modelos de Riscos Proporcionais , Medição de Risco , Adulto Jovem
12.
Genet Med ; 21(12): 2706-2712, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31204389

RESUMO

PURPOSE: Biallelic pathogenic variants in the mismatch repair (MMR) genes cause a recessive childhood cancer predisposition syndrome known as constitutional mismatch repair deficiency (CMMRD). Family members with a heterozygous MMR variant have Lynch syndrome. We aimed at estimating cancer risk in these heterozygous carriers as a novel approach to avoid complicated statistical methods to correct for ascertainment bias. METHODS: Cumulative colorectal cancer incidence was estimated in a cohort of PMS2- and MSH6-associated families, ascertained by the CMMRD phenotype of the index, by using mutation probabilities based on kinship coefficients as analytical weights in a proportional hazard regression on the cause-specific hazards. Confidence intervals (CIs) were obtained by bootstrapping at the family level. RESULTS: The estimated cumulative colorectal cancer risk at age 70 years for heterozygous PMS2 variant carriers was 8.7% (95% CI 4.3-12.7%) for both sexes combined, and 9.9% (95% CI 4.9-15.3%) for men and 5.9% (95% CI 1.6-11.1%) for women separately. For heterozygous MSH6 variant carriers these estimates are 11.8% (95% CI 4.5-22.7%) for both sexes combined, 10.0% (95% CI 1.83-24.5%) for men and 11.7% (95% CI 2.10-26.5%) for women. CONCLUSION: Our findings are consistent with previous reports that used more complex statistical methods to correct for ascertainment bias. These results underline the need for MMR gene-specific surveillance protocols for Lynch syndrome.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/complicações , Neoplasias Colorretais/etiologia , Medição de Risco/métodos , Adulto , Idoso , Estudos de Coortes , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/metabolismo , Reparo de Erro de Pareamento de DNA , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Feminino , Predisposição Genética para Doença/genética , Mutação em Linhagem Germinativa , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Endonuclease PMS2 de Reparo de Erro de Pareamento/metabolismo , Mutação , Fatores de Risco
13.
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
14.
Aliment Pharmacol Ther ; 49(6): 636-643, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30740723

RESUMO

BACKGROUND: After liver transplantation primary sclerosing cholangitis (PSC), the condition returns in the transplanted liver in a subset of patients (recurrent primary sclerosing cholangitis, rPSC). AIM: To define risk factors for rPSC. METHODS: We searched Pubmed, Embase, Web of Science, and Cochrane library for articles published until March 2018. Studies addressing risk factors for developing rPSC were eligible for inclusion. A random effects meta-analysis was conducted using hazard ratios (HR) as effect measure. Study quality was evaluated with the Newcastle Ottawa scale. Statistical analysis was performed using Cochrane Review Manager. RESULTS: The electronic database search yielded 449 results. Twenty-one retrospective cohort studies met the inclusion criteria for the review; 14 were included in the meta-analysis. The final cohort included 2159 patients (age range 31-49 years, 68.8% male), of whom 17.7% developed rPSC. Colectomy before liver transplantation, HR 0.65 (95% CI: 0.42-0.99), cholangiocarcinoma before liver transplantation, HR 2.42 (95% CI: 1.20-4.86), inflammatory bowel disease, HR 1.73 (95% CI: 1.17-2.54), donor age, HR 1.24 (95% CI 1.0-1.45) per ten years, MELD score, HR 1.05 (95% CI: 1.02-1.08) per point and acute cellular rejection, HR of 1.94 (95% CI: 1.32-2.83) were associated with the risk of rPSC. CONCLUSIONS: Multiple risk factors for rPSC were identified. Colectomy before liver transplantation reduced the risk of rPSC.


Assuntos
Colangite Esclerosante/epidemiologia , Colectomia/tendências , Transplante de Fígado/efeitos adversos , Transplante de Fígado/tendências , Complicações Pós-Operatórias/epidemiologia , Colangite Esclerosante/diagnóstico , Seguimentos , Humanos , Fígado/patologia , Fígado/cirurgia , Complicações Pós-Operatórias/diagnóstico , Recidiva , Estudos Retrospectivos , Fatores de Risco
15.
Nat Commun ; 10(1): 35, 2019 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-30617297

RESUMO

Survival to extreme ages clusters within families. However, identifying genetic loci conferring longevity and low morbidity in such longevous families is challenging. There is debate concerning the survival percentile that best isolates the genetic component in longevity. Here, we use three-generational mortality data from two large datasets, UPDB (US) and LINKS (Netherlands). We study 20,360 unselected families containing index persons, their parents, siblings, spouses, and children, comprising 314,819 individuals. Our analyses provide strong evidence that longevity is transmitted as a quantitative genetic trait among survivors up to the top 10% of their birth cohort. We subsequently show a survival advantage, mounting to 31%, for individuals with top 10% surviving first and second-degree relatives in both databases and across generations, even in the presence of non-longevous parents. To guide future genetic studies, we suggest to base case selection on top 10% survivors of their birth cohort with equally long-lived family members.


Assuntos
Longevidade/genética , Característica Quantitativa Herdável , Estudos de Coortes , Feminino , Humanos , Masculino , Linhagem
16.
Clin Epigenetics ; 10: 53, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29686738

RESUMO

Background: Colorectal cancer is the fourth cause of cancer-related deaths worldwide, though detection at early stages associates with good prognosis. Thus, there is a clear demand for novel non-invasive tests for the early detection of colorectal cancer and premalignant advanced adenomas, to be used in population-wide screening programs. Aberrant DNA methylation detected in liquid biopsies, such as serum circulating cell-free DNA (cfDNA), is a promising source of non-invasive biomarkers. This study aimed to assess the feasibility of using cfDNA pooled samples to identify potential serum methylation biomarkers for the detection of advanced colorectal neoplasia (colorectal cancer or advanced adenomas) using microarray-based technology. Results: cfDNA was extracted from serum samples from 20 individuals with no colorectal findings, 20 patients with advanced adenomas, and 20 patients with colorectal cancer (stages I and II). Two pooled samples were prepared for each pathological group using equal amounts of cfDNA from 10 individuals, sex-, age-, and recruitment hospital-matched. We measured the methylation levels of 866,836 CpG positions across the genome using the MethylationEPIC array. Pooled serum cfDNA methylation data meets the quality requirements. The proportion of detected CpG in all pools (> 99% with detection p value < 0.01) exceeded Illumina Infinium methylation data quality metrics of the number of sites detected. The differential methylation analysis revealed 1384 CpG sites (5% false discovery rate) with at least 10% difference in the methylation level between no colorectal findings controls and advanced neoplasia, the majority of which were hypomethylated. Unsupervised clustering showed that cfDNA methylation patterns can distinguish advanced neoplasia from healthy controls, as well as separate tumor tissue from healthy mucosa in an independent dataset. We also observed that advanced adenomas and stage I/II colorectal cancer methylation profiles, grouped as advanced neoplasia, are largely homogenous and clustered close together. Conclusions: This preliminary study shows the viability of microarray-based methylation biomarker discovery using pooled serum cfDNA samples as an alternative approach to tissue specimens. Our strategy sets an open door for deciphering new non-invasive biomarkers not only for colorectal cancer detection, but also for other types of cancers.


Assuntos
Biomarcadores Tumorais/genética , Ácidos Nucleicos Livres/sangue , Neoplasias Colorretais/diagnóstico , Metilação de DNA , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Idoso , Neoplasias Colorretais/genética , Ilhas de CpG , DNA de Neoplasias/sangue , Detecção Precoce de Câncer , Epigenômica/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Regiões Promotoras Genéticas , Sensibilidade e Especificidade , Aprendizado de Máquina não Supervisionado
17.
J Gerontol A Biol Sci Med Sci ; 73(10): 1295-1302, 2018 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-29596573

RESUMO

Members of longevous families live longer than individuals from similar birth cohorts and delay/escape age-related diseases. Insight into this familial component of longevity can provide important knowledge about mechanisms protecting against age-related diseases. This familial component of longevity was studied in the Leiden Longevity Study which consists of 944 longevous siblings (participants), their parents (N = 842), siblings (N = 2,302), and spouses (N = 809). Family longevity scores were estimated to explore whether human longevity is transmitted preferentially through the maternal or paternal line. Standardized mortality ratios (SMRs) were estimated to investigate whether longevous siblings have a survival advantage compared with longevous singletons and we investigated whether parents of longevous siblings harbor a life-long sustained survival advantage compared with the general Dutch population by estimating lifetime SMRs (L-SMRs). We found that sibships with long-lived mothers and non-long-lived fathers had 0.41 (p = .024) less observed deaths than sibships with long-lived fathers and non-long-lived mothers and 0.48 (p = .008) less observed deaths than sibships with both parents non-long lived. Participants had 18.6 per cent less deaths compared with matched singletons and parents had a life-long sustained survival advantage (L-SMR = 0.510 and 0.688). In conclusion, genetic longevity studies may incorporate the maternal transmission pattern and genes influencing the entire life-course of individuals.


Assuntos
Envelhecimento/genética , Longevidade/genética , Idoso de 80 Anos ou mais , Características da Família , Feminino , Humanos , Padrões de Herança , Estudos Longitudinais , Masculino , Herança Materna , Mortalidade , Países Baixos/epidemiologia , Pais , Herança Paterna , Linhagem , Irmãos , Cônjuges
18.
PLoS One ; 13(2): e0192853, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29462177

RESUMO

Building prediction models based on complex omics datasets such as transcriptomics, proteomics, metabolomics remains a challenge in bioinformatics and biostatistics. Regularized regression techniques are typically used to deal with the high dimensionality of these datasets. However, due to the presence of correlation in the datasets, it is difficult to select the best model and application of these methods yields unstable results. We propose a novel strategy for model selection where the obtained models also perform well in terms of overall predictability. Several three step approaches are considered, where the steps are 1) network construction, 2) clustering to empirically derive modules or pathways, and 3) building a prediction model incorporating the information on the modules. For the first step, we use weighted correlation networks and Gaussian graphical modelling. Identification of groups of features is performed by hierarchical clustering. The grouping information is included in the prediction model by using group-based variable selection or group-specific penalization. We compare the performance of our new approaches with standard regularized regression via simulations. Based on these results we provide recommendations for selecting a strategy for building a prediction model given the specific goal of the analysis and the sizes of the datasets. Finally we illustrate the advantages of our approach by application of the methodology to two problems, namely prediction of body mass index in the DIetary, Lifestyle, and Genetic determinants of Obesity and Metabolic syndrome study (DILGOM) and prediction of response of each breast cancer cell line to treatment with specific drugs using a breast cancer cell lines pharmacogenomics dataset.


Assuntos
Biologia Computacional/métodos , Antineoplásicos/uso terapêutico , Índice de Massa Corporal , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Análise por Conglomerados , Simulação por Computador , Humanos , Síndrome Metabólica/sangue , Síndrome Metabólica/genética , Metaboloma , Modelos Genéticos , Obesidade/sangue , Obesidade/genética , Análise de Regressão , Software , Transcriptoma
19.
Stat Methods Med Res ; 27(3): 933-954, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-27177884

RESUMO

In the field of aging research, family-based sampling study designs are commonly used to study the lifespans of long-lived family members. However, the specific sampling procedure should be carefully taken into account in order to avoid biases. This work is motivated by the Leiden Longevity Study, a family-based cohort of long-lived siblings. Families were invited to participate in the study if at least two siblings were 'long-lived', where 'long-lived' meant being older than 89 years for men or older than 91 years for women. As a result, more than 400 families were included in the study and followed for around 10 years. For estimation of marker-specific survival probabilities and correlations among life times of family members, delayed entry due to outcome-dependent sampling mechanisms has to be taken into account. We consider shared frailty models to model left-truncated correlated survival data. The treatment of left truncation in shared frailty models is still an open issue and the literature on this topic is scarce. We show that the current approaches provide, in general, biased estimates and we propose a new method to tackle this selection problem by applying a correction on the likelihood estimation by means of inverse probability weighting at the family level.


Assuntos
Longevidade/genética , Análise de Sobrevida , Idoso de 80 Anos ou mais , Apolipoproteína E2/genética , Apolipoproteína E4/genética , Viés , Bioestatística/métodos , Estudos de Coortes , Simulação por Computador , Família , Feminino , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Humanos , Funções Verossimilhança , Masculino , Modelos Estatísticos , Método de Monte Carlo , Países Baixos , Probabilidade , Software
20.
Sci Rep ; 7: 41151, 2017 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-28117344

RESUMO

While evidence for lung cancer screening implementation in Europe is awaited, Rapid Diagnostic Units have been established in many hospitals to accelerate the early diagnosis of lung cancer. We seek to develop an algorithm to detect lung cancer in a symptomatic population attending such unit, based on a sensitive serum marker panel. Serum concentrations of Epidermal Growth Factor, sCD26, Calprotectin, Matrix Metalloproteinases -1, -7, -9, CEA and CYFRA 21.1 were determined in 140 patients with respiratory symptoms (lung cancer and controls with/without benign pathology). Logistic Lasso regression was performed to derive a lung cancer prediction model, and the resulting algorithm was tested in a validation set. A classification rule based on EGF, sCD26, Calprotectin and CEA was established, able to reasonably discriminate lung cancer with 97% sensitivity and 43% specificity in the training set, and 91.7% sensitivity and 45.4% specificity in the validation set. Overall, the panel identified with high sensitivity stage I non-small cell lung cancer (94.7%) and 100% small-cell lung cancers. Our study provides a sensitive 4-marker classification algorithm for lung cancer detection to aid in the management of suspicious lung cancer patients in the context of Rapid Diagnostic Units.


Assuntos
Biomarcadores Tumorais/sangue , Neoplasias Pulmonares/diagnóstico , Idoso , Algoritmos , Feminino , Humanos , Neoplasias Pulmonares/sangue , Masculino , Estadiamento de Neoplasias , Sensibilidade e Especificidade
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