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1.
Hum Mutat ; 2021 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-33600035

RESUMO

BAP1 germline pathogenic sequence variants (PSVs) underlie a unique tumor predisposition syndrome (BAP1 - TPDS) associated with increased lifetime risk for developing primarily pleural and peritoneal mesothelioma and uveal and cutaneous melanoma. Overwhelmingly, BAP1 PSVs are unique, family specific inactivating variants. We identified seven families, 6 of Jewish Iraqi origin, harboring an identical BAP1 splice variant (c.783+2T>C), currently assigned a "likely pathogenic" status. Given a non-classical BAP1-TPDS tumor type clustering, and low penetrance in these families, the pathogenicity of this variant was re-evaluated by a combined approach including literature analysis, revised bioinformatics analysis, allelic loss, effect on transcript, and tumor protein expression patterns. None of three available tumors showed allelic loss, there was no discernable effect on alternative splicing based on reverse transcription PCR, and there was no decrease or loss of somatic protein expression in 2/3 analyzed tumors. This led to assigning a Benign Strong (BS) criteria, BS4, supporting BS3 criteria, and to weakening the Pathogenic Supporting (PP) criteria PP5. Combined, these data suggest that this sequence variant should be re-classified as a variant of unknown significance by ACMG criteria. This article is protected by copyright. All rights reserved.

2.
Genomics ; 2020 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-33053411

RESUMO

Next Generation Sequencing (NGS), and specifically targeted panel sequencing is the state-of-the-art in clinical genetic diagnosis of Mendelian diseases. However, the bioinformatics analysis and interpretation of the generated data can be challenging. A spotlight on the default transcript selection of a user-friendly, commercially available software that is widely used by genetics professionals, i.e. Illumina® VariantStudio®, is presented. For the sake of comparison, we employed Ensembl VEP, an open-source command-line tool, as it provides flexibility regarding transcript selection. The analysis of NGS data deriving from sequencing of 857 germline DNA samples of cancer patients indicated a concordance of 82.82% between the two software programs. Significantly, using the default transcript configuration of VariantStudio®, we failed to annotate correctly 11.45% of the identified loss-of-function variants. Our results underline the importance of cautious software and transcript selection and the need for reliable, white-box data analysis, along with bioinformatics expertise in clinical diagnostics.

3.
NPJ Breast Cancer ; 6: 44, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32964118

RESUMO

Germline genetic variation has been suggested to influence the survival of breast cancer patients independently of tumor pathology. We have studied survival associations of genetic variants in two etiologically unique groups of breast cancer patients, the carriers of germline pathogenic variants in BRCA1 or BRCA2 genes. We found that rs57025206 was significantly associated with the overall survival, predicting higher mortality of BRCA1 carrier patients with estrogen receptor-negative breast cancer, with a hazard ratio 4.37 (95% confidence interval 3.03-6.30, P = 3.1 × 10-9). Multivariable analysis adjusted for tumor characteristics suggested that rs57025206 was an independent survival marker. In addition, our exploratory analyses suggest that the associations between genetic variants and breast cancer patient survival may depend on tumor biological subgroup and clinical patient characteristics.

4.
Int J Cancer ; 147(5): 1334-1342, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32022259

RESUMO

Germline BRCA1 and BRCA2 loss-of-function variants have been linked to increased breast and ovarian cancer risk, with more than 5,000 distinct pathogenic variants being reported worldwide. Among individuals of Greek descent, the BRCA1/2 variant spectrum is heterogeneous, but characterized by strong founder effects. As patients from certain geographical regions of Greece (like Crete) were underrepresented in previous studies, we hypothesized that isolated Cretans, a southern Greece islanders' population with distinct demographic, cultural and genetic features, could harbor founder BRCA1/2 mutations. A total of 304 breast or/and ovarian cancer patients of Cretan descent, fulfilling NCCN criteria for genetic testing, were tested by NGS or Sanger sequencing, followed by MLPA. Haplotype analysis was subsequently performed to investigate potential founder effects of recurrent alleles. Overall, 16.5% (50/304) of the tested patients carried 22 different pathogenic variants; 48% in BRCA1, 52% in BRCA2. Three variants, namely two in BRCA2 (Δexons 12 and 13 and c.7806-2A>T) and one in BRCA1 (c.5492del), constituting approximately half (48%) of all detected pathogenic variants, were shown to have a founder effect, with all carriers sharing common haplotypes. Remarkably, these variants were confined to Cretans and have not been identified in other regions of Greece. The high prevalence of specific BRCA1/2 pathogenic variants among Cretans, provides the possibility of cost- and time-efficient screening of the Cretan population. Integrating this knowledge in local public health services may have a significant impact on cancer prevention, and may serve as a starting point for the implementation of testing on a population level.

5.
Clin Breast Cancer ; 20(2): 152-159, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31980407

RESUMO

INTRODUCTION: BRCA1/BRCA2 mutation carriers indefinitely comprise a distinct group of patients with breast cancer (BC), with their tumors displaying specific pathologic characteristics. Although these connections are known, they are not fully elucidated. We therefore sought to investigate the clinicopathologic characteristics and overall survival of Greek patients with BC carrying BRCA1/BRCA2 mutations. PATIENTS AND METHODS: Greek patients with BC diagnosed between 1999 and 2016, fulfilling the National Comprehensive Cancer Network criteria for genetic testing, were analyzed for BRCA1/BRCA2 mutations by Sanger sequencing or by a 94-gene panel. Medical records and pathology reports were retrospectively reviewed to retrieve patient and tumor baseline characteristics. Potential associations with mutation status were assessed using the Fisher exact, Pearson χ2, and Mann-Whitney tests. RESULTS: Of 2096 selected patients with BC, we identified 297 (14.2%) BRCA1 and 88 (4.2%) BRCA2 carriers. The mean age at BC diagnosis was 40 and 42.6 years, respectively (P = .02). Tumor histologic subtypes in BRCA1 and BRCA2 carriers were predominantly ductal (79%) followed by medullary (10%), and ductal (72%) followed by lobular (15%), respectively. A significantly higher percentage of BRCA2 tumors were human epidermal growth factor receptor 2-positive, compared with BRCA1 tumors (21.7% vs. 5.8%; P < .001). Second primary cancer diagnosis was more frequent in BRCA1 compared with BRCA2 mutation carriers (36.2% vs. 10.7%; P < .001), whereas there was no difference in 15-year overall survival (hazard ratio, 0.92; 95% confidence interval, 0.48-1.83; P = .804) between the 2 groups. CONCLUSIONS: These data confirm established observations in the pathology of BRCA-related tumors and provide further insight on the association of rare histologic entities with mutations in these genes, which can be clinically beneficial.

6.
J Med Genet ; 57(1): 53-61, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31300551

RESUMO

BACKGROUND: Gene panel testing has become the norm for assessing breast cancer (BC) susceptibility, but actual cancer risks conferred by genes included in panels are not established. Contrarily, deciphering the missing hereditability on BC, through identification of novel candidates, remains a challenge. We aimed to investigate the mutation prevalence and spectra in a highly selected cohort of Greek patients with BC, questioning an extensive number of genes, implicated in cancer predisposition and DNA repair, while calculating gene-specific BC risks that can ultimately lead to important associations. METHODS: To further discern BC susceptibility, a comprehensive 94-cancer gene panel was implemented in a cohort of 1382 Greek patients with BC, highly selected for strong family history and/or very young age (<35 years) at diagnosis, followed by BC risk calculation, based on a case-control analysis. RESULTS: Herein, 31.5% of patients tested carried pathogenic variants (PVs) in 28 known, suspected or candidate BC predisposition genes. In total, 24.8% of the patients carried BRCA1/2 loss-of-function variants. An additional 6.7% carried PVs in additional genes, the vast majority of which can be offered meaningful clinical changes. Significant association to BC predisposition was observed for ATM, PALB2, TP53, RAD51C and CHEK2 PVs. Primarily, compared with controls, RAD51C PVs and CHEK2 damaging missense variants were associated with high (ORs 6.19 (Exome Aggregation Consortium (ExAC)) and 12.6 (Fabulous Ladies Over Seventy (FLOSSIES)), p<0.01) and moderate BC risk (ORs 3.79 (ExAC) and 5.9 (FLOSSIES), p<0.01), respectively. CONCLUSION: Studying a large and unique cohort of highly selected patients with BC, deriving from a population with founder effects, provides important insight on distinct associations, pivotal for patient management.


Assuntos
Neoplasias da Mama/genética , Reparo do DNA , Predisposição Genética para Doença , Mutação de Sentido Incorreto , Adulto , Neoplasias da Mama/epidemiologia , Estudos de Casos e Controles , Estudos de Coortes , Enzimas Reparadoras do DNA , Feminino , Grécia/epidemiologia , Humanos , Mutação com Perda de Função , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Medição de Risco , Adulto Jovem
7.
Int J Epidemiol ; 49(4): 1117-1131, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31872213

RESUMO

BACKGROUND: Conventional epidemiologic studies have evaluated associations between circulating lipid levels and breast cancer risk, but results have been inconsistent. As Mendelian randomization analyses may provide evidence for causal inference, we sought to evaluate potentially unbiased associations between breast cancer risk and four genetically predicted lipid traits. METHODS: Previous genome-wide association studies (GWAS) have identified 164 discrete variants associated with high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), triglycerides and total cholesterol. We used 162 of these unique variants to construct weighted genetic scores (wGSs) for a total of 101 424 breast cancer cases and 80 253 controls of European ancestry from the Breast Cancer Association Consortium (BCAC). Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for associations between per standard deviation increase in genetically predicted lipid traits and breast cancer risk. Additional Mendelian randomization analysis approaches and sensitivity analyses were conducted to assess pleiotropy and instrument validity. RESULTS: Corresponding to approximately 15 mg/dL, one standard deviation increase in genetically predicted HDL-C was associated with a 12% increased breast cancer risk (OR: 1.12, 95% CI: 1.08-1.16). Findings were consistent after adjustment for breast cancer risk factors and were robust in several sensitivity analyses. Associations with genetically predicted triglycerides and total cholesterol were inconsistent, and no association for genetically predicted LDL-C was observed. CONCLUSIONS: This study provides strong evidence that circulating HDL-C may be associated with an increased risk of breast cancer, whereas LDL-C may not be related to breast cancer risk.

8.
Cancer Genet ; 237: 90-96, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31447071

RESUMO

PURPOSE: Multiple lines of evidence have suggested a likely causative role in breast/ovarian cancer (BrCa/OvCa) predisposition for the BRCA1 p.(Val1833Met) variant, predominantly found among Greek patients. Our aim was to study the variant's prevalence and founder effect on the Greek population, while providing additional data for its pathogenicity. METHODS: We genotyped 3531 BrCa/OvCa patients using Sanger and next generation sequencing, as well as 1558 healthy, age-matched females with real-time PCR. Carriers underwent haplotype analysis to determine a founder effect. A co-segregation analysis was applied to estimate the likelihood ratio for pathogenicity. RESULTS: In total, 27 BrCa/OvCa patients (0.77%; 27/3531) were found to carry the p.(Val1833Met) variant. No carriers were identified in the control group diagnosis. A common shared haplotype, spanning 2.76 Mb on chromosome 17 was demonstrated among carriers, establishing the founder effect. BRCA1, p.(Val1833Met) is possibly a disease-associated variant, supported by a likelihood ratio of 1.88, while a correlation to ovarian cancer is suspected. CONCLUSIONS: Altogether, BRCA1, p.(Val1833Met) variant is a Greek founder and is very likely to predispose for BrCa/OvCa. Therefore, such carriers should be counselled accordingly, with clinical recommendations supporting surveillance and risk-reduction strategies, while providing the option for targeted therapeutic interventions.


Assuntos
Efeito Fundador , Genes BRCA1 , Predisposição Genética para Doença , Neoplasias Ovarianas/epidemiologia , Feminino , Grécia/epidemiologia , Humanos , Funções Verossimilhança , Neoplasias Ovarianas/genética , Prevalência
9.
Case Rep Oncol Med ; 2019: 9357924, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31223512

RESUMO

We report a case of a 58-year-old female with ovarian cancer. The patient presented with ascites, and the biopsies revealed a low-grade adenocarcinoma, either a serous papillary ovarian cancer with peritoneal implants or a primary peritoneal carcinoma. She received neoadjuvant chemotherapy and after 5 cycles achieved partial response, and then, she underwent a total hysterectomy/bilateral salpingo-oophorectomy. The patient underwent germline gene-panel testing for the detection of mutations in cancer predisposing genes. A truncating mutation in the Fanconi anemia complementation group M (FANCM) gene was detected in heterozygosity, namely, p.Arg658Ter (c.1972C>T, rs368728266). The patient's family history is unremarkable, with no reported cases of breast or ovarian cancer, a fact that can be attributed to the significant lower penetrance of FANCM mutations.

10.
Hum Mutat ; 40(11): e1-e23, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31209999

RESUMO

BRCA1 BRCA2 mutational spectrum in the Middle East, North Africa, and Southern Europe is not well characterized. The unique history and cultural practices characterizing these regions, often involving consanguinity and inbreeding, plausibly led to the accumulation of population-specific founder pathogenic sequence variants (PSVs). To determine recurring BRCA PSVs in these locales, a search in PUBMED, EMBASE, BIC, and CIMBA was carried out combined with outreach to researchers from the relevant countries for unpublished data. We identified 232 PSVs in BRCA1 and 239 in BRCA2 in 25 of 33 countries surveyed. Common PSVs that were detected in four or more countries were c.5266dup (p.Gln1756Profs), c.181T>G (p.Cys61Gly), c.68_69del (p.Glu23Valfs), c.5030_5033del (p.Thr1677Ilefs), c.4327C>T (p.Arg1443Ter), c.5251C>T (p.Arg1751Ter), c.1016dup (p.Val340Glyfs), c.3700_3704del (p.Val1234Glnfs), c.4065_4068del (p.Asn1355Lysfs), c.1504_1508del (p.Leu502Alafs), c.843_846del (p.Ser282Tyrfs), c.798_799del (p.Ser267Lysfs), and c.3607C>T (p.Arg1203Ter) in BRCA1 and c.2808_2811del (p.Ala938Profs), c.5722_5723del (p.Leu1908Argfs), c.9097dup (p.Thr3033Asnfs), c.1310_1313del (p. p.Lys437Ilefs), and c.5946del (p.Ser1982Argfs) for BRCA2. Notably, some mutations (e.g., p.Asn257Lysfs (c.771_775del)) were observed in unrelated populations. Thus, seemingly genotyping recurring BRCA PSVs in specific populations may provide first pass BRCA genotyping platform.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Predisposição Genética para Doença , Variação Genética , Grupos Populacionais/genética , África do Norte , Grupo com Ancestrais do Continente Africano , Alelos , Mineração de Dados , Bases de Dados Genéticas , Europa (Continente) , Grupo com Ancestrais do Continente Europeu , Genótipo , Humanos , Oriente Médio , Projetos de Pesquisa
11.
J Hum Genet ; 64(8): 767-773, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31089269

RESUMO

PALB2 loss-of-function variants play an important role in breast, pancreatic and possibly, ovarian and gastric cancer susceptibility. Their frequency can be influenced by founder effects, already described in some populations. Herein, we have assessed the possible founder effect of PALB2 c.2257C>T (p.Arg753*) truncating variant among Greek breast cancer patients, while investigating possible correlations with cancer diagnoses. Following a lead deriving from a background study of highly selected Greek breast cancer patients, a total of 2496 breast and 697 ovarian cancer patients were directly genotyped for the PALB2 c.2257C>T truncating variant. Consequently, haplotype analysis was conducted on identified carriers, using seven microsatellite markers. The prevalence of the PALB2 variant was 0.24% (6/2496) and 0.14% (1/697) among breast and ovarian cases, respectively. Family history seems to be an important factor for the variant identification, although not reaching statistical significance. Microsatellite analysis on 12 carriers revealed a common shared haplotype, spanning a chromosomal region of ~1.2 Mb; the variant was possibly introduced in the Greek population ~1600 years ago. The variant confers high breast cancer risk, as illustrated by comparison with publicly available control groups. Genetic testing for PALB2, especially for the Greek founder c.2257C>T truncating variant, should be seriously considered in Greek breast cancer cases, since such findings could assist appropriate clinical management for the patients and their families.


Assuntos
Alelos , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Efeito Fundador , Mutação em Linhagem Germinativa , Deleção de Sequência , Adulto , Idoso , Idoso de 80 Anos ou mais , Substituição de Aminoácidos , Neoplasias da Mama/diagnóstico , Estudos de Casos e Controles , Análise Mutacional de DNA , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Grécia/epidemiologia , Haplótipos , Síndrome Hereditária de Câncer de Mama e Ovário/diagnóstico , Síndrome Hereditária de Câncer de Mama e Ovário/epidemiologia , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Humanos , Mutação com Perda de Função , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Linhagem , Medição de Risco , Fatores de Risco , Adulto Jovem
12.
Hum Mutat ; 40(5): 631-648, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30851065

RESUMO

Genetic testing for cancer predisposition leads to the identification of a number of variants with uncertain significance. To some extent, variants of BRCA1/2 have been classified, in contrast to variants of other genes. CHEK2 is a typical example, in which a large number of variants of unknown clinical significance were identified and still remained unclassified. Herein, the CHEK2 variant assessment was performed through an in vivo, yeast-based, functional assay. In total, 120 germline CHEK2 missense variants, distributed along the protein sequence, and two large in-frame deletions were tested, originating from genetic test results in breast cancer families, or selected from the ClinVar database. Of these, 32 missense and two in-frame deletions behaved as non-functional, 73 as functional, and 15 as semi-functional, after comparing growth rates of each strain with positive and negative controls. The majority of non-functional variants were localized in the CHK2 kinase and forkhead-associated domains. In vivo results from the non-functional variants were in agreement with in silico predictions, and, where available, with strong breast cancer family history, to a great extent. The results of the largest, to date, yeast-based assay, evaluating CHEK2 variants, can complement and assist in the classification of rare CHEK2 variants with unclear clinical significance.


Assuntos
Quinase do Ponto de Checagem 2/genética , Mutação , Saccharomyces cerevisiae/genética , Alelos , Substituição de Aminoácidos , Quinase do Ponto de Checagem 2/metabolismo , Biologia Computacional/métodos , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Modelos Moleculares , Linhagem , Conformação Proteica , Saccharomyces cerevisiae/metabolismo
14.
J Hum Genet ; 63(11): 1149-1158, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30111881

RESUMO

RAD51D gene's protein product is known to be involved in the DNA repair mechanism by homologous recombination. RAD51D germline mutations have been recently associated with ovarian and breast cancer (OC and BC, respectively) predisposition. Our aim was to evaluate the frequency of hereditary RAD51D mutations in Greek patients. To address this, we have screened for RAD51D germline mutations 609 BRCA1- and BRCA2-negative patients diagnosed with OC, unselected for age or family history, and 569 BC patients diagnosed under 55 years and with an additional relative with BC or OC. We identified four pathogenic mutations in four unrelated individuals with family history of BC and/or OC. Three of the RAD51D carriers had developed BC, while the other one was an OC patient, thus accounting for a mutation frequency of 0.16% in the OC cohort and 0.53% in the BC cohort. One of the detected mutations is novel (c.738 + 1G > A), whereas the rest had been detected previously (p.Gln151Ter, p.Arg186Ter, and p.Arg300Ter). It is noteworthy that the 4 carrier families had 13 BC cases and only 4 OC cases. Our data support that RAD51D should be implemented into the comprehensive multigene panel, as mutation carriers may benefit from the administration of PARP inhibitors.


Assuntos
Neoplasias da Mama/genética , Proteínas de Ligação a DNA/genética , Mutação em Linhagem Germinativa , Proteínas de Neoplasias/genética , Neoplasias Ovarianas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/epidemiologia , Feminino , Grécia/epidemiologia , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/epidemiologia
15.
J Natl Cancer Inst ; 110(8): 855-862, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-30099541

RESUMO

BACKGROUND: Germline genetic testing with hereditary cancer gene panels can identify women at increased risk of breast cancer. However, those at increased risk of triple-negative (estrogen receptor-negative, progesterone receptor-negative, human epidermal growth factor receptor-negative) breast cancer (TNBC) cannot be identified because predisposition genes for TNBC, other than BRCA1, have not been established. The aim of this study was to define the cancer panel genes associated with increased risk of TNBC. METHODS: Multigene panel testing for 21 genes in 8753 TNBC patients was performed by a clinical testing laboratory, and testing for 17 genes in 2148 patients was conducted by a Triple Negative Breast Cancer Consortium (TNBCC) of research studies. Associations between deleterious mutations in cancer predisposition genes and TNBC were evaluated using results from TNBC patients and reference controls. RESULTS: Germline pathogenic variants in BARD1, BRCA1, BRCA2, PALB2, and RAD51D were associated with high risk (odds ratio > 5.0) of TNBC and greater than 20% lifetime risk for overall breast cancer among Caucasians. Pathogenic variants in BRIP1, RAD51C, and TP53 were associated with moderate risk (odds ratio > 2) of TNBC. Similar trends were observed for the African American population. Pathogenic variants in these TNBC genes were detected in 12.0% (3.7% non-BRCA1/2) of all participants. CONCLUSIONS: Multigene hereditary cancer panel testing can identify women with elevated risk of TNBC due to mutations in BARD1, BRCA1, BRCA2, PALB2, and RAD51D. These women can potentially benefit from improved screening, risk management, and cancer prevention strategies. Patients with mutations may also benefit from specific targeted therapeutic strategies.


Assuntos
Biomarcadores Tumorais , Estudos de Associação Genética , Predisposição Genética para Doença , Testes Genéticos , Neoplasias de Mama Triplo Negativas/diagnóstico , Neoplasias de Mama Triplo Negativas/genética , Adulto , Idade de Início , Alelos , Estudos de Casos e Controles , Feminino , Frequência do Gene , Estudos de Associação Genética/métodos , Testes Genéticos/métodos , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Razão de Chances , Fatores de Risco , Neoplasias de Mama Triplo Negativas/epidemiologia , Adulto Jovem
16.
J Hum Genet ; 63(8): 877-886, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29785007

RESUMO

Germline CHEK2 mutations confer increased cancer risk, for breast and other types, which is variable depending on the specific mutation. Of these, Large Genomic Rearrangements (LGRs) have been rarely reported; to date only eight LGRs have been published with just the Czech founder mutation, the deletion of exons 9 and 10, being molecularly characterized and studied extensively. The present study aimed to molecularly define and determine the contribution of two rare, apparently novel CHEK2 LGRs, among Greek breast cancer patients. These specifically involve a ~6 kb in-frame deletion of exons 2 & 3 that removes CHEK2's FHA domain and a ~7.5 kb in-frame deletion of exon 6, which removes an α-helix of CHEK2's kinase domain. The latter was identified in 5 out of 2355 (0.22%) patients tested, while haplotype analysis revealed a common disease-associated haplotype, suggesting a single common ancestor and a Greek founder. Although in-frame, this LGR is predicted to be damaging by a yeast-based functional assay and structure-function predictions. The present study highlights the existence of rare, population-specific, genomic events in a known breast cancer predisposing gene, which can explain a proportion of hereditary breast cancer. Identification of such mutation carriers is rather important since appropriate clinical actionability will be inferred.


Assuntos
Neoplasias da Mama/genética , Quinase do Ponto de Checagem 2/genética , Deleção de Genes , Predisposição Genética para Doença , Adulto , Idoso , Neoplasias da Mama/patologia , Simulação por Computador , Análise Mutacional de DNA , Feminino , Rearranjo Gênico , Grécia , Haplótipos/genética , Humanos , Masculino , Repetições de Microssatélites/genética , Pessoa de Meia-Idade , Linhagem , Polimorfismo de Nucleotídeo Único/genética , Prevalência , Saccharomyces cerevisiae/metabolismo , Relação Estrutura-Atividade , Adulto Jovem
17.
Fertil Steril ; 109(4): 708-719.e8, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29605411

RESUMO

OBJECTIVE: To systematically review and appraise the existing evidence in relation to the efficacy and safety of pulsatile gonadotropin-releasing hormone (pGnRH) for the treatment of women with hypothalamic amenorrhea (HA). DESIGN: Systematic review and meta-analysis. SETTING: Not applicable. PATIENT(S): A total of 35 studies (three randomized and 32 observational) encompassing 1,002 women with HA. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Primary outcomes: ovulation rate (OvR), pregnancy per ovulatory cycle rate (POR), and live birth per ovulatory cycle rate (LBOR). SECONDARY OUTCOMES: multiple gestation (MG), ovarian hyperstimulation syndrome (OHSS), and superficial thrombophlebitis (ST) rates. The summary measures were expressed as proportions and 95% confidence intervals (CI). RESULT(S): Pulsatile GnRH treatment appears to achieve high OvRs. A trend toward high PORs and LBORs among women with HA is demonstrated. SC pGnRH achieves comparable OvR compared with IV pGnRH. The incidence of OHSS is low and of mild severity. Treatment with pGnRH is associated with low but slightly higher MG rates compared with the general population. IV administered pGnRH is rarely associated with ST. CONCLUSION(S): The high OvRs leading to a high rate of singleton pregnancies and the low likelihood of OHSS render the pGnRH treatment modality both effective and safe for the treatment of women with HA of either primary or secondary origin.


Assuntos
Amenorreia/tratamento farmacológico , Fármacos para a Fertilidade Feminina/administração & dosagem , Hormônio Liberador de Gonadotropina/administração & dosagem , Hipotálamo/fisiopatologia , Infertilidade Feminina/tratamento farmacológico , Indução da Ovulação/métodos , Ovulação/efeitos dos fármacos , Adolescente , Adulto , Amenorreia/complicações , Amenorreia/diagnóstico , Amenorreia/fisiopatologia , Feminino , Fármacos para a Fertilidade Feminina/efeitos adversos , Hormônio Liberador de Gonadotropina/efeitos adversos , Humanos , Infertilidade Feminina/diagnóstico , Infertilidade Feminina/etiologia , Infertilidade Feminina/fisiopatologia , Nascimento Vivo , Indução da Ovulação/efeitos adversos , Gravidez , Taxa de Gravidez , Pulsoterapia , Medição de Risco , Fatores de Risco , Resultado do Tratamento , Adulto Jovem
18.
Cancer Genet ; 220: 19-23, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29310834

RESUMO

Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant disorder caused by germline mutations in the STK11 tumor suppressor gene. PJS patients face a cumulative cancer risk as high as 93% for all sites combined. The present study reports the spectrum of STK11 mutations in eight families with clinical diagnosis of PJS, summarizes the clinical characteristics of sixteen mutation carriers and launches a National Registry for PJS in Greece. STK11 loss-of-function (LoF) mutations were detected in 87.5% of index patients. Carriers presented with their first manifestation at a median age of 24.9 years, while early-onset breast cancer was the most frequent malignancy observed, highlighting the need for breast surveillance. Out of the deleterious STK11 mutations identified, two were novel: c.375_376delGT and c.676_679dupAACG, with 57.2% of these potentially occurring de novo. Using all available clinical and genetic data, the National Registry for Greek PJS was established in an attempt to better characterize the syndrome and raise awareness among patients and clinicians (available at https://www.peutzjeghersgreece.org). This is the first comprehensive genetic analysis and clinical characterization of Greek PJS patients, where a high incidence of breast cancer was observed and the first attempt to centralize all data in a National Registry.


Assuntos
Testes Genéticos/métodos , Síndrome de Peutz-Jeghers/genética , Adulto , Feminino , Grécia , Humanos , Masculino , Síndrome de Peutz-Jeghers/patologia , Sistema de Registros , Adulto Jovem
19.
Breast Cancer Res Treat ; 169(1): 105-113, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29335925

RESUMO

PURPOSE: Male breast cancer (MBC) is a rare cancer entity, with mutations in BRCA1 and BRCA2 genes accounting for ~ 10% of patients. Multiple-gene sequencing has already entered clinical practice for female breast cancer, whereas the performance of panel testing in MBC has not been studied extensively. Therefore, the aim of this study was to evaluate the clinical utility of panel testing for MBC, by the largest gene panel used so far, through investigation of patients deriving from a population with known founder effects. METHODS: Genomic DNA from one hundred and two Greek MBC patients, unselected for age and family history, was used to prepare libraries which capture the entire coding regions of 94 cancer genes. RESULTS: Loss-of-function (LoF) mutations were found in 12.7% of the cases, distributed in six genes: BRCA2, ATM, BRCA1, CHEK2, PMS2, and FANCL. BRCA2 mutations were the most frequent, followed by ATM mutations, accounting for 6.9 and 2%, respectively, while mutations in other genes were detected in single cases. Age at diagnosis or family history was not predictive of mutation status. Beyond mutations in established breast cancer predisposing genes, LoF mutations in PMS2 and FANCL among MBC patients are reported here for the first time. CONCLUSIONS: Our findings, using the largest gene panel for MBC patients so far, indicate that BRCA testing should be the primary concern for MBC patients. Until sufficient evidence arises from larger studies, multiple-gene panels may be of limited benefit for MBC and their families, at least for MBC patients of specific descent.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama Masculina/genética , Predisposição Genética para Doença , Idoso , Neoplasias da Mama Masculina/epidemiologia , Neoplasias da Mama Masculina/patologia , Quinase do Ponto de Checagem 2/genética , Efeito Fundador , Testes Genéticos , Mutação em Linhagem Germinativa/genética , Humanos , Mutação com Perda de Função/genética , Masculino , Pessoa de Meia-Idade , Deleção de Sequência/genética
20.
Sci Rep ; 7(1): 16697, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-29196670

RESUMO

Tuberous sclerosis complex (TSC) is a rare autosomal dominant disorder causing benign tumors in the brain and other vital organs. The genes implicated in disease development are TSC1 and TSC2. Here, we have performed mutational analysis followed by a genotype-phenotype correlation study based on the clinical characteristics of the affected individuals. Twenty unrelated probands or families from Greece have been analyzed, of whom 13 had definite TSC, whereas another 7 had a possible TSC diagnosis. Using direct sequencing, we have identified pathogenic mutations in 13 patients/families (6 in TSC1 and 7 in TSC2), 5 of which were novel. The mutation identification rate for patients with definite TSC was 85%, but only 29% for the ones with a possible TSC diagnosis. Multiplex ligation-dependent probe amplification (MLPA) did not reveal any genomic rearrangements in TSC1 and TSC2 in the samples with no mutations identified. In general, TSC2 disease was more severe than TSC1, with more subependymal giant cell astrocytomas and angiomyolipomas, higher incidence of pharmacoresistant epileptic seizures, and more severe neuropsychiatric disorders. To our knowledge, this is the first comprehensive TSC1 and TSC2 mutational analysis carried out in TSC patients in Greece.


Assuntos
Proteína 1 do Complexo Esclerose Tuberosa/genética , Proteína 2 do Complexo Esclerose Tuberosa/genética , Esclerose Tuberosa/patologia , Adulto , Criança , Análise Mutacional de DNA , Éxons , Feminino , Deleção de Genes , Estudos de Associação Genética , Grécia , Humanos , Masculino , Mutação de Sentido Incorreto , Linhagem , Estrutura Terciária de Proteína , Esclerose Tuberosa/genética
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