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1.
Clin Transl Oncol ; 21(8): 1076-1084, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30617925

RESUMO

PURPOSE: Germline mutations in BRCA1 and/or BRCA2 genes (gBRCA1/2m) are associated with an increased risk of breast cancer (BC) and ovarian cancer (OC). The aim of this study was to estimate the efficiency of providing germline BRCA1/2 testing to high-grade epithelial ovarian cancer (HGEOC) patients without family history of OC or BC and the subsequent testing and management of their relatives with gBRCA1/2m in Spain. METHODS/PATIENTS: Incident HGEOC patients without family history of OC or BC who were gBRCA1/2m carriers and their relatives were simulated in a 50-year time horizon. The study compared two scenarios: BRCA1/2 testing vs no testing, using the perspective of the Spanish National Health Service. Cancer risk among gBRCA1/2m carriers was estimated based on their age and whether they had undergone risk-reducing surgeries. Direct healthcare costs and utilities of patients who developed EOC and BC were also included. A probabilistic sensitivity analysis (PSA) with 5 thousand simulations was developed considering ± 25% of the base-case value. RESULTS: The BRCA1/2-testing scenario amounted to €13,437,897.43 while the no-testing scenario amounted to €12,053,291.17. It was estimated that the screening test improved the quality of life among the patients' relatives by 43.8 quality-adjusted life years (QALYs). The incremental cost-utility ratio (ICUR) was €31,621.33/QALY in the base case. The PSA showed that 89.12% of the simulations were below the €50,000/QALY threshold. CONCLUSION: Providing this screening test to HGEOC patients and their relatives is cost-effective and it allows one to identify a target population with high risk of cancer to provide effective prevention strategies.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Carcinoma Epitelial do Ovário/economia , Análise Custo-Benefício , Testes Genéticos/economia , Mutação em Linhagem Germinativa , Custos de Cuidados de Saúde/estatística & dados numéricos , Adulto , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/economia , Neoplasias da Mama/genética , Carcinoma Epitelial do Ovário/diagnóstico , Carcinoma Epitelial do Ovário/genética , Feminino , Seguimentos , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Prognóstico , Qualidade de Vida , Anos de Vida Ajustados por Qualidade de Vida , Espanha
2.
J Gene Med ; 19(4)2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28306219

RESUMO

BACKGROUND: We identified a new and a recurrent POLD1 mutation associated with predisposition to colorectal cancer (CRC). We characterized the molecular and clinical nature of the potential POLD1 founder mutation in families from Valencia (Spain). METHODS: Clinical and molecular data were collected from four independent families known to have a POLD1 Leu474Pro mutation. To establish its founder effect, haplotype construction was performed using 14 flanking POLD1 polymorphic markers. We calculated penetrance estimates and clinical expressivity, globally and stratified by age and sex. RESULTS: We included 32 individuals from the four families: 20 carriers and 12 noncarriers. A common haplotype was identified in these families in a region comprising 2,995 Mb, confirming L474P as the first founder POLD1 mutation identified. Thirteen tumors diagnosed in 10 POLD1 carriers: eight CRC, three endometrial and two other tumors were considered. The median age of cancer onset for POLD1 mutation carriers was 48 years. The observed penetrance was 50% and the cumulative risk at age of 50 years was 30%. CONCLUSIONS: The findings of the present study contribute to a better understanding of CRC genetics in the Spanish population. The clinical phenotype for this mutation is similar to that in Lynch syndrome. Future studies using next generation sequencing with large gene panels for any hereditary cancer condition will offer the possibility of detecting POLE/POLD1 mutations in unsuspected clinical situations, demonstrating a more real and unbiased picture of the associated phenotype.


Assuntos
DNA Polimerase III/genética , Grupo com Ancestrais do Continente Europeu/genética , Efeito Fundador , Genética Populacional , Mutação de Sentido Incorreto , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Feminino , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Haplótipos , Heterozigoto , Humanos , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade , Penetrância , Fenótipo , Polimorfismo de Nucleotídeo Único , Vigilância da População , Espanha , Adulto Jovem
3.
Fam Cancer ; 15(2): 193-200, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26723934

RESUMO

The study aims to identify the relevance of immunohistochemistry (IHC), copy number aberrations (CNA) and epigenetic disorders in BRCAness breast cancers (BCs). We studied 95 paraffin included BCs, of which 41 carried BRCA1/BRCA2 germline mutations and 54 were non hereditary (BRCAX/Sporadic). Samples were assessed for BRCA1ness and CNAs by Multiplex Ligation-dependent Probe Amplification (MLPA); promoter methylation (PM) was assessed by methylation-specific-MLPA and the expression of miR-4417, miR-423-3p, miR-590-5p and miR-187-3p by quantitative RT-PCR. IHC markers Ki67, ER, PR, HER2, CK5/6, EGFR and CK18 were detected with specific primary antibodies (DAKO, Denmark). BRCAness association with covariates was performed using multivariate binary logistic regression (stepwise backwards Wald option). BRCA1/2 mutational status (p = 0.027), large tumor size (p = 0.041) and advanced histological grade (p = 0.017) among clinic-pathological variables; ER (p < 0.001) among IHC markers; MYC (p < 0.001) among CNA; APC (p = 0.065), ATM (p = 0.014) and RASSF1 (p = 0.044) among PM; and miR-590-5p (p = 0.001), miR-4417 (p = 0.019) and miR-423 (p = 0.013) among microRNA expression, were the selected parameters significantly related with the BRCAness status. The logistic regression performed with all these parameters selected ER+ as linked with the lack of BRCAness (p = 0.001) and MYC CNA, APC PM and miR-590-5p expression with BRCAness (p = 0.014, 0.045 and 0.007, respectively). In conclusion, the parameters ER expression, APC PM, MYC CNA and miR-590-5p expression, allowed detection of most BRCAness BCs. The identification of BRCAness can help establish a personalized medicine addressed to predict the response to specific treatments.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Epigênese Genética , Dosagem de Genes , MicroRNAs , Adulto , Idoso , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Metilação de DNA , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , MicroRNAs/genética , Pessoa de Meia-Idade , Mutação
4.
Breast Cancer Res ; 17: 93, 2015 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-26163143

RESUMO

INTRODUCTION: Mammographic density (MD) is one of the strongest determinants of sporadic breast cancer (BC). In this study, we compared MD in BRCA1/2 mutation carriers and non-carriers from BRCA1/2 mutation-positive families and investigated the association between MD and BC among BRCA1/2 mutation carriers per type of mutation and tumor subtype. METHODS: The study was carried out in 1039 female members of BRCA1 and BRCA2 mutation-positive families followed at 16 Spanish Genetic Counseling Units. Participants' density was scored retrospectively from available mammograms by a single blinded radiologist using a 5-category scale (<10 %, 10-25 %, 25-50 %, 50-75 %, >75 %). In BC cases, we selected mammograms taken prior to diagnosis or from the contralateral breast, whereas, in non-cases, the last screening mammogram was evaluated. MD distribution in carriers and non-carriers was compared using ordinal logistic models, and the association between MD and BC in BRCA1/2 mutation carriers was studied using logistic regression. Huber-White robust estimators of variance were used to take into account correlations between family members. A similar multinomial model was used to explore this association by BC subtype. RESULTS: We identified and scored mammograms from 341 BRCA1, 350 BRCA2 mutation carriers and 229 non-carriers. Compared to non-carriers, MD was significantly lower among BRCA2 mutation carriers (odds ratio (OR) =0.71; P-value=0.04), but not among BRCA1 carriers (OR=0.84; P-value=0.33). MD was associated with subsequent development BC (OR per category of MD=1.45; 95 % confidence interval=1.18-1.78, P-value<0.001), with no significant differences between BRCA1 and BRCA2 mutation carriers (P-value=0.48). Finally, no statistically significant differences were observed in the association of MD with specific BC subtypes. CONCLUSIONS: Our study, the largest to date on this issue, confirms that MD is an independent risk factor for all BC subtypes in either BRCA1 and BRCA2 mutation carriers, and should be considered a phenotype risk marker in this context.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Família , Glândulas Mamárias Humanas/anormalidades , Adulto , Densidade da Mama , Neoplasias da Mama/epidemiologia , Feminino , Genes BRCA1 , Genes BRCA2 , Predisposição Genética para Doença , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Síndrome Hereditária de Câncer de Mama e Ovário/patologia , Heterozigoto , Humanos , Mamografia , Pessoa de Meia-Idade , Mutação , Razão de Chances , Fatores de Risco
5.
Gastroenterology ; 149(3): 563-6, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26052075

RESUMO

Identification of genes associated with hereditary cancers facilitates management of patients with family histories of cancer. We performed exome sequencing of DNA from 3 individuals from a family with colorectal cancer who met the Amsterdam criteria for risk of hereditary nonpolyposis colorectal cancer. These individuals had mismatch repair-proficient tumors and each carried nonsense variant in the FANCD2/FANCI-associated nuclease 1 gene (FAN1), which encodes a nuclease involved in DNA inter-strand cross-link repair. We sequenced FAN1 in 176 additional families with histories of colorectal cancer and performed in vitro functional analyses of the mutant forms of FAN1 identified. We detected FAN1 mutations in approximately 3% of families who met the Amsterdam criteria and had mismatch repair-proficient cancers with no previously associated mutations. These findings link colorectal cancer predisposition to the Fanconi anemia DNA repair pathway, supporting the connection between genome integrity and cancer risk.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo do DNA/genética , Exodesoxirribonucleases/genética , Mutação em Linhagem Germinativa , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Pré-Escolar , Neoplasias Colorretais Hereditárias sem Polipose/enzimologia , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Exodesoxirribonucleases/metabolismo , Feminino , Predisposição Genética para Doença , Células HEK293 , Hereditariedade , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Adulto Jovem
6.
J Med Genet ; 52(7): 498-502, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25908759

RESUMO

BACKGROUND: The prevalence of MLH1 constitutional epimutations in the general population is unknown. We sought to analyse the prevalence of MLH1 constitutional epimutations in unselected and selected series of patients with colorectal cancer (CRC). METHODS: Patients with diagnoses of CRC (n=2123) were included in the unselected group. For comparison, a group of 847 selected patients with CRC who fulfilled the revised Bethesda guidelines (rBG) were also included. Somatic and constitutional MLH1 methylation was assayed via methylation-specific multiplex ligation-dependent probe amplification of cases lacking MLH1 expression. Germline alterations in mismatch-repair (MMR) genes were assessed via Sanger sequencing and methylation-specific multiplex ligation-dependent probe amplification. RESULTS: Loss of MLH1 expression occurred in 5.5% of the unselected series and 12.5% of the selected series (p<0.0001). No constitutional epimutations in MLH1 were detected in the unselected population (0/62); five cases from the selected series were positive for MLH1 epimutations (15.6%, 5/32; p=0.004). CONCLUSIONS: Our results suggest a negligible prevalence of MLH1 constitutional epimutations in unselected cases of CRC. Therefore, MLH1 constitutional epimutation analysis should be conducted only for patients who fulfil the rBG and who lack MLH1 expression with methylated MLH1.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Metilação de DNA/genética , Epigênese Genética/genética , Mutação/genética , Proteínas Nucleares/genética , Sequência de Bases , Reparo de Erro de Pareamento de DNA/genética , Testes Genéticos/normas , Humanos , Repetições de Microssatélites/genética , Dados de Sequência Molecular , Proteína 1 Homóloga a MutL , Prevalência , Regiões Promotoras Genéticas/genética , Análise de Sequência de DNA , Estatísticas não Paramétricas
7.
Eur J Cancer ; 50(13): 2241-50, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24953332

RESUMO

BACKGROUND AND AIMS: Individuals with tumours showing mismatch repair (MMR) deficiency not linked to germline mutations or somatic methylation of MMR genes have been recently referred as having 'Lynch-like syndrome' (LLS). The genetic basis of these LLS cases is unknown. MUTYH-associated polyposis patients show some phenotypic similarities to Lynch syndrome patients. The aim of this study was to investigate the prevalence of germline MUTYH mutations in a large series of LLS patients. METHODS: Two hundred and twenty-five probands fulfilling LLS criteria were included in this study. Screening of MUTYH recurrent mutations, whole coding sequencing and a large rearrangement analysis were undertaken. Age, sex, clinical, pathological and molecular characteristics of tumours including KRAS mutations were assessed. RESULTS: We found a prevalence of 3.1% of MAP syndrome in the whole series of LLS (7/225) and 3.9% when only cases fulfilling clinical criteria were considered (7/178). Patients with MUTYH biallelic mutations had more adenomas than monoallelic (P=0.02) and wildtype patients (P<0.0001). Six out of nine analysed tumours from six biallelic MUTYH carriers harboured KRAS-p.G12C mutation. This mutation was found to be associated with biallelic MUTYH germline mutation when compared with reported series of unselected colorectal cancer cohorts (P<0.0001). CONCLUSIONS: A proportion of unexplained LLS cases is caused by biallelic MUTYH mutations. The obtained results further justify the inclusion of MUTYH in the diagnostic strategy for Lynch syndrome-suspected patients.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , DNA Glicosilases/genética , Mutação em Linhagem Germinativa , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas p21(ras) , Proteínas ras/genética
8.
PLoS One ; 8(11): e79737, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24244552

RESUMO

BACKGROUND: Lynch syndrome (LS) is a hereditary condition that increases the risk for endometrial and other cancers. The identification of endometrial cancer (EC) patients with LS has the potential to influence life-saving interventions. We aimed to study the prevalence of LS among EC patients in our population. METHODS: Universal screening for LS was applied for a consecutive series EC. Tumor testing using microsatellite instability (MSI), immunohistochemistry (IHC) for mismatch-repair (MMR) protein expression and MLH1-methylation analysis, when required, was used to select LS-suspicious cases. Sequencing of corresponding MMR genes was performed. RESULTS: One hundred and seventy-three EC (average age, 63 years) were screened. Sixty-one patients (35%) had abnormal IHC or MSI results. After MLH1 methylation analysis, 27 cases were considered suspicious of LS. From these, 22 were contacted and referred for genetic counseling. Nineteen pursued genetic testing and eight were diagnosed of LS. Mutations were more frequent in younger patients (<50 yrs). Three cases had either intact IHC or MSS and reinforce the need of implement the EC screening with both techniques. CONCLUSION: The prevalence of LS among EC patients was 4.6% (8/173); with a predictive frequency of 6.6% in the Spanish population. Universal screening of EC for LS is recommended.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/complicações , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias do Endométrio/complicações , Proteínas Adaptadoras de Transdução de Sinal/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Metilação de DNA , Reparo de Erro de Pareamento de DNA , Neoplasias do Endométrio/diagnóstico , Feminino , Mutação em Linhagem Germinativa , Humanos , Imuno-Histoquímica , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL , Gradação de Tumores , Estadiamento de Neoplasias , Proteínas Nucleares/genética , Prevalência
9.
Breast Cancer Res Treat ; 142(1): 19-30, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24129975

RESUMO

This study aims to identify signatures of miR associated with hereditary, BRCA1 or BRCA2 mutation positive breast cancer (BC), and non-hereditary BC, either sporadic (SBC) or non-informative (BRCAX). Moreover, we search for signatures associated with tumor stage, immunohistochemistry and tumor molecular profile. Twenty formalin fixed paraffin embedded (FFPE) BCs, BRCA1, BRCA2, BRCAX and SBC, five per group were studied. Affymetrix platform miRNA v.3.0 was used to perform miR expression analysis. ER, PR, HER2 and Ki67 protein expression was analyzed by immunohistochemistry. BRCA1, BRCA2 and RASSF1 methylation analysis, AURKA copy number variations, and BRCA1 and BRCA2 deletions, were studied by MLPA. We validated eight of the miR selected by the arrays in 77 BCs by qRT-PCR. The miR profiles associated with tumor features were studied applying the Sparse Partial Least Squares Discriminant Analysis. MiR discrimination capability to distinguish hereditary and non-hereditary BC was analyzed by the discriminant function. With 15 out of 1,733 hsa-miRs, it was possible to differentiate the four groups. BRCA1, BRCA2 and SBC were associated with clusters of hyper-expressed miRs, and BRCAX with hypo-expressed miRs. Hsa-miR-4417 and hsa-miR-423-3p expressions (included among the eight validated miRs) differentiated 70.1 % of hereditary and non-hereditary BCs. We found miR profiles associated with tumor features like node involvement, histological grade, ER, PR and HER2 expression. Regarding molecular parameters, we only found a weak association of miRs in BC harboring losses in AURKA. We conclude that array miR expression profiles can differentiate the four study groups using FFPE BC. However, miRs expression estimated by qRT-PCR differentiates only hereditary and non-inherited BCs. The miR expression array is a simple and rapid approach that could be useful to facilitate the identification of those SBC carrying genetic or epigenetic changes in BRCA genes responsible of BRCA-like phenotype. These patients could benefit from the treatment with PARP inhibitors.


Assuntos
Neoplasias da Mama/congênito , MicroRNAs/genética , Transcriptoma , Adulto , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Proteína BRCA2/genética , Proteína BRCA2/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Análise por Conglomerados , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Reprodutibilidade dos Testes
10.
Fam Cancer ; 12(4): 767-77, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23479189

RESUMO

During the first 6 years of the Program of Genetic Counselling in Cancer of Valencia (eastern Spain), 310 mutations (155 in BRCA1 and 155 in BRCA2) in 1,763 hereditary breast (BC) and ovarian cancer (OC) families were identified. Of the mutations found 105 were distinct (53 in BRCA1 and 52 in BRCA2), eight new and 37 recurrent. Two of the novel mutations were frame-shift placed in exons 2 and 11 of BRCA1 and the remaining six were placed in BRCA2; four frame-shift (three in exon 11 and one in exon 23), one deletion of the entire exon 19 and one in the intervening sequence of exon 22. The BRCA1 mutations with higher recurrence were c.66_68delAG, c.5123C > A, c.1961delA, c.3770_3771delAG and c.5152+5G > A that covered 45.2% of mutations of this gene. The age of onset of BCs of c.68_69delAG mutation carriers occurs later than for the other recurrent mutations of this gene (45 vs. 37 years; p = 0.008). The BRCA2 mutations with higher recurrence were c.9026_9030delATCAT, c.3264insT and c.8978_8991del14 which represented 43.2% of all mutations in this gene, being the most recurrent mutation by far c.9026_9030delATCAT that represents 21.3% of BRCA2 mutations and 10.6% of all mutations. Probands with family histories of BC and OC, or OC and/or BC in at least two first degree relatives, were the more likely to have BRCA1/BRCA2 mutations (35.2% of the total mutations). And that most BRCA1mutations (73.19% mutations) occurred in probands with early-onset BC or with family history of OC.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Aconselhamento Genético , Predisposição Genética para Doença , Mutação/genética , Neoplasias Ovarianas/genética , Adulto , Idade de Início , Idoso , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/epidemiologia , DNA de Neoplasias/genética , Detecção Precoce de Câncer , Família , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/epidemiologia , Fenótipo , Reação em Cadeia da Polimerase , Prevalência , Prognóstico , Espanha/epidemiologia , Adulto Jovem
12.
Fam Cancer ; 11(1): 49-56, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21918853

RESUMO

The true prevalence of BRCA1/BRCA2 (BRCAs) germline mutations in sporadic breast or ovarian cancer (SBC/SOC) in Caucasian population is not well established. The aim of the study is to establish the prevalence of BRCAs mutations in SBC to ponder its relevance in the programs of genetic counseling in cancer and to explore the genotype-phenotype relationship of these particular breast cancers. The study was performed in 495 SBC. We sought 46 BRCA1 and 53 BRCA2 pathogenic mutations reported in the Spanish population. We followed a high resolution melting method performed in the LightCycler 480 (Roche Diagnostics) for the screening of these Spanish mutations using 49 primer pairs. Eight different deleterious mutations, one of them novel, were detected in nine patients, five without family history of BC/OC, what yields a true prevalence of 1.05% for BRCAs mutations in SBC. Furthermore, we found 18 unknown variants. Larger tumour size (T > 1) and earlier presentation are the independent parameters associated with the presence of BRCAs pathogenic mutations in SBC (P < 0.01) and the BRCA1 mutations carriers develop steroid-receptors negative tumors. Our results indicate that the true prevalence of BRCAs germline deleterious mutations in SBC of Spaniards is low. However, this does not lessens its relevance since the presence of BRCAs mutations in SBC could represent circa 16% of total BRCAs mutations detected in BC. SBCs of BRCAs mutation carriers have phenotype more aggressiveness than SBC without BRCAs mutation.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Grupo com Ancestrais do Continente Europeu/genética , Predisposição Genética para Doença , Mutação/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/epidemiologia , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/secundário , Carcinoma Intraductal não Infiltrante/epidemiologia , Carcinoma Intraductal não Infiltrante/genética , Carcinoma Intraductal não Infiltrante/secundário , Carcinoma Lobular/epidemiologia , Carcinoma Lobular/genética , Carcinoma Lobular/secundário , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Linhagem , Espanha/epidemiologia
13.
BMC Med Genet ; 12: 12, 2011 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-21247423

RESUMO

BACKGROUND: Lynch syndrome (LS) is an autosomal dominant inherited cancer syndrome characterized by early onset cancers of the colorectum, endometrium and other tumours. A significant proportion of DNA variants in LS patients are unclassified. Reports on the pathogenicity of the c.1852_1853AA>GC (p.Lys618Ala) variant of the MLH1 gene are conflicting. In this study, we provide new evidence indicating that this variant has no significant implications for LS. METHODS: The following approach was used to assess the clinical significance of the p.Lys618Ala variant: frequency in a control population, case-control comparison, co-occurrence of the p.Lys618Ala variant with a pathogenic mutation, co-segregation with the disease and microsatellite instability in tumours from carriers of the variant. We genotyped p.Lys618Ala in 1034 individuals (373 sporadic colorectal cancer [CRC] patients, 250 index subjects from families suspected of having LS [revised Bethesda guidelines] and 411 controls). Three well-characterized LS families that fulfilled the Amsterdam II Criteria and consisted of members with the p.Lys618Ala variant were included to assess co-occurrence and co-segregation. A subset of colorectal tumour DNA samples from 17 patients carrying the p.Lys618Ala variant was screened for microsatellite instability using five mononucleotide markers. RESULTS: Twenty-seven individuals were heterozygous for the p.Lys618Ala variant; nine had sporadic CRC (2.41%), seven were suspected of having hereditary CRC (2.8%) and 11 were controls (2.68%). There were no significant associations in the case-control and case-case studies. The p.Lys618Ala variant was co-existent with pathogenic mutations in two unrelated LS families. In one family, the allele distribution of the pathogenic and unclassified variant was in trans, in the other family the pathogenic variant was detected in the MSH6 gene and only the deleterious variant co-segregated with the disease in both families. Only two positive cases of microsatellite instability (2/17, 11.8%) were detected in tumours from p.Lys618Ala carriers, indicating that this variant does not play a role in functional inactivation of MLH1 in CRC patients. CONCLUSIONS: The p.Lys618Ala variant should be considered a neutral variant for LS. These findings have implications for the clinical management of CRC probands and their relatives.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Mutação , Proteínas Nucleares/genética , Estudos de Casos e Controles , Neoplasias Colorretais/genética , Neoplasias Colorretais Hereditárias sem Polipose/classificação , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Família , Genótipo , Humanos , Instabilidade de Microssatélites , Proteína 1 Homóloga a MutL
14.
J Mol Diagn ; 12(6): 765-70, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20864635

RESUMO

The standard genetic test for Lynch syndrome (LS) frequently reveals an absence of pathogenic mutations in DNA mismatch repair genes known to be associated with LS. It was recently shown that germ line deletions in the last exons of EPCAM are involved in the etiology of LS. The aim of this study was to evaluate the prevalence of EPCAM deletions in a Spanish population and the clinical implications of deletion. Probands from 501 families suspected of having LS were enrolled in the study. Twenty-five cases with MSH2 loss were identified: 10 had mutations of MSH2, five had mutations of MSH6, and 10 did not show MSH2/MSH6 mutations. These 25 cases were analyzed for EPCAM deletions using multiplex ligation-dependent probe amplification, and deletions were mapped using long-range PCR analysis. One subject with no MSH2/MSH6 mutations had a large deletion in the EPCAM locus that extended for 8.7 kb and included exons 8 and 9. The tumor exhibited MSH2 promoter hypermethylation. EPCAM deletion analysis followed by MSH2 methylation testing of the tumor is a fast low-cost procedure that can be used to identify mutations that cause LS. We propose that this procedure be incorporated into clinical genetic analysis strategies and present a decision-support flow diagram for the diagnosis of LS.


Assuntos
Antígenos de Neoplasias/genética , Moléculas de Adesão Celular/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA/genética , Testes Genéticos/métodos , Mutação em Linhagem Germinativa , Deleção de Sequência , Proteínas Adaptadoras de Transdução de Sinal/genética , Adulto , Sequência de Bases , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Metilação de DNA , Análise Mutacional de DNA/métodos , Proteínas de Ligação a DNA/genética , Molécula de Adesão da Célula Epitelial , Feminino , Humanos , Masculino , Dados de Sequência Molecular , Proteína 1 Homóloga a MutL , Proteína 2 Homóloga a MutS/genética , Proteínas Nucleares/genética , Linhagem , Regiões Promotoras Genéticas , Espanha
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