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1.
J Clin Oncol ; 38(7): 674-685, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31841383

RESUMO

PURPOSE: To estimate age-specific relative and absolute cancer risks of breast cancer and to estimate risks of ovarian, pancreatic, male breast, prostate, and colorectal cancers associated with germline PALB2 pathogenic variants (PVs) because these risks have not been extensively characterized. METHODS: We analyzed data from 524 families with PALB2 PVs from 21 countries. Complex segregation analysis was used to estimate relative risks (RRs; relative to country-specific population incidences) and absolute risks of cancers. The models allowed for residual familial aggregation of breast and ovarian cancer and were adjusted for the family-specific ascertainment schemes. RESULTS: We found associations between PALB2 PVs and risk of female breast cancer (RR, 7.18; 95% CI, 5.82 to 8.85; P = 6.5 × 10-76), ovarian cancer (RR, 2.91; 95% CI, 1.40 to 6.04; P = 4.1 × 10-3), pancreatic cancer (RR, 2.37; 95% CI, 1.24 to 4.50; P = 8.7 × 10-3), and male breast cancer (RR, 7.34; 95% CI, 1.28 to 42.18; P = 2.6 × 10-2). There was no evidence for increased risks of prostate or colorectal cancer. The breast cancer RRs declined with age (P for trend = 2.0 × 10-3). After adjusting for family ascertainment, breast cancer risk estimates on the basis of multiple case families were similar to the estimates from families ascertained through population-based studies (P for difference = .41). On the basis of the combined data, the estimated risks to age 80 years were 53% (95% CI, 44% to 63%) for female breast cancer, 5% (95% CI, 2% to 10%) for ovarian cancer, 2%-3% (95% CI females, 1% to 4%; 95% CI males, 2% to 5%) for pancreatic cancer, and 1% (95% CI, 0.2% to 5%) for male breast cancer. CONCLUSION: These results confirm PALB2 as a major breast cancer susceptibility gene and establish substantial associations between germline PALB2 PVs and ovarian, pancreatic, and male breast cancers. These findings will facilitate incorporation of PALB2 into risk prediction models and optimize the clinical cancer risk management of PALB2 PV carriers.

2.
Int J Cancer ; 145(10): 2692-2700, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30927251

RESUMO

Mutations in BRCA1 and BRCA2 genes predispose to breast and ovarian cancer (BC/OC) with a high lifetime risk, whereas mutations in PALB2, CHEK2, ATM, FANCM, RAD51C and RAD51D genes cause a moderately elevated risk. In the Finnish population, recurrent mutations have been identified in all of these genes, the latest being CHEK2 c.319+2T>A and c.444+1G>A. By genotyping 3,156 cases and 2,089 controls, we estimated the frequencies of CHEK2 c.319+2T>A and c.444+1G>A in Finnish BC patients. CHEK2 c.319+2T>A was detected in 0.7% of the patients, and it was associated with a high risk of BC in the unselected patient group (OR = 5.40 [95% CI 1.58-18.45], p = 0.007) and similarly in the familial patient group. CHEK2 c.444+1G>A was identified in 0.1% of all patients. Additionally, we evaluated the combined prevalence of recurrent moderate-risk gene mutations in 2,487 BC patients, 556 OC patients and 261 BRCA1/2 carriers from 109 families. The overall frequency of the mutations was 13.3% in 1,141 BRCA1/2-negative familial BC patients, 7.5% in 1,727 unselected BC patients and 7.2% in 556 unselected OC patients. At least one moderate-risk gene mutation was found in 12.5% of BRCA1 families and 7.1% of BRCA1 index patients, as well as in 17.0% of BRCA2 families and 11.3% of BRCA2 index patients, and the mutations were associated with an additional risk in the BRCA1/2 index patients (OR = 2.63 [1.15-5.48], p = 0.011). These results support gene panel testing of even multiple members of BC families where several mutations may segregate in different individuals.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Predisposição Genética para Doença , Neoplasias Ovarianas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/epidemiologia , Estudos de Casos e Controles , Estudos de Coortes , Conjuntos de Dados como Assunto , Feminino , Finlândia/epidemiologia , Testes Genéticos/métodos , Heterozigoto , Humanos , Anamnese , Pessoa de Meia-Idade , Mutação , Neoplasias Ovarianas/epidemiologia , Prevalência , Medição de Risco/métodos , Adulto Jovem
3.
J Clin Endocrinol Metab ; 103(11): 4283-4292, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30099503

RESUMO

Context: Mutations in the gene encoding Mediator complex subunit MED12 are dominant drivers of uterine fibroids (UFs) in women of diverse racial and ethnic origins. Previously, we showed that UF-linked mutations in MED12 disrupt its ability to activate cyclin C-CDK8/19 in Mediator. However, validation of Mediator kinase disruption in the clinically relevant setting of MED12-mutant UFs is currently lacking. Objective: The objective of this study was twofold. First, to extend the ethnic distribution profile of MED12 mutations by establishing their frequency in UFs from Hispanic women of South Texas. Second, to examine the impact of MED12 mutations on Mediator kinase activity in patient-derived UFs. Methods: We screened 219 UFs from 76 women, including 170 tumors from 57 Hispanic patients, for MED12 exon 2 mutations, and further examined CDK8/19 activity in Mediator complexes immunoprecipitated from MED12 mutation-negative and MED12 mutation-positive UFs. Results: MED12 exon 2 mutations in UFs from Hispanic women are somatic in nature, predominantly monoallelic, and occur at high frequency (54.1%). We identified a minimal cyclin C-CDK8 activation domain on MED12 spanning amino acids 15 through 80 that includes all recorded UF-linked mutations in MED12, suggesting that disruption of Mediator kinase activity is a principal biochemical defect arising from these pathogenic alterations. Analysis of Mediator complexes recovered from patient UFs confirmed this, revealing that Mediator kinase activity is selectively impaired in MED12-mutant UFs. Conclusions: MED12 mutations are important drivers of UF formation in Hispanic women of South Texas. MED12 mutations disrupt Mediator kinase activity, implicating altered CDK8/19 function in UF pathogenesis.


Assuntos
Hispano-Americanos/genética , Leiomioma/genética , Complexo Mediador/genética , Neoplasias Uterinas/genética , Adulto , Quinase 8 Dependente de Ciclina/metabolismo , Quinases Ciclina-Dependentes/metabolismo , Análise Mutacional de DNA , Ensaios Enzimáticos , Éxons/genética , Feminino , Humanos , Leiomioma/patologia , Complexo Mediador/isolamento & purificação , Complexo Mediador/metabolismo , Pessoa de Meia-Idade , Mutação , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo , Texas , Neoplasias Uterinas/patologia , Útero/patologia
4.
Hum Reprod Open ; 2018(4): hoy020, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30895261

RESUMO

STUDY QUESTION: Do the uterine leiomyoma driver events - mediator complex subunit 12 (MED12) mutations, high mobility group AT-hook (HMGA2) overexpression, and fumarate hydratase (FH) inactivation - also contribute to the development of uterine adenomyomas? SUMMARY ANSWER: MED12 mutations and FH deficiency occur in a subset of uterine adenomyomas, but at lower frequencies than in leiomyomas. WHAT IS KNOWN ALREADY: Uterine adenomyomas are benign tumours with clinical features very similar to uterine leiomyomas. Mutations affecting MED12, HMGA2 and FH account for up to 80-90% of leiomyomas, but their contribution to adenomyomas is not known. STUDY DESIGN SIZE DURATION: Formalin-fixed paraffin-embedded adenomyoma samples from 21 patients operated on during 2012-2014 were collected at the pathology department's archives and analysed for uterine leiomyoma driver events. PARTICIPANTS/MATERIALS SETTING METHODS: Adenomyoma diagnoses were verified by a specialized pathologist and representative areas were marked on haematoxylin-eosin slides. DNA was extracted from the tissue samples and sequenced to detect mutations in MED12. Expression levels of HMGA2 and 2SC, a robust indirect method to detect FH inactivation, were analysed by immunohistochemistry (IHC). The coding region of FH was sequenced in one adenomyoma sample showing strong 2SC staining as well as in the same patient's normal tissue sample. All patients' medical histories were collected and reviewed. MAIN RESULTS AND THE ROLE OF CHANCE: MED12 mutation c.131G > A, p.G44D, the most common mutation in uterine leiomyomas, was identified in two samples (2/21; 9.5%). One adenomyoma displayed strong 2SC positivity and subsequent sequencing revealed a frameshift FH mutation c.911delC, p.P304fs in the tumour. The mutation was also present in the patient's normal tissue sample, indicating that she has a hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome. HMGA2 protein expression was normal in all adenomyomas. LIMITATIONS REASONS FOR CAUTION: Restricted sample size limits the determination of exact mutation frequencies of the studied aberrations in adenomyomas. WIDER IMPLICATIONS OF THE FINDINGS: Uterine leiomyoma driver mutations do contribute to the development of some adenomyomas. We also report an adenomyoma in the context of hereditary HLRCC syndrome. Despite clinical similarities, the pathogenic mechanisms of adenomyomas and leiomyomas are likely different. Large-scale genomic analyses are warranted to elucidate the complete molecular background of adenomyomas. STUDY FUNDING/COMPETING INTERESTS: This study was supported by The Academy of Finland, the Sigrid Jusélius Foundation, and the Cancer Society of Finland. The authors declare no conflict of interest.

5.
Hum Mutat ; 38(3): 269-274, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28054750

RESUMO

MED12 is a key component of the transcription-regulating Mediator complex. Specific missense and in-frame insertion/deletion mutations in exons 1 and 2 have been identified in uterine leiomyomas, breast tumors, and chronic lymphocytic leukemia. Here, we characterize the first MED12 5' end nonsense mutation (c.97G>T, p.E33X) identified in acute lymphoblastic leukemia and show that it escapes nonsense-mediated mRNA decay (NMD) by using an alternative translation initiation site. The resulting N-terminally truncated protein is unable to enter the nucleus due to the lack of identified nuclear localization signal (NLS). The absence of NLS prevents the mutant MED12 protein to be recognized by importin-α and subsequent loading into the nuclear pore complex. Due to this mislocalization, all interactions between the MED12 mutant and other Mediator components are lost. Our findings provide new mechanistic insights into the MED12 functions and indicate that somatic nonsense mutations in early exons may avoid NMD.


Assuntos
Códon sem Sentido , Complexo Mediador/genética , Degradação do RNAm Mediada por Códon sem Sentido , Motivos de Nucleotídeos , Alelos , Sequência de Aminoácidos , Substituição de Aminoácidos , Análise Mutacional de DNA , Humanos , Biossíntese de Proteínas , Transporte de RNA
6.
J Med Genet ; 53(12): 800-811, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27595995

RESUMO

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


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Neoplasias da Mama/metabolismo , Quinase do Ponto de Checagem 2/genética , Predisposição Genética para Doença , Mutação , Proteínas Nucleares/genética , Neoplasias da Próstata/metabolismo , Proteínas Supressoras de Tumor/genética , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Estudos de Casos e Controles , Proteína do Grupo de Complementação N da Anemia de Fanconi , Feminino , Estudos de Associação Genética , Humanos , Masculino , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/genética , Risco
7.
Br J Cancer ; 114(12): 1405-11, 2016 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-27187686

RESUMO

BACKGROUND: Uterine leiomyomas from hereditary leiomyomatosis and renal cell cancer (HLRCC) patients are driven by fumarate hydratase (FH) inactivation or occasionally by mediator complex subunit 12 (MED12) mutations. The aim of this study was to analyse whether MED12 mutations and FH inactivation are mutually exclusive and to determine the contribution of MED12 mutations on HLRCC patients' myomagenesis. METHODS: MED12 exons 1 and 2 mutation screening and 2SC immunohistochemistry indicative for FH deficiency was performed on a comprehensive series of HLRCC patients' (122 specimens) and sporadic (66 specimens) tumours. Gene expression analysis was performed using Affymetrix GeneChip Human Exon Arrays (Affymetrix, Santa Clara, CA, USA). RESULTS: Nine tumours from HLRCC patients harboured a somatic MED12 mutation and were negative for 2SC immunohistochemistry. All remaining successfully analysed lesions (107/116) were deficient for FH. Of sporadic tumours, 35/64 were MED12 mutation positive and none displayed a FH defect. In global gene expression analysis FH-deficient tumours clustered together, whereas HLRCC patients' MED12 mutation-positive tumours clustered together with sporadic MED12 mutation-positive tumours. CONCLUSIONS: Somatic MED12 mutations and biallelic FH inactivation are mutually exclusive in both HLRCC syndrome-associated and sporadic uterine leiomyomas. The great majority of HLRCC patients' uterine leiomyomas are caused by FH inactivation, but incidental tumours driven by somatic MED12 mutations also occur. These MED12 mutation-positive tumours display similar expressional profiles with their sporadic counterparts and are clearly separate from FH-deficient tumours.


Assuntos
Biomarcadores Tumorais/genética , Fumarato Hidratase/metabolismo , Leiomioma/enzimologia , Leiomioma/genética , Complexo Mediador/genética , Neoplasias Uterinas/enzimologia , Neoplasias Uterinas/genética , Ativação Enzimática , Feminino , Mutação em Linhagem Germinativa , Humanos , Imuno-Histoquímica , Complexo Mediador/metabolismo , Mutação , Transcriptoma
8.
PLoS Genet ; 12(2): e1005850, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26891131

RESUMO

Uterine leiomyosarcomas (ULMSs) are aggressive smooth muscle tumors associated with poor clinical outcome. Despite previous cytogenetic and molecular studies, their molecular background has remained elusive. To examine somatic variation in ULMS, we performed exome sequencing on 19 tumors. Altogether, 43 genes were mutated in at least two ULMSs. Most frequently mutated genes included tumor protein P53 (TP53; 6/19; 33%), alpha thalassemia/mental retardation syndrome X-linked (ATRX; 5/19; 26%), and mediator complex subunit 12 (MED12; 4/19; 21%). Unlike ATRX mutations, both TP53 and MED12 alterations have repeatedly been associated with ULMSs. All the observed ATRX alterations were either nonsense or frameshift mutations. ATRX protein levels were reliably analyzed by immunohistochemistry in altogether 44 ULMSs, and the majority of tumors (23/44; 52%) showed clearly reduced expression. Loss of ATRX expression has been associated with alternative lengthening of telomeres (ALT), and thus the telomere length was analyzed with telomere-specific fluorescence in situ hybridization. The ALT phenotype was confirmed in all ULMSs showing diminished ATRX expression. Exome data also revealed one nonsense mutation in death-domain associated protein (DAXX), another gene previously associated with ALT, and the tumor showed ALT positivity. In conclusion, exome sequencing revealed that TP53, ATRX, and MED12 are frequently mutated in ULMSs. ALT phenotype was commonly seen in tumors, indicating that ATR inhibitors, which were recently suggested as possible new drugs for ATRX-deficient tumors, could provide a potential novel therapeutic option for ULMS.


Assuntos
DNA Helicases/genética , Leiomiossarcoma/genética , Complexo Mediador/genética , Proteínas Nucleares/genética , Proteína Supressora de Tumor p53/genética , Neoplasias Uterinas/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Idoso , Idoso de 80 Anos ou mais , Proteínas Correpressoras , Exoma , Feminino , Regulação Neoplásica da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Leiomiossarcoma/mortalidade , Pessoa de Meia-Idade , Chaperonas Moleculares , Taxa de Mutação , Homeostase do Telômero , Neoplasias Uterinas/mortalidade , Proteína Nuclear Ligada ao X
9.
Prostate ; 76(1): 22-31, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26383637

RESUMO

BACKGROUND: Mediator is a multiprotein interface between eukaryotic gene-specific transcription factors and RNA polymerase II. Mutations in exon 2 of the gene encoding MED12, a key subunit of the regulatory kinase module in Mediator, are extremely frequent in uterine leiomyomas, breast fibroadenomas, and phyllodes tumors. These mutations disrupt kinase module interactions and lead to diminished Mediator-associated kinase activity. MED12 mutations in exon 26, resulting in a substitution of leucine 1224 to phenylalanine (L1224F), have been recurrently observed in prostate cancer. METHODS: To elucidate the molecular mechanisms leading to tumorigenesis in prostate cancer, we analyzed global interaction profiles of wild-type and L1224F mutant MED12 with quantitative affinity purification-mass spectrometry (AP-MS). Immunoprecipitation and kinase activity assay were used to further assess the interactions between Mediator complex subunits and kinase activity. The presence of L1224F mutation was analyzed in altogether 877 samples representing prostate hyperplasia, prostate cancer, and various tumor types in which somatic MED12 mutations have previously been observed. RESULTS: In contrast to N-terminal MED12 mutations observed in uterine leiomyomas, the L1224F mutation compromises neither the interaction of MED12 with kinase module subunits Cyclin C and CDK8/19 nor Mediator-associated CDK activity. Instead, the L1224F mutation was shown to affect interactions between MED12 and other Mediator components (MED1, MED13, MED13L, MED14, MED15, MED17, and MED24). Mutation screening revealed one mutation in a Finnish (Caucasian) prostate cancer patient, whereas no mutations in any other tumor type were observed. CONCLUSIONS: Specific somatic MED12 mutations in prostate cancer and uterine leiomyomas accumulate in two separate regions of the gene and promote tumorigenesis through clearly distinct mechanisms.


Assuntos
Leiomioma , Complexo Mediador/genética , Neoplasias da Próstata , Neoplasias Uterinas , Idoso , Carcinogênese/genética , Transformação Celular Neoplásica/genética , Feminino , Humanos , Leiomioma/genética , Leiomioma/patologia , Masculino , Espectrometria de Massas/métodos , Pessoa de Meia-Idade , Mutação , Estadiamento de Neoplasias , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Fatores de Transcrição/genética , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologia
10.
Oncotarget ; 6(10): 7390-407, 2015 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-25823661

RESUMO

We have utilized a two-stage study design to search for SNPs associated with the survival of breast cancer patients treated with adjuvant chemotherapy. Our initial GWS data set consisted of 805 Finnish breast cancer cases (360 treated with adjuvant chemotherapy). The top 39 SNPs from this stage were analyzed in three independent data sets: iCOGS (n=6720 chemotherapy-treated cases), SUCCESS-A (n=3596), and POSH (n=518). Two SNPs were successfully validated: rs6500843 (any chemotherapy; per-allele HR 1.16, 95% C.I. 1.08-1.26, p=0.0001, p(adjusted)=0.0091), and rs11155012 (anthracycline therapy; per-allele HR 1.21, 95% C.I. 1.08-1.35, p=0.0010, p(adjusted)=0.0270). The SNP rs6500843 was found to specifically interact with adjuvant chemotherapy, independently of standard prognostic markers (p(interaction)=0.0009), with the rs6500843-GG genotype corresponding to the highest hazard among chemotherapy-treated cases (HR 1.47, 95% C.I. 1.20-1.80). Upon trans-eQTL analysis of public microarray data, the rs6500843 locus was found to associate with the expression of a group of genes involved in cell cycle control, notably AURKA, the expression of which also exhibited differential prognostic value between chemotherapy-treated and untreated cases in our analysis of microarray data. Based on previously published information, we propose that the eQTL genes may be connected to the rs6500843 locus via a RBFOX1-FOXM1 -mediated regulatory pathway.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antraciclinas/administração & dosagem , Neoplasias da Mama/mortalidade , Neoplasias da Mama/cirurgia , Quimioterapia Adjuvante , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Feminino , Estudo de Associação Genômica Ampla , Humanos , Pessoa de Meia-Idade , Análise Multivariada , Polimorfismo de Nucleotídeo Único , Prognóstico , Locos de Características Quantitativas , Análise de Sobrevida , Taxoides/administração & dosagem , Adulto Jovem
11.
Oncotarget ; 6(3): 1884-8, 2015 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-25595892

RESUMO

Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. We performed systematic database search and identified highly specific MED12 mutations in CLL patients. To study this further, we collected three independent sample series comprising over 700 CLL samples and screened MED12 exons 1 and 2 by direct sequencing. Mutations were identified at significant frequency in all three series with a combined mutation frequency of 5.2% (37/709). Positive mutation status was found to be associated with unmutated IGHV and ZAP70 expression, which are well-known poor prognosis markers in CLL. Our results recognize CLL as the first extrauterine cancer type where 5'terminus of MED12 is mutated at significant frequency. Functional analyses have shown that these mutations lead to dissociation of Cyclin C-CDK8/19 from the core Mediator and to the loss of Mediator-associated CDK kinase activity. Additional studies on the role of MED12 mutation status as a putative prognostic factor as well as mutations' exact tumorigenic mechanism in CLL are warranted.


Assuntos
Leucemia Linfocítica Crônica de Células B/genética , Complexo Mediador/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Aminoácidos , Feminino , Humanos , Complexo Mediador/genética , Pessoa de Meia-Idade , Dados de Sequência Molecular , Mutação , Prognóstico
12.
PLoS One ; 9(11): e109973, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25390939

RESUMO

Genetic variations, such as single nucleotide polymorphisms (SNPs) in microRNAs (miRNA) or in the miRNA binding sites may affect the miRNA dependent gene expression regulation, which has been implicated in various cancers, including breast cancer, and may alter individual susceptibility to cancer. We investigated associations between miRNA related SNPs and breast cancer risk. First we evaluated 2,196 SNPs in a case-control study combining nine genome wide association studies (GWAS). Second, we further investigated 42 SNPs with suggestive evidence for association using 41,785 cases and 41,880 controls from 41 studies included in the Breast Cancer Association Consortium (BCAC). Combining the GWAS and BCAC data within a meta-analysis, we estimated main effects on breast cancer risk as well as risks for estrogen receptor (ER) and age defined subgroups. Five miRNA binding site SNPs associated significantly with breast cancer risk: rs1045494 (odds ratio (OR) 0.92; 95% confidence interval (CI): 0.88-0.96), rs1052532 (OR 0.97; 95% CI: 0.95-0.99), rs10719 (OR 0.97; 95% CI: 0.94-0.99), rs4687554 (OR 0.97; 95% CI: 0.95-0.99, and rs3134615 (OR 1.03; 95% CI: 1.01-1.05) located in the 3' UTR of CASP8, HDDC3, DROSHA, MUSTN1, and MYCL1, respectively. DROSHA belongs to miRNA machinery genes and has a central role in initial miRNA processing. The remaining genes are involved in different molecular functions, including apoptosis and gene expression regulation. Further studies are warranted to elucidate whether the miRNA binding site SNPs are the causative variants for the observed risk effects.


Assuntos
Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , MicroRNAs/genética , Polimorfismo de Nucleotídeo Único , Regiões 3' não Traduzidas , Sítios de Ligação , Estudos de Casos e Controles , Mapeamento Cromossômico , Biologia Computacional , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Receptores Estrogênicos/metabolismo
13.
N Engl J Med ; 371(6): 497-506, 2014 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-25099575

RESUMO

BACKGROUND: Germline loss-of-function mutations in PALB2 are known to confer a predisposition to breast cancer. However, the lifetime risk of breast cancer that is conferred by such mutations remains unknown. METHODS: We analyzed the risk of breast cancer among 362 members of 154 families who had deleterious truncating, splice, or deletion mutations in PALB2. The age-specific breast-cancer risk for mutation carriers was estimated with the use of a modified segregation-analysis approach that allowed for the effects of PALB2 genotype and residual familial aggregation. RESULTS: The risk of breast cancer for female PALB2 mutation carriers, as compared with the general population, was eight to nine times as high among those younger than 40 years of age, six to eight times as high among those 40 to 60 years of age, and five times as high among those older than 60 years of age. The estimated cumulative risk of breast cancer among female mutation carriers was 14% (95% confidence interval [CI], 9 to 20) by 50 years of age and 35% (95% CI, 26 to 46) by 70 years of age. Breast-cancer risk was also significantly influenced by birth cohort (P<0.001) and by other familial factors (P=0.04). The absolute breast-cancer risk for PALB2 female mutation carriers by 70 years of age ranged from 33% (95% CI, 25 to 44) for those with no family history of breast cancer to 58% (95% CI, 50 to 66) for those with two or more first-degree relatives with breast cancer at 50 years of age. CONCLUSIONS: Loss-of-function mutations in PALB2 are an important cause of hereditary breast cancer, with respect both to the frequency of cancer-predisposing mutations and to the risk associated with them. Our data suggest the breast-cancer risk for PALB2 mutation carriers may overlap with that for BRCA2 mutation carriers. (Funded by the European Research Council and others.).


Assuntos
Neoplasias da Mama/congênito , Genes BRCA2 , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Proteínas Nucleares/genética , Proteínas Supressoras de Tumor/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/genética , Proteína do Grupo de Complementação N da Anemia de Fanconi , Feminino , Heterozigoto , Humanos , Pessoa de Meia-Idade , Receptor ErbB-2/análise , Receptores Estrogênicos/análise , Receptores de Progesterona/análise , Risco , Deleção de Sequência
14.
Breast Cancer Res Treat ; 144(2): 437-41, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24562772

RESUMO

Hereditary predisposition to breast cancer is largely affected by the mutations in the genes of the DNA repair pathways. Novel genes involved in DNA repair are therefore prospective candidates also for breast cancer susceptibility genes. The RHINO (Rad9, Rad1, Hus1-interacting nuclear orphan) gene plays a central role in DNA damage response and in cell cycle regulation. RHINO interacts with Rad9-Rad1-Hus1 (9-1-1) complex and with ATR activator TopBP1, which recruit it to the site of DNA damage. We analyzed the effects of the germline variation in RHINO on breast cancer risk. We sequenced the coding region of the RHINO gene 466 index cases of Finnish breast cancer families and in 507 population controls. The genotypes of the most likely functional variant were further determined in a large dataset of 2,944 cases and 1,976 controls. We analyzed the common variation of the RHINO locus and determined the haplotypes using five SNPs in 1,531 cases and 1,233 controls. We identified seven variants including four missense variations, a 5' UTR variant, a silent variant, and a nonsense variant c.250C>T, R84X (rs140887418). All variants were also present in control individuals with frequencies close to those of the cases (P > 0.05). The c.250C>T variant was present in 12 breast cancer patients (0.4 %) and of 16 controls (0.8 %) with the difference not statistically significant (OR = 0.50, 95 %CI: 0.24-1.06, P = 0.066). The haplotype frequencies did not differ in cases and controls (P = 0.59). Germline variation in the RHINO gene is unlikely to influence inherited susceptibility to breast cancer.


Assuntos
Proteínas de Transporte/genética , Mutação em Linhagem Germinativa , Neoplasias da Mama/sangue , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Estudos de Casos e Controles , Dano ao DNA , Expansão das Repetições de DNA , Feminino , Finlândia/epidemiologia , Predisposição Genética para Doença , Genótipo , Humanos , Mutação de Sentido Incorreto
15.
BMC Syst Biol ; 7 Suppl 1: S2, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24267921

RESUMO

BACKGROUND: Cancers are complex diseases arising from accumulated genetic mutations that disrupt intracellular signaling networks. While several predisposing genetic mutations have been found, these individual mutations account only for a small fraction of cancer incidence and mortality. With large-scale measurement technologies, such as single nucleotide polymorphism (SNP) microarrays, it is now possible to identify combinatorial effects that have significant impact on cancer patient survival. RESULTS: The identification of synergetic functioning SNPs on genome-scale is a computationally daunting task and requires advanced algorithms. We introduce a novel algorithm, Geninter, to identify SNPs that have synergetic effect on survival of cancer patients. Using a large breast cancer cohort we generate a simulator that allows assessing reliability and accuracy of Geninter and logrank test, which is a standard statistical method to integrate genetic and survival data. CONCLUSIONS: Our results show that Geninter outperforms the logrank test and is able to identify SNP-pairs with synergetic impact on survival.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Simulação por Computador , Marcadores Genéticos , Genótipo , Humanos , Modelos Genéticos , Polimorfismo de Nucleotídeo Único
16.
Breast Cancer Res Treat ; 141(1): 79-88, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23974830

RESUMO

Abnormal translation of mRNAs frequently occurring during carcinogenesis is among the mechanisms that can affect the expression of proteins involved in tumor development and progression. Eukaryotic initiation factor eIF4E is a key regulator of translation of many cancer-related transcripts and its expression is altered in various cancers and has been associated with worse survival. We determined the eIF4E protein levels using immunohistochemistry (IHC) in 1,233 breast tumors on tissue microarrays. We analyzed the effects of the IHC expression level on tumor characteristics and patient survival, also with stratification by adjuvant chemotherapy treatment. In 1,085 successfully stained tumors, high level of eIF4E protein expression was associated with features of aggressive tumor phenotype, namely grade, estrogen and progesterone receptor negativity, HER2 receptor positivity, and high expression of p53 and Ki67, and with triple negative subtype (p < 0.001). High eIF4E expression was associated with worse breast cancer-specific survival with a hazard ratio (HR) of 1.99 (95 % CI 1.32-3.00, p = 0.0008) and was in a multivariate analysis an independent prognostic factor. High eIF4E expression was associated with worse outcome also after detection of distant metastasis (HR = 1.88, 95 % CI 1.20-2.94, p = 0.0060). In the subgroup analysis the survival effect was strongest among patients treated with anthracycline chemotherapy (HR = 3.34, 95 % CI 1.72-6.48, p = 0.0002), whereas no such effect was seen among patients who had not received anthracycline with significant difference in heterogeneity between the two groups (p = 0.0358). High expression of eIF4E is associated with adverse tumor characteristics and predicts poor breast cancer-specific survival. This effect is emphasized in patients treated with anthracycline chemotherapy. eIF4E as a treatment predictive factor warrants further studies.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/química , Carcinoma/química , Fator de Iniciação 4E em Eucariotos/análise , Regulação Neoplásica da Expressão Gênica , Proteínas de Neoplasias/análise , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Biomarcadores Tumorais/análise , Neoplasias da Mama/classificação , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Carcinoma/classificação , Carcinoma/tratamento farmacológico , Carcinoma/mortalidade , Carcinoma/patologia , Carcinoma/terapia , Quimioterapia Adjuvante , Ciclofosfamida/administração & dosagem , Citarabina/administração & dosagem , Doxorrubicina/administração & dosagem , Epirubicina/administração & dosagem , Fator de Iniciação 4E em Eucariotos/biossíntese , Fator de Iniciação 4E em Eucariotos/genética , Feminino , Humanos , Estimativa de Kaplan-Meier , Gradação de Tumores , Invasividade Neoplásica , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Inclusão em Parafina , Fenótipo , Prognóstico , Biossíntese de Proteínas , Análise Serial de Tecidos , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/química , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologia
17.
Breast ; 22(5): 817-23, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23489758

RESUMO

We assessed whether variants in 22 oxidative stress-related genes are associated with mortality of breast cancer patients and whether the associations differ according to radiotherapy. Using a prospective cohort of 1348 postmenopausal breast cancer patients, we estimated hazard ratios (HR) and 95% confidence intervals (CI) for 109 single nucleotide polymorphisms (SNPs) using Cox proportional hazards regression. Validation of results was attempted using two Scandinavian studies. Eleven SNPs in MT2A, NFE2L2, NQO1, PRDX1, and PRDX6 were significantly associated with overall mortality after a median follow-up of 5.7 years. Three SNPs in NQO1 (rs2917667) and in PRDX6 (rs7314, rs4916362) were consistently associated with increased risk of dying across all three study populations (pooled: HRNQO1_rs2917667 1.20, 95% CI 1.00-1.44, p = 0.051; HRPRDX6_rs7314 1.16, 95% CI 1.00-1.35, p = 0.056, HRPRDX6_rs4916362 1.14 95% CI 1.00-1.32, p = 0.062). Potential effect modification by radiotherapy was found for CAT_rs769218. In conclusion, genetic variants in NQO1 and PRDX6 may modify breast cancer prognosis.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Estresse Oxidativo/genética , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/radioterapia , Catalase/genética , Feminino , Genótipo , Histona Desacetilases/genética , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , NAD(P)H Desidrogenase (Quinona)/genética , Fator 2 Relacionado a NF-E2/genética , Peroxirredoxina VI/genética , Peroxirredoxinas/genética , Polimorfismo de Nucleotídeo Único , Prognóstico , Estudos Prospectivos , Proteínas Repressoras/genética
18.
Int J Cancer ; 132(9): 2044-55, 2013 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-23034890

RESUMO

Germline variation in the TP53 network genes PRKAG2, PPP2R2B, CCNG1, PIAS1 and YWHAQ was previously suggested to have an impact on drug response in vitro. Here, we investigated the effect on breast cancer survival of germline variation in these genes in 925 Finnish breast cancer patients and further analyzed five single nucleotide polymorphisms (SNPs) in PRKAG2 (rs1029946, rs4726050, rs6464153, rs7789699) and PPP2R2B (rs10477313) for 10-year survival in breast cancer patients, interaction with TP53 R72P and MDM2-SNP309, outcome after specific adjuvant therapy and correlation to tumor characteristics in 4,701 invasive cases from four data sets. We found evidence for carriers of PRKAG2-rs1029946 and PRKAG2-rs4726050 having improved survival in the pooled data (HR 0.53, 95% CI 0.3-0.9; p = 0.023 for homozygous carriers of the rare G-allele and HR 0.85, 95% CI 0.7-0.9; p = 0.049 for carriers of the rare G allele, respectively). PRKAG2-rs4726050 showed a significant interaction with MDM2-SNP309, with PRKAG2-rs4726050 rare G-allele having a dose-dependent effect for better breast cancer survival confined only to MDM2 SNP309 rare G-allele carriers (HR 0.45, 95% CI 0.2-0.7; p = 0.001). This interaction also emerged as an independent predictor of better survival (p = 0.047). PPP2R2B-rs10477313 rare A-allele was found to predict better survival (HR 0.82, 95% CI 0.6-0.9; p = 0.018), especially after hormonal therapy (HR 0.66, 95% CI 0.5-0.9; p = 0.048). These findings warrant further studies and suggest that genetic markers in TP53 network genes such as PRKAG2 and PPP2R2B might affect prognosis and treatment outcome in breast cancer patients.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/genética , Carcinoma Ductal de Mama/genética , Carcinoma Lobular/genética , Redes Reguladoras de Genes/genética , Mutação em Linhagem Germinativa/genética , Proteína Supressora de Tumor p53/genética , Proteínas Quinases Ativadas por AMP/genética , Adulto , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/mortalidade , Carcinoma Lobular/tratamento farmacológico , Carcinoma Lobular/mortalidade , Feminino , Genótipo , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Invasividade Neoplásica , Metástase Neoplásica , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único/genética , Prognóstico , Proteína Fosfatase 2/genética , Proteínas Proto-Oncogênicas c-mdm2/genética , RNA Mensageiro/genética , RNA Neoplásico/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Taxa de Sobrevida
19.
Twin Res Hum Genet ; 15(5): 615-623, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22794196

RESUMO

Recent Genome-Wide Association Studies (GWAS) have identified four low-penetrance ovarian cancer susceptibility loci. We hypothesized that further moderate- or low-penetrance variants exist among the subset of single-nucleotide polymorphisms (SNPs) not well tagged by the genotyping arrays used in the previous studies, which would account for some of the remaining risk. We therefore conducted a time- and cost-effective stage 1 GWAS on 342 invasive serous cases and 643 controls genotyped on pooled DNA using the high-density Illumina 1M-Duo array. We followed up 20 of the most significantly associated SNPs, which are not well tagged by the lower density arrays used by the published GWAS, and genotyping them on individual DNA. Most of the top 20 SNPs were clearly validated by individually genotyping the samples used in the pools. However, none of the 20 SNPs replicated when tested for association in a much larger stage 2 set of 4,651 cases and 6,966 controls from the Ovarian Cancer Association Consortium. Given that most of the top 20 SNPs from pooling were validated in the same samples by individual genotyping, the lack of replication is likely to be due to the relatively small sample size in our stage 1 GWAS rather than due to problems with the pooling approach. We conclude that there are unlikely to be any moderate or large effects on ovarian cancer risk untagged by less dense arrays. However, our study lacked power to make clear statements on the existence of hitherto untagged small-effect variants.


Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Neoplasias Ovarianas/genética , Polimorfismo de Nucleotídeo Único , Idoso , Austrália , Estudos de Casos e Controles , Feminino , Humanos , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Tamanho da Amostra
20.
Hum Pathol ; 43(9): 1363-75, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22204715

RESUMO

Tumor biomarkers increasingly provide information for predicting outcomes with chemotherapeutic regimens (personalized medicine). Topo2A is a DNA helicase targeted by anthracyclines, cytotoxic therapeutics used in both adjuvant and palliative treatments of breast cancer. TOP2A gene amplification/deletion is implicated in response to anthracycline-based chemotherapy. We describe an approach for analyzing formalin-fixed, paraffin-embedded breast tumors on tissue microarrays with TOP2A fluorescence in situ hybridization coupled with cytokeratin immunofluorescence to target tumor cells. Stained tissue from patient specimens was imaged and analyzed using Metafer/Metacyte (Metasystems, Waltham, MA, USA), including customized image classifiers. TOP2A/CEN17 ratios of 2.0 or greater (amplified) and 0.8 or less (deleted) were observed for 10.0% and 6.1% of the patients, respectively. Patient outcomes for adjuvant chemotherapy (cyclophosphamide-epirubicin-fluorouracil, cyclophosphamide-methotrexate-fluorouracil, no chemotherapy) were evaluated. No statistical significance was achieved for clinical end points regarding TOP2A status in anthracycline-treated patients. However, patients with TOP2A aberrations receiving methotrexate-based therapy exhibited a significant decrease in 5-year distant disease-free survival and breast cancer-specific overall survival, especially for patients with TOP2A deletions (disease-free survival: hazard ratio, 5.31 [P = .001], and breast cancer-specific overall survival: hazard ratio, 6.45 [P ≤ .001]). No significant differences were seen in patients included in the no-chemotherapy group. Topo2A protein levels were assessed by immunohistochemistry with no correlative statistical relevance to immunofluorescence/fluorescence in situ hybridization-based prognosis for cyclophosphamide-epirubicin-fluorouracil or cyclophosphamide-methotrexate-fluorouracil groups. Interestingly, aberrant (under)expressing patients in the no-chemotherapy group exhibited better 5-year distant disease-free survival (hazard ratio, 0.39; P = .004), trending toward more favorable breast cancer-specific overall survival (hazard ratio, 0.61; P = .11). Our results indicate a strategy by which fluorescence in situ hybridization scoring targeted to cytokeratin-positive tumor cells may provide a tool for added precision and efficiency in TOP2A evaluation from tumor tissue.


Assuntos
Antígenos de Neoplasias/genética , Neoplasias da Mama/genética , DNA Topoisomerases Tipo II/genética , Proteínas de Ligação a DNA/genética , Queratinas/genética , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Ciclofosfamida/uso terapêutico , Intervalo Livre de Doença , Feminino , Fluoruracila/uso terapêutico , Humanos , Hibridização in Situ Fluorescente , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Proteínas de Ligação a Poli-ADP-Ribose , Análise Serial de Tecidos , Resultado do Tratamento
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