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1.
J Med Genet ; 59(4): 346-350, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-33782093

RESUMO

DICER1 syndrome is a rare paediatric autosomal dominant inherited disorder predisposing to various benign and malignant tumours. It is caused by a germline pathogenic variant in DICER1, and the second hit for tumour development is usually a missense hotspot pathogenic variant in the DICER1 ribonuclease IIIb domain. While DICER1 predisposing variants account for about 60% of ovarian Sertoli-Leydig cell tumours, no DICER1-related testicular stromal tumours have been described. Here we report the first two cases of testicular stromal tumours in children carrying a DICER1 germline pathogenic variant: a case of Sertoli cell tumour and a case of Leydig cell tumour diagnosed at 2 and 12 years of age, respectively. A somatic DICER1 hotspot pathogenic variant was detected in the Sertoli cell tumour. This report extends the spectrum of DICER1-related tumours to include testicular Sertoli cell tumour and potentially testicular Leydig cell tumour. Diagnosis of a testicular Sertoli cell tumour should prompt DICER1 genetic testing so that patients with a DICER1 germline pathogenic variant can benefit from established surveillance guidelines. DICER1 genetic evaluation may be considered for testicular Leydig cell tumour. Our findings suggest that miRNA dysregulation underlies the aetiology of some testicular stromal tumours.


Assuntos
Tumor de Células de Leydig , Síndromes Neoplásicas Hereditárias , Neoplasias Ovarianas , Tumor de Células de Sertoli , Tumor de Células de Sertoli-Leydig , Neoplasias Testiculares , Criança , RNA Helicases DEAD-box/genética , Feminino , Humanos , Tumor de Células de Leydig/diagnóstico , Tumor de Células de Leydig/genética , Masculino , Neoplasias Ovarianas/genética , Ribonuclease III/genética , Tumor de Células de Sertoli/genética , Tumor de Células de Sertoli-Leydig/genética , Tumor de Células de Sertoli-Leydig/patologia , Neoplasias Testiculares/genética
2.
Breast Cancer Res ; 23(1): 79, 2021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34344426

RESUMO

BACKGROUND: Diagnostic ionizing radiation is a risk factor for breast cancer (BC). BC risk increases with increased dose to the chest and decreases with increased age at exposure, with possible effect modification related to familial or genetic predisposition. While chest X-rays increase the BC risk of BRCA1/2 mutation carriers compared to non-carriers, little is known for women with a hereditary predisposition to BC but who tested negative for a BRCA1 or BRCA2 (BRCA1/2) mutation. METHODS: We evaluated the effect of chest X-rays from diagnostic medical procedures in a dataset composed of 1552 BC cases identified through French family cancer clinics and 1363 unrelated controls. Participants reported their history of X-ray exposures in a detailed questionnaire and were tested for 113 DNA repair genes. Logistic regression and multinomial logistic regression models were used to assess the association with BC. RESULTS: Chest X-ray exposure doubled BC risk. A 3% increased BC risk per additional exposure was observed. Being 20 years old or younger at first exposure or being exposed before first full-term pregnancy did not seem to modify this risk. Birth after 1960 or carrying a rare likely deleterious coding variant in a DNA repair gene other than BRCA1/2 modified the effect of chest X-ray exposure. CONCLUSION: Ever/never chest X-ray exposure increases BC risk 2-fold regardless of age at first exposure and, by up to 5-fold when carrying 3 or more rare variants in a DNA repair gene. Further studies are needed to evaluate other DNA repair genes or variants to identify those which could modify radiation sensitivity. Identification of subpopulations that are more or less susceptible to ionizing radiation is important and potentially clinically relevant.


Assuntos
Neoplasias da Mama/etiologia , Predisposição Genética para Doença/genética , Radiografia/efeitos adversos , Adulto , Neoplasias da Mama/genética , Reparo do DNA/genética , Feminino , Genes BRCA1 , Genes BRCA2 , Humanos , Pessoa de Meia-Idade , Mutação , Radiografia/estatística & dados numéricos , Risco , Fatores de Risco , Adulto Jovem
3.
Int J Cancer ; 148(8): 1895-1909, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33368296

RESUMO

Single-nucleotide polymorphisms (SNPs) in over 180 loci have been associated with breast cancer (BC) through genome-wide association studies involving mostly unselected population-based case-control series. Some of them modify BC risk of women carrying a BRCA1 or BRCA2 (BRCA1/2) mutation and may also explain BC risk variability in BC-prone families with no BRCA1/2 mutation. Here, we assessed the contribution of SNPs of the iCOGS array in GENESIS consisting of BC cases with no BRCA1/2 mutation and a sister with BC, and population controls. Genotyping data were available for 1281 index cases, 731 sisters with BC, 457 unaffected sisters and 1272 controls. In addition to the standard SNP-level analysis using index cases and controls, we performed pedigree-based association tests to capture transmission information in the sibships. We also performed gene- and pathway-level analyses to maximize the power to detect associations with lower-frequency SNPs or those with modest effect sizes. While SNP-level analyses identified 18 loci, gene-level analyses identified 112 genes. Furthermore, 31 Kyoto Encyclopedia of Genes and Genomes and 7 Atlas of Cancer Signaling Network pathways were highlighted (false discovery rate of 5%). Using results from the "index case-control" analysis, we built pathway-derived polygenic risk scores (PRS) and assessed their performance in the population-based CECILE study and in a data set composed of GENESIS-affected sisters and CECILE controls. Although these PRS had poor predictive value in the general population, they performed better than a PRS built using our SNP-level findings, and we found that the joint effect of family history and PRS needs to be considered in risk prediction models.


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença/genética , Mutação , Polimorfismo de Nucleotídeo Único , Transdução de Sinais/genética , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Proteína BRCA2/genética , Proteína BRCA2/metabolismo , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/metabolismo , Estudos de Casos e Controles , Feminino , Redes Reguladoras de Genes/genética , Testes Genéticos/métodos , Estudo de Associação Genômica Ampla/métodos , Humanos , Mapas de Interação de Proteínas/genética , Curva ROC , Irmãos
4.
Am J Obstet Gynecol ; 225(1): 51.e1-51.e17, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33493488

RESUMO

BACKGROUND: Ovarian cancer risk in BRCA1 and BRCA2 mutation carriers has been shown to decrease with longer duration of oral contraceptive use. Although the effects of using oral contraceptives in the general population are well established (approximately 50% risk reduction in ovarian cancer), the estimated risk reduction in mutation carriers is much less precise because of potential bias and small sample sizes. In addition, only a few studies on oral contraceptive use have examined the associations of duration of use, time since last use, starting age, and calendar year of start with risk of ovarian cancer. OBJECTIVE: This study aimed to investigate in more detail the associations of various characteristics of oral contraceptive use and risk of ovarian cancer, to provide healthcare providers and carriers with better risk estimates. STUDY DESIGN: In this international retrospective study, ovarian cancer risk associations were assessed using oral contraceptives data on 3989 BRCA1 and 2445 BRCA2 mutation carriers. Age-dependent-weighted Cox regression analyses were stratified by study and birth cohort and included breast cancer diagnosis as a covariate. To minimize survival bias, analyses were left truncated at 5 years before baseline questionnaire. Separate analyses were conducted for each aspect of oral contraceptive use and in a multivariate analysis, including all these aspects. In addition, the analysis of duration of oral contraceptive use was stratified by recency of use. RESULTS: Oral contraceptives were less often used by mutation carriers who were diagnosed with ovarian cancer (ever use: 58.6% for BRCA1 and 53.5% BRCA2) than by unaffected carriers (ever use: 88.9% for BRCA1 and 80.7% for BRCA2). The median duration of use was 7 years for both BRCA1 and BRCA2 carriers who developed ovarian cancer and 9 and 8 years for unaffected BRCA1 and BRCA2 carriers with ovarian cancer, respectively. For BRCA1 mutation carriers, univariate analyses have shown that both a longer duration of oral contraceptive use and more recent oral contraceptive use were associated with a reduction in the risk of ovarian cancer. However, in multivariate analyses, including duration of use, age at first use, and time since last use, duration of oral contraceptive use proved to be the prominent protective factor (compared with <5 years: 5-9 years [hazard ratio, 0.67; 95% confidence interval, 0.40-1.12]; >10 years [hazard ratio, 0.37; 95% confidence interval, 0.19-0.73]; Ptrend=.008). The inverse association between duration of use and ovarian cancer risk persisted for more than 15 years (duration of ≥10 years; BRCA1 <15 years since last use [hazard ratio, 0.24; 95% confidence interval, 0.14-0.43]; BRCA1 >15 years since last use [hazard ratio, 0.56; 95% confidence interval, 0.18-0.59]). Univariate results for BRCA2 mutation carriers were similar but were inconclusive because of limited sample size. CONCLUSION: For BRCA1 mutation carriers, longer duration of oral contraceptive use is associated with a greater reduction in ovarian cancer risk, and the protection is long term.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Anticoncepcionais Orais/administração & dosagem , Mutação , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/prevenção & controle , Adulto , Estudos de Coortes , Europa (Continente)/epidemiologia , Feminino , Seguimentos , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/epidemiologia , Modelos de Riscos Proporcionais , Estudos Retrospectivos
5.
Psychooncology ; 28(8): 1679-1686, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31152683

RESUMO

OBJECTIVE: Intrafamilial disclosure of hereditary cancer predisposition in BRCA1/2 and mismatch repair gene (MMR) syndromes allows appropriate prevention strategies in at-risk relatives. We previously showed in a nationwide study that the uptake of genetic targeted testing (GTT) in these families was only 30%. We aimed to identify the clinical and psychosocial factors affecting the probands' intrafamilial disclosure and relatives' uptake of GTT in BRCA1/2 or MMR syndromes. METHODS: We assessed clinical variables, family history, and psychosocial variables of probands (depressive symptoms, anxiety, alexithymia, optimism, coping, family relationship, perception of cancer risks, and of hereditary transmission), together with disclosure and uptake of GTT within 103 French BRCA1/2 or MMR families. RESULTS: Among relatives eligible for GTT, 68% were informed of the predisposition, and 37% underwent GTT, according to probands' reports. Intrafamilial disclosure was inversely associated with the degree of kinship (P < .01). In multivariable analysis, disclosure increased with time since probands' genetic diagnosis (P < .01) and probands' feeling of family cohesion (0.01). GTT uptake increased with probands' depressive symptoms (0.02) and decreased with probands' perception of cancer risks (0.03). BRCA1/2 and MMR groups did not differ concerning family information and GTT uptake. CONCLUSIONS: This study identified factors affecting disclosure to relatives and GTT uptake in BRCA1/2 and MMR syndromes and gives new insights to improve probands' follow-up and intrafamilial sharing of genetic information.


Assuntos
Proteína BRCA1 , Proteína BRCA2 , Reparo de Erro de Pareamento de DNA/genética , Revelação , Família , Predisposição Genética para Doença , Testes Genéticos , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação
6.
Dis Colon Rectum ; 62(4): 470-475, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30640315

RESUMO

BACKGROUND: Almost no prospective data on endoscopy in MUTYH monoallelic carriers are available. OBJECTIVE: This study aimed to define the prevalence of colorectal and duodenal adenomas in a population of people presenting with a single mutation of the MUTYH gene and being first-degree relatives of biallelic MUTYH mutation carriers. DESIGN: This study is a prospective cohort evaluation. PATIENTS: Patients were first-degree relatives of a patient who had polyposis with biallelic MUTYH mutation and carrying a single gene mutation of the gene from 12 French centers. SETTINGS: This is a multicenter study. INTERVENTION: Detailed data on life habits (tobacco, alcohol, and nonsteroidal anti-inflammatory drugs), extraintestinal manifestations, and germline analysis were recorded. Complete endoscopic evaluation (colonoscopy and upper endoscopy) with chromoendoscopy was performed. RESULTS: Sixty-two patients were prospectively included (34 women (55%), mean age of 54, range 30-70 years). Thirty-two patients (52%) presented with colorectal polyps at colonoscopy. Of these patients with polyps, 15 (25%) had only adenomas, 8 (13%) had only hyperplastic polyps, 1 (1%) had sessile serrated adenomas, and 8 (13%) had adenomas and/or sessile serrated adenomas. We detected, in total, 29 adenomas with low-grade dysplasia, 5 adenomas with high-grade dysplasia, and 6 sessile serrated adenomas. Fourteen patients (23%) presented with a single adenoma, and 10 (16%) had 1 to 5 adenomas. No patient had more than 5 adenomas. At upper endoscopy, 3 had a limited number of fundic gland polyps; none had duodenal adenomas. The 2 main missense mutations c.1145G>A, p.Gly382Asp and c.494A>G, p.Tyr165Cys were associated with the development of colorectal adenomas/serrated polyps in these monoallelic carriers. LIMITATIONS: This study was limited by the small number of patients. CONCLUSIONS: This prospective study provides unique prospective data suggesting that monoallelic mutation carriers related to patients with polyposis show no colorectal polyposis and have very limited upper GI manifestations justifying an endoscopic follow-up. See Video Abstract at http://links.lww.com/DCR/A862.


Assuntos
Adenoma , Polipose Adenomatosa do Colo , Neoplasias Colorretais , DNA Glicosilases/genética , Neoplasias Duodenais , Endoscopia do Sistema Digestório/métodos , Adenoma/genética , Adenoma/patologia , Polipose Adenomatosa do Colo/diagnóstico , Polipose Adenomatosa do Colo/epidemiologia , Polipose Adenomatosa do Colo/genética , Adulto , Idoso , Estudos de Coortes , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Corantes/farmacologia , Neoplasias Duodenais/genética , Neoplasias Duodenais/patologia , Saúde da Família , Feminino , França/epidemiologia , Humanos , Aumento da Imagem/métodos , Masculino , Pessoa de Meia-Idade , Mutação , Avaliação de Resultados em Cuidados de Saúde , Estudos Prospectivos
7.
Gastric Cancer ; 22(4): 899-903, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30515673

RESUMO

In 2017, we implemented CTNNA1 germline analysis in probands suspected of having hereditary diffuse gastric cancer. Here, we report the results from a retrospective series of 41 cases, including the identification of a new family with a CTNNA1 mutation and the first prophylactic total gastrectomy in an asymptomatic carrier after a normal upper endoscopy. Diffuse gastric cancer foci with loss of catenin alpha-1 expression were seen in the resected tissue, suggesting that CTNNA1 and CDH1 germline mutations behave in a similar manner. Life-changing prophylactic total gastrectomy should therefore also be considered in CTNNA1 mutation carriers.


Assuntos
Doenças Assintomáticas/terapia , Carcinoma de Células em Anel de Sinete/genética , Mutação em Linhagem Germinativa , Neoplasias Gástricas/genética , alfa Catenina/genética , Adulto , Carcinoma de Células em Anel de Sinete/metabolismo , Carcinoma de Células em Anel de Sinete/patologia , Carcinoma de Células em Anel de Sinete/cirurgia , Feminino , Seguimentos , Gastrectomia , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Prognóstico , Estudos Retrospectivos , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia , alfa Catenina/metabolismo
8.
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.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteína BRCA1/genética , Neoplasias da Mama Masculina/genética , Neoplasias da Mama/genética , Predisposição Genética para Doença , Adulto , Idoso , Ataxia Telangiectasia/complicações , Ataxia Telangiectasia/genética , Ataxia Telangiectasia/patologia , Proteína BRCA2/genética , Neoplasias da Mama/classificação , Neoplasias da Mama/complicações , Neoplasias da Mama/patologia , Neoplasias da Mama Masculina/classificação , Neoplasias da Mama Masculina/complicações , Neoplasias da Mama Masculina/patologia , Dano ao DNA/genética , Reparo do DNA/genética , Feminino , Testes Genéticos , Genômica , Mutação em Linhagem Germinativa/genética , Humanos , Perda de Heterozigosidade/genética , Masculino , Pessoa de Meia-Idade , Deleção de Sequência/genética
9.
Reprod Biomed Online ; 36(2): 154-163, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29203382

RESUMO

This study provides an overview of preimplantation genetic diagnosis (PGD) for single gene diseases and the management of expanding indications in the context of a fully financially covered service at Montpellier's regional hospital centre. Within the framework of a restrictive law ruling PGD in France, only the parental genetic risk can be studied in embryos (concurrent aneuploidy screening is not allowed). PCR-based techniques were developed combining mutation detection and closely linked short tandem repeat markers within or flanking the affected genes, and set up more than 100 different robust fluorescent multiplex assays for 61 monogenic disorders. This strategy was used to analyse blastomeres from cleavage-stage embryos. Overall, 893 cycles were initiated in 384 couples; 727 cycles proceeded to oocyte retrieval and 608 cycles to embryo transfer, resulting in 184 deliveries. Clinical pregnancy rate per transfer, implantation and miscarriage rates were 33.6%, 25.1% and 8.8%, respectively. Our PGD programme resulted in the birth of 214 healthy babies for 162 out of 358 couples (45.3%), constituting a relevant achievement within an organizational framework that does not allow aneuploidy screening but provides equal access to PGD, both geographically and socioeconomically. This is a rare example of a fully free-of-charge PGD service.


Assuntos
Diagnóstico Pré-Implantação/estatística & dados numéricos , Feminino , França , Doenças Genéticas Inatas/diagnóstico , Hospitais Públicos/estatística & dados numéricos , Humanos , Masculino , Programas Nacionais de Saúde , Gravidez , Estudos Retrospectivos
10.
J Med Genet ; 54(2): 125-133, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27856506

RESUMO

BACKGROUND: Germline mutations in the SDHD tumour suppressor gene (11q23.1) predispose to phaeochromocytomas and paragangliomas (PPGL) mainly on a paternal transmission. However, PPGL have been recently reported in three carriers of a maternally inherited SDHD mutation. OBJECTIVE: To assess the risk of PPGL occurrence on maternal transmission of SDHD mutation. METHODS: Pedigrees of 80 SDHD-related families have been reviewed. 35 asymptomatic subjects carrying a maternally transmitted SDHD mutation were identified. 20 of them accepted to benefit from a PPGL imaging screening. RESULTS: A unique histologically proven biochemically negative phaeochromocytoma has been diagnosed in a 35-year-old woman. Molecular investigations carried out on tumour tissue revealed that the loss of heterozygosity encompassed the paternally derived q arm and the maternally derived p arm of chromosome 11. CONCLUSIONS: This study demonstrates that the risk of developing PPGL for a subject carrying a germline SDHD mutation on the maternal allele remains a rare scenario but does exist. Our data suggest an adjustment of current genetic counselling and clinical care recommendations for at-risk subjects. A targeted familial genetic test should be proposed from the age of 18 years to every subject having a mother carrying a germline SDHD mutation and a first medical workup, including imaging, should be recommended to SDHD-positive mutation carriers.


Assuntos
Neoplasias das Glândulas Suprarrenais/genética , Paraganglioma/genética , Feocromocitoma/genética , Succinato Desidrogenase/genética , Adolescente , Neoplasias das Glândulas Suprarrenais/patologia , Adulto , Cromossomos Humanos Par 11/genética , Feminino , Testes Genéticos , Mutação em Linhagem Germinativa/genética , Heterozigoto , Humanos , Perda de Heterozigosidade/genética , Herança Materna/genética , Paraganglioma/patologia , Linhagem , Feocromocitoma/patologia , Medição de Risco
11.
J Med Genet ; 54(9): 607-612, 2017 09.
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 do Exoma
12.
Carcinogenesis ; 38(10): 994-1003, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-28981872

RESUMO

Recent studies have linked constitutive telomere length (TL) to aging-related diseases including cancer at different sites. ATM participates in the signaling of telomere erosion, and inherited mutations in ATM have been associated with increased risk of cancer, particularly breast cancer. The goal of this study was to investigate whether carriage of an ATM mutation and TL interplay to modify cancer risk in ataxia-telangiectasia (A-T) families.The study population consisted of 284 heterozygous ATM mutation carriers (HetAT) and 174 non-carriers (non-HetAT) from 103 A-T families. Forty-eight HetAT and 14 non-HetAT individuals had cancer, among them 25 HetAT and 6 non-HetAT were diagnosed after blood sample collection. We measured mean TL using a quantitative PCR assay and genotyped seven single-nucleotide polymorphisms (SNPs) recurrently associated with TL in large population-based studies.HetAT individuals were at increased risk of cancer (OR = 2.3, 95%CI = 1.2-4.4, P = 0.01), and particularly of breast cancer for women (OR = 2.9, 95%CI = 1.2-7.1, P = 0.02), in comparison to their non-HetAT relatives. HetAT individuals had longer telomeres than non-HetAT individuals (P = 0.0008) but TL was not associated with cancer risk, and no significant interaction was observed between ATM mutation status and TL. Furthermore, rs9257445 (ZNF311) was associated with TL in HetAT subjects and rs6060627 (BCL2L1) modified cancer risk in HetAT and non-HetAT women.Our findings suggest that carriage of an ATM mutation impacts on the age-related TL shortening and that TL per se is not related to cancer risk in ATM carriers. TL measurement alone is not a good marker for predicting cancer risk in A-T families.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Ataxia Telangiectasia/complicações , Mutação , Neoplasias/genética , Telômero/genética , Ataxia Telangiectasia/genética , Neoplasias da Mama/genética , Feminino , Predisposição Genética para Doença , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Encurtamento do Telômero/genética , Proteína bcl-X/genética
13.
Breast Cancer Res Treat ; 166(2): 631-639, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28779219

RESUMO

PURPOSE: This report compares the risk factors, the tumor phenotypes, and the BRCA1/BRCA2 genotype of early onset breast cancer (EOBC) patients between Southern Europe and North Africa. METHODS: Four hundred and fifty six women with invasive EOBC (≤40 years) were prospectively included from four centers in France (n = 270) and four centers in North Africa (Algeria, Egypt, Morocco, Tunisia; n = 186). Life style, tumor phenotype, familial history, BRCA1/BRCA2 genotype were compared between the two populations. RESULTS: We found an older age at menarche, a higher number of childbearing, a more frequent breastfeeding, a higher body mass index, a lower use of oral contraceptives in North African women compared to French women. TNM stage at diagnosis was higher in North African women than in French women. North African women had a lower incidence of triple negative and proliferative (Ki 67 index > 20%) tumors. There was a lower rate of BRCA1 mutation in North Africa (7 vs. 15%, P = 0.02). Three putative BRCA1/2 founder mutations were identified in North Africa. CONCLUSIONS: In EOBC, we found significant differences in risk factors, phenotype and a higher incidence of BRCA1 mutations in Southern Europe as compared to North Africa. The worst prognosis previously reported for EOBC in North Africa is more likely due to a higher stage at diagnosis than to a more aggressive phenotype, since triple negative tumors are more common in Southern Europe and advanced tumors in North Africa.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/patologia , África do Norte , Idade de Início , Neoplasias da Mama/genética , Feminino , França , Genótipo , Humanos , Estadiamento de Neoplasias , Estudos Prospectivos , Fatores de Risco
14.
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
15.
J Med Genet ; 52(6): 426-30, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25911086

RESUMO

BACKGROUND: Many cases of familial renal cell carcinoma (RCC) remain unexplained by mutations in the known predisposing genes or shared environmental factors. There are therefore additional, still unidentified genes involved in familial RCC. PBRM1 is a tumour suppressor gene and somatic mutations are found in 30-45% of sporadic clear cell (cc) RCC. METHODS: We selected 35 unrelated patients with unexplained personal history of ccRCC and at least one affected first-degree relative, and sequenced the PBRM1 gene. RESULTS: A germline frameshift mutation (c.3998_4005del [p.Asp1333Glyfs]) was found in one patient. The patient's mother, his sister and one niece also had ccRCC. The mutation co-segregated with the disease as the three affected relatives were carriers, while an unaffected sister was not, according with autosomal-dominant transmission. Somatic studies supported these findings, as we observed both loss of heterozygosity for the mutation and loss of protein expression in renal tumours. CONCLUSIONS: We show for the first time that an inherited mutation in PBRM1 predisposes to RCC. International studies are necessary to estimate the contribution of PBRM1 to RCC susceptibility, estimate penetrance and then integrate the gene into routine clinical practice.


Assuntos
Carcinoma de Células Renais/genética , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Neoplasias Renais/genética , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Carcinoma de Células Renais/diagnóstico , Análise Mutacional de DNA , Proteínas de Ligação a DNA , Éxons , Feminino , Heterozigoto , Humanos , Imuno-Histoquímica , Neoplasias Renais/diagnóstico , Masculino , Proteínas Nucleares/metabolismo , Linhagem , Fatores de Transcrição/metabolismo
16.
Hum Mutat ; 36(9): 894-902, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26077438

RESUMO

Beckwith-Wiedemann syndrome (BWS) is an imprinting disorder associating macroglossia, abdominal wall defects, visceromegaly, and a high risk of childhood tumor. Molecular anomalies are mostly epigenetic; however, mutations of CDKN1C are implicated in 8% of cases, including both sporadic and familial forms. We aimed to describe the phenotype of BWS patients with CDKN1C mutations and develop a functional test for CDKN1C mutations. For each propositus, we sequenced the three exons and intron-exon boundaries of CDKN1C in patients presenting a BWS phenotype, including abdominal wall defects, without 11p15 methylation defects. We developed a functional test based on flow cytometry. We identified 37 mutations in 38 pedigrees (50 patients and seven fetuses). Analysis of parental samples when available showed that all mutations tested but one was inherited from the mother. The four missense mutations led to a less severe phenotype (lower frequency of exomphalos) than the other 33 mutations. The following four tumors occurred: one neuroblastoma, one ganglioneuroblastoma, one melanoma, and one acute lymphoid leukemia. Cases of BWS caused by CDKN1C mutations are not rare. CDKN1C sequencing should be performed for BWS patients presenting with abdominal wall defects or cleft palate without 11p15 methylation defects or body asymmetry, or in familial cases of BWS.


Assuntos
Síndrome de Beckwith-Wiedemann/diagnóstico , Síndrome de Beckwith-Wiedemann/genética , Inibidor de Quinase Dependente de Ciclina p57/genética , Estudos de Associação Genética , Impressão Genômica , Fenótipo , Alelos , Sequência de Aminoácidos , Substituição de Aminoácidos , Inibidor de Quinase Dependente de Ciclina p57/metabolismo , Feminino , Genótipo , Humanos , Masculino , Dados de Sequência Molecular , Mutação , Linhagem , Alinhamento de Sequência
18.
Eur J Hum Genet ; 2024 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-38997469

RESUMO

In paediatric oncology, genomics raises new ethical, legal and psychological issues, as somatic and constitutional situations intersect throughout the care pathway. The discovery of potential predisposition in this context is sometimes carried out outside the usual framework. This article focuses on the views of children, adolescents, and young adults (AYA) with cancer and their parents about their experience with genomic testing. Forty-eight semi-structured interviews were performed with children or AYAs with cancer and one of their parents, before and/or after receiving the genetic test results. The interviews were fully transcribed, coded and thematically analysed using an inductive method. This analysis revealed several themes that are key issues: perceived understanding and consenting, apprehension about the test outcomes (expectations and fears), perception and attitude towards incidental findings. The main expectation was an aetiological explanation. Children and AYAs also emphasised the altruistic meaning of genetic testing, while parents seemed to expect a therapeutic and preventive approach for their child and the rest of the family. Parents were more concerned about a family risk, while patients were more afraid of cancer relapse or transmission to their descendants. Both groups suggested possible feelings of guilt concerning family transmission and imaginary representations of what genomics may allow. Incidental findings were not understood by patients, while some parents perceived the related issues and hesitated between wanting or not to know. A multidisciplinary approach would be an interesting way to help parents and children and AYAs to better grasp the complexity of genetic and/or genomic testing.

19.
Neuro Oncol ; 2024 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-39093628

RESUMO

BACKGROUND: Rhabdoid tumors (RT) are aggressive, rare tumors predominantly affecting young children, characterized by bi-allelic SMARCB1 gene inactivation. While most SMARCB1 alterations are acquired de novo, a third of cases exhibit germline alterations, defining Rhabdoid Tumors Predisposition Syndrome (RTPS1). With increased sensitivity of next-generation sequencing (NGS), mosaicisms in genes linked to genetic diseases are more detectable. This study focuses on exploring SMARCB1 germline alterations, notably mosaicism in blood samples of children with RT and in parents, using a custom NGS panel. METHODS: A cohort of 280 children and 140 parents with germline analysis was studied. Germline DNA from 111 children with RT and 32 parents were re-analyzed with a custom NGS panel with 1,500X average depth targeting the SMARCB1 gene to identify intragenic variants not detected with conventional low-sensitivity methods. Follow-up data was obtained for 77 patients. RESULTS: Nine previously undetected mosaicism cases were identified, totaling 17/280 patients with a mosaic variant (6.1%) in the cohort, with variant allele frequencies between 0.9% and 33%, thus highlighting the prior underestimation of its prevalence. Follow-up data showed that 4 out of 7 survivors with mosaic variants developed distinct novel tumors, two sharing SMARCB1 alterations with the initial tumor, emphasizing the potential clinical impact of SMARCB1 mosaicism. CONCLUSIONS: The hitherto underestimated rate of SMARCB1 mosaicism in RT underscores the need for optimized genetic counseling and oncological monitoring. The findings have significant medical implications, considering the dire prognosis of RT.

20.
Oncotarget ; 14: 111-125, 2023 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-36749285

RESUMO

In oncogenetics, some patients could be considered as "extreme phenotypes", such as those with very early onset presentation or multiple primary malignancies, unusually high numbers of cancers of the same spectrum or rare cancer types in the same parental branch. For these cases, a genetic predisposition is very likely, but classical candidate gene panel analyses often and frustratingly remains negative. In the framework of the EX2TRICAN project, exploring unresolved extreme cancer phenotypes, we applied exome sequencing on rare familial cases with male breast cancer, identifying a novel pathogenic variant of ATR (p.Leu1808*). ATR has already been suspected as being a predisposing gene to breast cancer in women. We next identified 3 additional ATR variants in a cohort of both male and female with early onset and familial breast cancers (c.7762-2A>C; c.2078+1G>A; c.1A>G). Further molecular and cellular investigations showed impacts on transcripts for variants affecting splicing sites and reduction of ATR expression and phosphorylation of the ATR substrate CHEK1. This work further demonstrates the interest of an extended genetic analysis such as exome sequencing to identify very rare variants that can play a role in cancer predisposition in extreme phenotype cancer cases unexplained by classical cancer gene panels testing.


Assuntos
Neoplasias da Mama , Feminino , Humanos , Masculino , Alelos , Proteínas Mutadas de Ataxia Telangiectasia/genética , Neoplasias da Mama/genética , Predisposição Genética para Doença , Fenótipo , Fosforilação , Neoplasias da Mama Masculina/genética
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