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1.
Mol Genet Genomic Med ; : e913, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31568710

RESUMO

BACKGROUND: Retinoblastoma (Rb) is a rare intraocular malignant tumor in children with high overall survival. Predisposition to Rb is linked to RB1 germline mutations with high penetrance, but rare RB1 low-penetrance variants are also known. Rb survivors are at risk of second primary malignancies (SPMs), mostly osteosarcoma and soft-tissue sarcoma. Nevertheless, the risk of primary osteosarcoma developing without prior Rb has not been reported in RB1 germline mutation carriers. METHODS: We report a patient in whom osteosarcoma developed at age 17 as a first primary malignancy within a family context of sarcoma. RESULTS: Unexpectedly, genetic testing identified a low-penetrance germline mutation in RB1 [NM_000321.2: c.45_76dup; p.(Pro26Leufs*50)]. In eight additional similar cases from published and unpublished reports of families, first primary osteosarcomas and sarcomas mostly developed in RB1 low-penetrance mutation carriers without prior Rb. CONCLUSION: We propose that first primary sarcoma and osteosarcoma could be a novel clinical presentation of a RB1-related hereditary predisposition syndrome linked to RB1 low-penetrance germline mutations. In these families, careful screening of primary non-Rb cancer and SPMs is required by maintaining enhanced clinical vigilance. Implementing lifelong periodic whole-body MRI screening might be a complementary strategy for unaffected carrier relatives in these families.

2.
Bull Cancer ; 2019 Oct 11.
Artigo em Francês | MEDLINE | ID: mdl-31610911

RESUMO

Inactivating germline pathogenic variants of the DICER1 gene are responsible for a spectrum of rare diseases, which expanded a lot in recent years. The constitution of an U.S. registry with these patients and their families as well as the registration of patients in European databases of rare tumors helped to better identify diseases encountered in this syndrome but also to study its pathophysiology (major role in miRNA maturation and recently discovered functions, e.g. in genome integrity maintenance). Most encountered disorders are pediatric malignancies, mainly the pulmonary pneumoblastoma and Sertoli-Leydig tumours. However, benign pathologies such as thyroid goiters, cystic nephromas or pulmonary cystic lesions are also frequently reported. Homogeneous guidelines regimens written by the European groups working on very rare pediatric tumors are proposed but it is important to underscore that they rely on rare scientific data; therefore overall consensus remains precarious. The genetic counseling to families is still difficult due to the large observed spectrum of tumors and the incomplete penetrance. In this article, the authors update current knowledge on the DICER1 syndrome.

3.
Bull Cancer ; 106(2): 162-172, 2019 Feb.
Artigo em Francês | MEDLINE | ID: mdl-30551794

RESUMO

Inherited mono-allelic mutation in one of the 4 major MMR genes results in Lynch syndrome which predisposes, in adulthood, mainly to colorectal and endometrial tumors characterized by microsatellite instability (MSI phenotype). Individuals with bi-allelic mutations of one of these genes developed early and multiple malignancies, most often in childhood. This recessively inherited condition is named CMMRD for Constitutional Mismatch Repair Deficiency. The spectrum of tumors is distinct from Lynch syndrome. Malignant brain tumors are at least as frequent as gastrointestinal tumors and in more than a third of cases haematological malignancies were also reported. Patients also displayed clinical features similar of neurofibromatosis type 1, especially café au lait spots. The most commonly involved genes are PMS2 and MSH6 while bi-allelic MLH1 and MSH2 mutations are rare. The digestive tumors of these patients show MSI whereas the brain tumors can be "microsatellite stable". Because of variable clinical presentation and phenotypical overlaps with other cancer syndromes, CMMRD syndrome is frequently unrecognized by clinicians and its incidence is almost certainly underestimated. A better knowledge of clinical criteria and diagnosis methods should improve the identification of these patients at least at the time when they develop their first tumor or even before. This will allow adjusting treatment modalities and offering surveillance strategies of other tumor risks, not only for patients themselves but also for their relatives.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA , Instabilidade de Microssatélites , Neoplasias Encefálicas/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais Hereditárias sem Polipose/terapia , Proteínas de Ligação a DNA/genética , Neoplasias Gastrointestinais/genética , Neoplasias Hematológicas/genética , Humanos , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Proteína 1 Homóloga a MutL/genética , Proteína 2 Homóloga a MutS/genética , Mutação/genética , Síndromes Neoplásicas Hereditárias/genética , Neurofibromatose 1/genética , Linhagem
5.
Eur J Med Genet ; 2018 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-30031154

RESUMO

Retinoblastoma (Rb) results from biallelic inactivation of the RB1 gene. Hereditary Rb patients i. e germline carriers of a RB1 mutation also have a risk of developing subsequent malignant neoplasms (SMN) such as osteosarcomas. This SMN risk is maximized by external beam radiotherapy treatments (EBRT), which is why these treatments are now avoided. Nevertheless, EBRT is still a matter of great concern, as EBRT-treated patients are in their adulthood and SMNs remain the major cause of death for patients. To decipher the relationship between RB1 genotype and SMN development in EBRT treated patients, we conducted a retrospective study in a cohort of 160 irradiated hereditary Rbs with fully resolved RB1 mutational status. Median follow-up was 22 years [1-51] and median age of patients was 27 years old [7-53]. Among these 160 Rb patients, 120 did not develop any SMN (75%) and 40 developed SMNs (25%). The age at which EBRT is given (i.e. before or after the age of 12 months) was not correlated to SMN development (p = 0.6). We didn't find any difference in RB1 mutation type between patients with or without SMN, neither could we detect any linkage between mutation type and SMN location, SMN type and age at diagnosis. Interestingly, among 13 carriers of a RB1 low penetrance mutation, 3 of them developed sarcomas, a rare tumor that cannot be attributed to the general population. Our study cannot explain why a RB1 mutation leads or not to a SMN but demonstrated that EBRT patients with a low penetrance mutation remain at risk of SMN and should be cautiously monitored.

7.
Breast Cancer Res ; 20(1): 28, 2018 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-29665859

RESUMO

BACKGROUND: The ataxia telangiectasia mutated (ATM) gene is a moderate-risk breast cancer susceptibility gene; germline loss-of-function variants are found in up to 3% of hereditary breast and ovarian cancer (HBOC) families who undergo genetic testing. So far, no clear histopathological and molecular features of breast tumours occurring in ATM deleterious variant carriers have been described, but identification of an ATM-associated tumour signature may help in patient management. METHODS: To characterise hallmarks of ATM-associated tumours, we performed systematic pathology review of tumours from 21 participants from ataxia-telangiectasia families and 18 participants from HBOC families, as well as copy number profiling on a subset of 23 tumours. Morphology of ATM-associated tumours was compared with that of 599 patients with no BRCA1 and BRCA2 mutations from a hospital-based series, as well as with data from The Cancer Genome Atlas. Absolute copy number and loss of heterozygosity (LOH) profiles were obtained from the OncoScan SNP array. In addition, we performed whole-genome sequencing on four tumours from ATM loss-of-function variant carriers with available frozen material. RESULTS: We found that ATM-associated tumours belong mostly to the luminal B subtype, are tetraploid and show LOH at the ATM locus at 11q22-23. Unlike tumours in which BRCA1 or BRCA2 is inactivated, tumours arising in ATM deleterious variant carriers are not associated with increased large-scale genomic instability as measured by the large-scale state transitions signature. Losses at 13q14.11-q14.3, 17p13.2-p12, 21p11.2-p11.1 and 22q11.23 were observed. Somatic alterations at these loci may therefore represent biomarkers for ATM testing and harbour driver mutations in potentially 'druggable' genes that would allow patients to be directed towards tailored therapeutic strategies. CONCLUSIONS: Although ATM is involved in the DNA damage response, ATM-associated tumours are distinct from BRCA1-associated tumours in terms of morphological characteristics and genomic alterations, and they are also distinguishable from sporadic breast tumours, thus opening up the possibility to identify ATM variant carriers outside the ataxia-telangiectasia disorder and direct them towards effective cancer risk management and therapeutic strategies.

8.
Pediatr Blood Cancer ; 65(6): e27005, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29469200

RESUMO

Germline DICER1 pathogenic variants predispose to numerous benign and malignant tumors. In this report, we describe DICER1 gene analysis in an adolescent diagnosed with multinodular goiter, ovarian Sertoli-Leydig cell tumor, and lung cyst. DICER1 mutational screening at the DNA level failed to detect any pathogenic variant. Subsequent messenger RNA (mRNA) analysis revealed a 132 nucleotide intronic sequence exonization. This truncating event was caused by a deep intronic mutation generating a de novo acceptor splice site. This study demonstrates that some undetected DICER1 mutations should be investigated at the mRNA level.

9.
Eur J Hum Genet ; 25(12): 1345-1353, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29255180

RESUMO

RAD51 paralogs (RAD51B, RAD51C, RAD51D, XRCC2, and XRCC3) have recently been involved in breast and ovarian cancer predisposition: RAD51B, RAD51C, and RAD51D in ovarian cancer, RAD51B and XRCC2 in breast cancer. The aim of this study was to estimate the contribution of deleterious variants in the five RAD51 paralogs to breast and ovarian cancers. The five RAD51 paralog genes were analyzed by next-generation sequencing technologies in germline DNA from 2649 consecutive patients diagnosed with breast and/or ovarian cancer. Twenty-one different deleterious variants were identified in the RAD51 paralogs in 30 patients: RAD51B (n = 4), RAD51C (n = 12), RAD51D (n = 7), XRCC2 (n = 2), and XRCC3 (n = 5). The overall deleterious variant rate was 1.13% (95% confidence interval (CI): 0.72-1.55%) (30/2649), including 15 variants in breast cancer only cases (15/2063; 0.73% (95% CI: 0.34-1.11%)) and 15 variants in cases with at least one ovarian cancer (15/570; 2.63% (95% CI: 1.24-4.02%)). This study is the first evaluation of the five RAD51 paralogs in breast and ovarian cancer predisposition and it demonstrates that deleterious variants can be present in breast cancer only cases. Moreover, this is the first time that XRCC3 deleterious variants have been identified in breast and ovarian cancer cases.


Assuntos
Neoplasias da Mama/genética , Neoplasias Ovarianas/genética , Rad51 Recombinase/genética , Adulto , Idoso , Neoplasias da Mama/patologia , Proteínas de Ligação a DNA/genética , Feminino , Mutação em Linhagem Germinativa , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia
10.
J Med Genet ; 54(9): 607-612, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28592523

RESUMO

BACKGROUND: Sarcomas are rare mesenchymal malignancies whose pathogenesis is poorly understood; both environmental and genetic risk factors could contribute to their aetiology. METHODS AND RESULTS: We performed whole-exome sequencing (WES) in a familial aggregation of three individuals affected with soft-tissue sarcoma (STS) without TP53 mutation (Li-Fraumeni-like, LFL) and found a shared pathogenic mutation in CDKN2A tumour suppressor gene. We searched for individuals with sarcoma among 474 melanoma-prone families with a CDKN2A-/+ genotype and for CDKN2A mutations in 190 TP53-negative LFL families where the index case was a sarcoma. Including the initial family, eight independent sarcoma cases carried a germline mutation in the CDKN2A/p16INK4A gene. In five out of seven formalin-fixed paraffin-embedded sarcomas, heterozygosity was lost at germline CDKN2A mutations sites demonstrating complete loss of function. As sarcomas are rare in CDKN2A/p16INK4A carriers, we searched in constitutional WES of nine carriers for potential modifying rare variants and identified three in platelet-derived growth factor receptor (PDGFRA) gene. Molecular modelling showed that two never-described variants could impact the PDGFRA extracellular domain structure. CONCLUSION: Germline mutations in CDKN2A/P16INK4A, a gene known to predispose to hereditary melanoma, pancreatic cancer and tobacco-related cancers, account also for a subset of hereditary sarcoma. In addition, we identified PDGFRA as a candidate modifier gene.


Assuntos
Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor de Quinase Dependente de Ciclina p18/genética , Genes p16 , Mutação em Linhagem Germinativa , Sarcoma/genética , Neoplasias de Tecidos Moles/genética , Feminino , Determinismo Genético , Predisposição Genética para Doença , Heterozigoto , Humanos , Masculino , Linhagem , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Sequenciamento Completo do Exoma
11.
Eur J Hum Genet ; 25(3): 381-383, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28000698

RESUMO

In sporadic cases, a post-zygotic mutational event signifies a somatic mosaicism in the affected child only, which implies that these mutations affect only a portion of the body. Therefore siblings do not need follow-up. On the other hand, a pre-zygotic mutation transmitted by an unaffected mosaic parent implies recurrent risks in offspring. To better estimate the contribution of pre- and post-zygotic events, we analysed 124 consecutive bilateral retinoblastoma probands, carrying a heterozygous RB1 pathogenic variant and their unaffected, non-carrier parents. In order to evaluate somatic mosaicism in blood, the deleterious RB1 pathogenic variant identified in the proband, was searched for in the unaffected parents, using targeted deep sequencing. Observed recurrences, which represent an estimation of germline and somatic mosaicisms, were recorded and computed in the sibships. Deep sequencing revealed one mosaic-unaffected parent out of 124 tested couples, which provides an estimation of the maximal risk of recurrence, due to parental mosaicism, at 0.4%. Follow-up in the sibships showed one recurrence, providing a maximal recurrence risk, due to parental mosaicism, at 0.8%. Two different statistical strategies led to close estimates (0.4 and 0.8% risks) which appeared 266-533-fold higher, as compared with the general population. These recurrence estimates could be considered when counselling couples with retinoblastoma or diseases with a high de novo mutation rate.


Assuntos
Testes Genéticos/métodos , Mosaicismo , Diagnóstico Pré-Natal/métodos , Proteínas de Ligação a Retinoblastoma/genética , Retinoblastoma/genética , Ubiquitina-Proteína Ligases/genética , Aconselhamento Genético/métodos , Mutação em Linhagem Germinativa , Heterozigoto , Humanos , Taxa de Mutação , Pais , Retinoblastoma/diagnóstico , Irmãos
12.
PLoS One ; 11(7): e0158801, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27463617

RESUMO

Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA1 and BRCA 2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95%CI: 0.68 to 0.79, p-value 2× 10-16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95%CI: 0.59 to 0.80, p-value 1.0 × 10-6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population.


Assuntos
Cromossomos Humanos Par 9 , Genes BRCA1 , Genes BRCA2 , Triagem de Portadores Genéticos , Predisposição Genética para Doença , Neoplasias Ovarianas/genética , Mapeamento Cromossômico , Feminino , Humanos , Polimorfismo de Nucleotídeo Único
13.
PLoS Genet ; 12(2): e1005888, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26925970

RESUMO

Retinoblastoma (Rb), the most common pediatric intraocular neoplasm, results from inactivation of both alleles of the RB1 tumor suppressor gene. The second allele is most commonly lost, as demonstrated by loss of heterozygosity studies. RB1 germline carriers usually develop bilateral tumors, but some Rb families display low penetrance and variable expressivity. In order to decipher the underlying mechanisms, 23 unrelated low penetrance pedigrees segregating the common c.1981C>T/p.Arg661Trp mutation and other low penetrance mutations were studied. In families segregating the c.1981C>T mutation, we demonstrated, for the first time, a correlation between the gender of the transmitting carrier and penetrance, as evidenced by Fisher's exact test: the probability of being unaffected is 90.3% and 32.5% when the mutation is inherited from the mother and the father, respectively (p-value = 7.10(-7). Interestingly, a similar correlation was observed in families segregating other low penetrance alleles. Consequently, we investigated the putative involvement of an imprinted, modifier gene in low penetrance Rb. We first ruled out a MED4-driven mechanism by MED4 methylation and expression analyses. We then focused on the differentially methylated CpG85 island located in intron 2 of RB1 and showing parent-of-origin-specific DNA methylation. This differential methylation promotes expression of the maternal c.1981C>T allele. We propose that the maternally inherited c.1981C>T/p.Arg661Trp allele retains sufficient tumor suppressor activity to prevent retinoblastoma development. In contrast, when the mutation is paternally transmitted, the low residual activity would mimic a null mutation and subsequently lead to retinoblastoma. This implies that the c.1981C>T mutation is not deleterious per se but needs to be destabilized in order to reach pRb haploinsufficiency and initiate tumorigenesis. We suggest that this phenomenon might be a general mechanism to explain phenotypic differences in low penetrance Rb families.


Assuntos
Mutação , Neoplasias da Retina/genética , Proteína do Retinoblastoma/genética , Retinoblastoma/genética , Ilhas de CpG , Metilação de DNA , Feminino , Heterozigoto , Humanos , Masculino , Complexo Mediador/genética , Complexo Mediador/metabolismo , Linhagem , Penetrância , Fenótipo , Neoplasias da Retina/patologia , Retinoblastoma/patologia , Proteína do Retinoblastoma/metabolismo
14.
Hum Mutat ; 37(5): 488-94, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26857394

RESUMO

We have investigated whether the mutation rate varies between genes and sites using de novo mutations (DNMs) from three genes associated with Mendelian diseases (RB1, NF1, and MECP2). We show that the relative frequency of mutations at CpG dinucleotides relative to non-CpG sites varies between genes and relative to the genomic average. In particular we show that the rate of transition mutation at CpG sites relative to the rate of non-CpG transversion is substantially higher in our disease genes than amongst DNMs in general; the rate of CpG transition can be several hundred-fold greater than the rate of non-CpG transversion. We also show that the mutation rate varies significantly between sites of a particular mutational type, such as non-CpG transversion, within a gene. We estimate that for all categories of sites, except CpG transitions, there is at least a 30-fold difference in the mutation rate between the 10% of sites with the highest and lowest mutation rates. However, our best estimate is that the mutation rate varies by several hundred-fold variation. We suggest that the presence of hypermutable sites may be one reason certain genes are associated with disease.


Assuntos
Predisposição Genética para Doença/genética , Proteína 2 de Ligação a Metil-CpG/genética , Taxa de Mutação , Neurofibromina 1/genética , Proteínas de Ligação a Retinoblastoma/genética , Ubiquitina-Proteína Ligases/genética , Algoritmos , Códon sem Sentido , Ilhas de CpG , Heterogeneidade Genética , Humanos
15.
BMC Cancer ; 16: 13, 2016 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-26758370

RESUMO

BACKGROUND: Less than 20% of familial breast cancer patients who undergo genetic testing for BRCA1 and BRCA2 carry a pathogenic mutation in one of these two genes. The GENESIS (GENE SISter) study was designed to identify new breast cancer susceptibility genes in women attending cancer genetics clinics and with no BRCA1/2 mutation. METHODS: The study involved the French national network of family cancer clinics. It was based on enrichment in genetic factors of the recruited population through case selection relying on familial criteria, but also on the consideration of environmental factors and endophenotypes like mammary density or tumor characteristics to assess potential genetic heterogeneity. One of the initial aims of GENESIS was to recruit affected sibpairs. Siblings were eligible when index cases and at least one affected sister were diagnosed with infiltrating mammary or ductal adenocarcinoma, with no BRCA1/2 mutation. In addition, unrelated controls and unaffected sisters were recruited. The enrolment of patients, their relatives and their controls, the collection of the clinical, epidemiological, familial and biological data were centralized by a coordinating center. RESULTS: Inclusion of participants started in February 2007 and ended in December 2013. A total of 1721 index cases, 826 affected sisters, 599 unaffected sisters and 1419 controls were included. 98% of participants completed the epidemiological questionnaire, 97% provided a blood sample, and 76% were able to provide mammograms. Index cases were on average 59 years old at inclusion, were born in 1950, and were 49.7 years of age at breast cancer diagnosis. The mean age at diagnosis of affected sisters was slightly higher (51.4 years). The representativeness of the control group was verified. CONCLUSIONS: The size of the study, the availability of biological specimens and the clinical data collection together with the detailed and complete epidemiological questionnaire make this a unique national resource for investigation of the missing heritability of breast cancer, by taking into account environmental and life style factors and stratifying data on endophenotypes to decrease genetic heterogeneity.


Assuntos
Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Mutação em Linhagem Germinativa , Proteínas de Neoplasias/genética , Adulto , Idoso , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/patologia , Feminino , França/epidemiologia , Predisposição Genética para Doença , Testes Genéticos , Humanos , Pessoa de Meia-Idade
16.
Eur J Hum Genet ; 24(1): 99-105, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25873010

RESUMO

To determine if the at-risk single-nucleotide polymorphism (SNP) alleles for colorectal cancer (CRC) could contribute to clinical situations suggestive of an increased genetic risk for CRC, we performed a prospective national case-control study based on highly selected patients (CRC in two first-degree relatives, one before 61 years of age; or CRC diagnosed before 51 years of age; or multiple primary CRCs, the first before 61 years of age; exclusion of Lynch syndrome and polyposes) and controls without personal or familial history of CRC. SNPs were genotyped using SNaPshot, and statistical analyses were performed using Pearson's χ(2) test, Cochran-Armitage test of trend and logistic regression. We included 1029 patients and 350 controls. We confirmed the association of CRC risk with four SNPs, with odds ratio (OR) higher than previously reported: rs16892766 on 8q23.3 (OR: 1.88, 95% confidence interval (CI): 1.30-2.72; P=0.0007); rs4779584 on 15q13.3 (OR: 1.42, CI: 1.11-1.83; P=0.0061) and rs4939827 and rs58920878/Novel 1 on 18q21.1 (OR: 1.49, CI: 1.13-1.98; P=0.007 and OR: 1.49, CI: 1.14-1.95; P=0.0035). We found a significant (P<0.0001) cumulative effect of the at-risk alleles or genotypes with OR at 1.62 (CI: 1.10-2.37), 2.09 (CI: 1.43-3.07), 2.87 (CI: 1.76-4.70) and 3.88 (CI: 1.72-8.76) for 1, 2, 3 and at least 4 at-risk alleles, respectively, and OR at 1.71 (CI: 1.18-2.46), 2.29 (CI: 1.55-3.38) and 6.21 (CI: 2.67-14.42) for 1, 2 and 3 at-risk genotypes, respectively. Combination of SNPs may therefore explain a fraction of clinical situations suggestive of an increased risk for CRC.


Assuntos
Cromossomos Humanos Par 15 , Cromossomos Humanos Par 18 , Cromossomos Humanos Par 8 , Neoplasias Colorretais/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Adulto , Alelos , Estudos de Casos e Controles , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/patologia , Feminino , Frequência do Gene , Loci Gênicos , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Estudos Prospectivos , Fatores de Risco
17.
Breast Cancer Res Treat ; 154(3): 463-71, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26564480

RESUMO

Several population-based and family-based studies have demonstrated that germline mutations of the PALB2 gene (Partner and Localizer of BRCA2) are associated with an increased risk of breast cancer. Distinct mutation frequencies and spectrums have been described depending on the population studied. Here we describe the first complete PALB2 coding sequence screening in the French population. We screened the complete coding sequence and intron-exon boundaries of PALB2, using the EMMA technique, to assess the contribution of pathogenic mutations in a set of 835 familial breast cancer cases and 662 unrelated controls from the French national study GENESIS and the Paul Strauss Cancer Centre, all previously tested negative for BRCA1 and BRCA2 pathogenic mutations. Our analysis revealed the presence of four novel deleterious mutations: c.1186insT, c.1857delT and c.2850delC in three cases, c.3418dupT in one control. In addition, we identified two in-frame insertion/deletion, 19 missense substitutions (two of them predicted as pathogenic), 9 synonymous variants, 28 variants located in introns and 2 in UTRs, as well as frequent variants. Truncating PALB2 mutations were found in 0.36% of familial breast cancer cases, a frequency lower than the one detected in comparable studies in other populations (0.73-3.40%). This suggests a small but significant contribution of PALB2 mutations to the breast cancer susceptibility in the French population.


Assuntos
Neoplasias da Mama/genética , Proteínas Nucleares/genética , Proteínas Supressoras de Tumor/genética , Adulto , Idoso , Neoplasias da Mama Masculina/genética , Estudos de Casos e Controles , Análise Mutacional de DNA , Éxons , Proteína do Grupo de Complementação N da Anemia de Fanconi , Feminino , França , Predisposição Genética para Doença , Genética Populacional , Mutação em Linhagem Germinativa , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Neoplasias Ovarianas/genética
18.
PLoS One ; 10(9): e0136192, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26406445

RESUMO

Breast Cancer is a complex multifactorial disease for which high-penetrance mutations have been identified. Approaches used to date have identified genomic features explaining about 50% of breast cancer heritability. A number of low- to medium penetrance alleles (per-allele odds ratio < 1.5 and 4.0, respectively) have been identified, suggesting that the remaining heritability is likely to be explained by the cumulative effect of such alleles and/or by rare high-penetrance alleles. Relatively few studies have specifically explored the mitochondrial genome for variants potentially implicated in breast cancer risk. For these reasons, we propose an exploration of the variability of the mitochondrial genome in individuals diagnosed with breast cancer, having a positive breast cancer family history but testing negative for BRCA1/2 pathogenic mutations. We sequenced the mitochondrial genome of 436 index breast cancer cases from the GENESIS study. As expected, no pathogenic genomic pattern common to the 436 women included in our study was observed. The mitochondrial genes MT-ATP6 and MT-CYB were observed to carry the highest number of variants in the study. The proteins encoded by these genes are involved in the structure of the mitochondrial respiration chain, and variants in these genes may impact reactive oxygen species production contributing to carcinogenesis. More functional and epidemiological studies are needed to further investigate to what extent variants identified may influence familial breast cancer risk.


Assuntos
Proteína BRCA1 , Proteína BRCA2 , Neoplasias da Mama/genética , Genoma Mitocondrial/genética , ATPases Mitocondriais Próton-Translocadoras/genética , Mutação , Neoplasias da Mama/diagnóstico , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Penetrância
19.
Gastroenterology ; 149(4): 1017-29.e3, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26116798

RESUMO

BACKGROUND & AIMS: Patients with bi-allelic germline mutations in mismatch repair (MMR) genes (MLH1, MSH2, MSH6, or PMS2) develop a rare but severe variant of Lynch syndrome called constitutional MMR deficiency (CMMRD). This syndrome is characterized by early-onset colorectal cancers, lymphomas or leukemias, and brain tumors. There is no satisfactory method for diagnosis of CMMRD because screens for mutations in MMR genes are noninformative for 30% of patients. MMR-deficient cancer cells are resistant to genotoxic agents and have microsatellite instability (MSI), due to accumulation of errors in repetitive DNA sequences. We investigated whether these features could be used to identify patients with CMMRD. METHODS: We examined MSI by PCR analysis and tolerance to methylating or thiopurine agents (functional characteristics of MMR-deficient tumor cells) in lymphoblastoid cells (LCs) from 3 patients with CMMRD and 5 individuals with MMR-proficient LCs (controls). Using these assays, we defined experimental parameters that allowed discrimination of a series of 14 patients with CMMRD from 52 controls (training set). We then used the same parameters to assess 23 patients with clinical but not genetic features of CMMRD. RESULTS: In the training set, we identified parameters, based on MSI and LC tolerance to methylation, that detected patients with CMMRD vs controls with 100% sensitivity and 100% specificity. Among 23 patients suspected of having CMMRD, 6 had MSI and LC tolerance to methylation (CMMRD highly probable), 15 had neither MSI nor LC tolerance to methylation (unlikely to have CMMRD), and 2 were considered doubtful for CMMRD based on having only 1 of the 2 features. CONCLUSION: The presence of MSI and tolerance to methylation in LCs identified patients with CMMRD with 100% sensitivity and specificity. These features could be used in diagnosis of patients.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais/diagnóstico , Resistencia a Medicamentos Antineoplásicos , Testes Genéticos , Mutação em Linhagem Germinativa , Linfócitos/efeitos dos fármacos , Instabilidade de Microssatélites , Síndromes Neoplásicas Hereditárias/diagnóstico , Proteínas Adaptadoras de Transdução de Sinal/genética , Adenosina Trifosfatases/genética , Adulto , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Células CACO-2 , Estudos de Casos e Controles , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Neoplasias Colorretais Hereditárias sem Polipose/tratamento farmacológico , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/metabolismo , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Análise Mutacional de DNA , Enzimas Reparadoras do DNA/genética , Proteínas de Ligação a DNA/genética , Feminino , Predisposição Genética para Doença , Testes Genéticos/métodos , Células HCT116 , Hereditariedade , Humanos , Linfócitos/metabolismo , Masculino , Metilação , Endonuclease PMS2 de Reparo de Erro de Pareamento , Reação em Cadeia da Polimerase Multiplex , Proteína 1 Homóloga a MutL , Proteína 2 Homóloga a MutS/genética , Síndromes Neoplásicas Hereditárias/tratamento farmacológico , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/metabolismo , Síndromes Neoplásicas Hereditárias/patologia , Proteínas Nucleares/genética , Fenótipo , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Transfecção , Adulto Jovem
20.
J Clin Oncol ; 33(21): 2345-52, 2015 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-26014290

RESUMO

PURPOSE: The aim of the study was to update the description of Li-Fraumeni syndrome (LFS), a remarkable cancer predisposition characterized by extensive clinical heterogeneity. PATIENTS AND METHODS: From 1,730 French patients suggestive of LFS, we identified 415 mutation carriers in 214 families harboring 133 distinct TP53 alterations and updated their clinical presentation. RESULTS: The 322 affected carriers developed 552 tumors, and 43% had developed multiple malignancies. The mean age of first tumor onset was 24.9 years, 41% having developed a tumor by age 18. In childhood, the LFS tumor spectrum was characterized by osteosarcomas, adrenocortical carcinomas (ACC), CNS tumors, and soft tissue sarcomas (STS) observed in 30%, 27%, 26%, and 23% of the patients, respectively. In adults, the tumor distribution was characterized by the predominance of breast carcinomas observed in 79% of the females, and STS observed in 27% of the patients. The TP53 mutation detection rate in children presenting with ACC or choroid plexus carcinomas, and in females with breast cancer before age 31 years, without additional features indicative of LFS, was 45%, 42% and 6%, respectively. The mean age of tumor onset was statistically different (P < .05) between carriers harboring dominant-negative missense mutations (21.3 years) and those with all types of loss of function mutations (28.5 years) or genomic rearrangements (35.8 years). Affected children, except those with ACC, harbored mostly dominant-negative missense mutations. CONCLUSION: The clinical gradient of the germline TP53 mutations, which should be validated by other studies, suggests that it might be appropriate to stratify the clinical management of LFS according to the class of the mutation.


Assuntos
Síndrome de Li-Fraumeni/genética , Proteína Supressora de Tumor p53/genética , Adolescente , Adulto , Idade de Início , Feminino , França/epidemiologia , Testes Genéticos , Genótipo , Mutação em Linhagem Germinativa , Humanos , Síndrome de Li-Fraumeni/epidemiologia , Masculino , Fenótipo , Análise de Sequência de DNA
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