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1.
Eur J Cancer Care (Engl) ; : e13173, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31571365

RESUMO

BACKGROUND: We performed a comprehensive assessment of the psychometrics of the "Psychosocial Aspects in Hereditary Cancer" (PAHC) questionnaire in French, German and Spanish. METHODS: Women consecutively approached in Cancer Genetic Clinics completed the PAHC, distress and satisfaction questionnaires at pre-testing (T1) and after test result disclosure (T2). In addition to standard psychometric attributes, we assessed the PAHC ability to respond to change (i.e. improvement or deterioration from T1 to T2) in perceived difficulties and computed minimal important differences (MID) in PAHC scores as compared with self-reported needs for additional counselling. RESULTS: Of 738 eligible counselees, 214 (90%) in France (Paris), 301 (92%) in Germany (Cologne) and 133 (77%) in Spain (Barcelona) completed the PAHC. A six-factor revised PAHC model yielded acceptable CFA goodness-of-fit indexes and good all scales internal consistencies. PAHC scales demonstrated expected conceptual differences with distress and satisfaction with counselling. Different levels of psychosocial difficulties were evidenced between counselees' subgroups and over time (p-values < .05). MID estimates ranged from 8 to 15 for improvement and 9 to 21 for deterioration. CONCLUSION: The PAHC French, German and Spanish versions are reliable and valid for evaluating the psychosocial difficulties of women at high BC risk attending genetic clinics.

3.
Psychol Health Med ; : 1-11, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31505944

RESUMO

The disclosure of genetic information is an important issue in cancer prevention. This study based on a French national cohort of BRCA1/2 mutation carriers (GENEPSO-PS cohort, N=233) aimed to assess the prevalence of parental disclosure of genetic information to children 10 years after genetic testing, with a focus on gender differences. Most participants (n = 193, 131 women) reported having children. A total of 72.0% of offspring had received genetic information (88.8% for adult offspring, p < .001), with no differences according to the gender of the mutation-carrying parent. While female carriers disclosed genetic information more often than male carriers (54.1% versus 38.3%, p = .029), they did so irrespective of the gender of their offspring. Moreover, female carriers who had developed incident cancer after genetic testing disclosed genetic information more frequently than unaffected female carriers (70.7% versus 48.5%, p = .005). A multivariate analysis confirmed the effects of both gender and cancer on disclosure to offspring. The same results were obtained when the analysis was restricted to adult offspring. This study reveals high rates of disclosure of positive BRCA1/2 mutation status to children 10 years after genetic testing, irrespective of the gender of the carrier/offspring. However, female carriers disclosed genetic information more frequently than male carriers.

4.
BMJ Open ; 9(9): e029926, 2019 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-31551380

RESUMO

OBJECTIVES AND SETTING: Advances in multigene panel testing for cancer susceptibility has increased the complexity of counselling, requiring particular attention to counselees' psychosocial needs. Changes in psychosocial problems before and after genetic testing were prospectively compared between genetic test results in women tested for breast or ovarian cancer genetic susceptibility in French, German and Spanish clinics. PARTICIPANTS AND MEASURES: Among 752 counselees consecutively approached, 646 (86%) were assessed after the initial genetic consultation (T1), including 510 (68%) affected with breast cancer, of which 460 (61%) were assessed again after receiving the test result (T2), using questionnaires addressing genetic-specific psychosocial problems (Psychosocial Aspects of Hereditary Cancer (PAHC)-six scales). Sociodemographic and clinical data were also collected. RESULTS: Seventy-nine (17.2%), 19 (4.1%), 259 (56.3%), 44 (9.6%) and 59 (12.8%) women received a BRCA1/2, another high/moderate-risk pathogenic variant (PV), negative uninformative, true negative (TN) or variant of uncertain significance result (VUS), respectively. On multiple regression analyses, compared with women receiving another result, those with a VUS decreased more in psychosocial problems related to hereditary predisposition (eg, coping with the test result) (ß=-0.11, p<0.05) and familial/social issues (eg, risk communication) (ß=-0.13, p<0.05), almost independently from their problems before testing. Women with a PV presented no change in hereditary predisposition problems and, so as women with a TN result, a non-significant increase in familial/social issues. Other PAHC scales (ie, emotions, familial cancer, personal cancer and children-related issues) were not affected by genetic testing. CONCLUSIONS: In women tested for breast or ovarian cancer genetic risk in European genetics clinics, psychosocial problems were mostly unaffected by genetic testing. Apart from women receiving a VUS result, those with another test result presented unchanged needs in counselling in particular about hereditary predisposition and familial/social issues.

5.
J Med Ethics ; 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31462451

RESUMO

Familial disclosure of genetic information is an important, long-standing ethical issue that still gives rise to much debate. In France, recent legislation has created an innovative and unprecedented procedure that allows healthcare professionals (HCPs), under certain conditions, to disclose relevant information to relatives of a person carrying a deleterious genetic mutation. This article will analyse how HCPs in two medical genetics clinics have reacted to these new legal provisions and show how their reticence to inform the patients' relatives on their behalf leads them to use this option sparingly.

6.
Psychooncology ; 28(9): 1894-1900, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31276266

RESUMO

OBJECTIVE: Genetic counseling in at-risk families is known to improve cancer prevention. Our study aimed to determine the rate of uptake of genetic counseling among adult children of BRCA1/2 mutation carriers and to identify the potential psychosocial factors associated with uptake of genetic counseling. METHODS: A self-reported questionnaire was mailed to 328 BRCA1/2 mutation carriers 10 years after BRCA1/2 test disclosure. Of the 233 carriers who returned the questionnaire (response rate = 71%), 135 reported having children over age 18 years and were therefore included in the analysis. Generalized estimating equations models were used to identify the factors associated with uptake of genetic counseling among adult children of mutation carriers. RESULTS: Data were gathered for a total of 296 children (46% male, 54% female). The vast majority were informed about the familial mutation (90.9%) and 113 (38%; 95% CI, 32%-44%) underwent genetic counseling. This percentage exceeded 80% in women over 40 years. In the multivariate model, female sex, advanced age, mutation in the father, diagnosis of cancer in the mutation-carrying parent after genetic testing, and good family relationships were all factors associated with higher uptake of genetic counseling. CONCLUSIONS: Adult children of BRCA1/2 mutation carriers in France do not undergo genetic counseling sufficiently often. Further studies should be conducted on the psychosocial factors that hinder the uptake of genetic counseling among adult children of BRCA1/2 mutation carriers.

8.
Hum Mutat ; 40(10): 1713-1730, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31050087

RESUMO

Ataxia-telangiectasia (A-T) is a recessive disorder caused by biallelic pathogenic variants of ataxia-telangiectasia mutated (ATM). This disease is characterized by progressive ataxia, telangiectasia, immune deficiency, predisposition to malignancies, and radiosensitivity. However, hypomorphic variants may be discovered associated with very atypical phenotypes, raising the importance of evaluating their pathogenic effects. In this study, multiple functional analyses were performed on lymphoblastoid cell lines from 36 patients, comprising 49 ATM variants, 24 being of uncertain significance. Thirteen patients with atypical phenotype and presumably hypomorphic variants were of particular interest to test strength of functional analyses and to highlight discrepancies with typical patients. Western-blot combined with transcript analyses allowed the identification of one missing variant, confirmed suspected splice defects and revealed unsuspected minor transcripts. Subcellular localization analyses confirmed the low level and abnormal cytoplasmic localization of ATM for most A-T cell lines. Interestingly, atypical patients had lower kinase defect and less altered cell-cycle distribution after genotoxic stress than typical patients. In conclusion, this study demonstrated the pathogenic effects of the 49 variants, highlighted the strength of KAP1 phosphorylation test for pathogenicity assessment and allowed the establishment of the Ataxia-TeLangiectasia Atypical Score to predict atypical phenotype. Altogether, we propose strategies for ATM variant detection and classification.

9.
Hum Mutat ; 40(10): 1690-1699, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31033087

RESUMO

Ataxia-telangiectasia-like disorder (ATLD) is a rare genomic instability syndrome caused by biallelic variants of MRE11 (meiotic recombination 11) characterized by progressive cerebellar ataxia and typical karyotype abnormalities. These symptoms are common to those of ataxia-telangiectasia, which is consistent with the key role of MRE11 in ataxia-telangiectasia mutated (ATM) activation after DNA double-strand breaks. Three unrelated French patients were referred with ataxia. Only one had typical karyotype abnormalities. Unreported biallelic MRE11 variants were found in these three cases. Interestingly, one variant (c.424G>A) was present in two cases and haplotype analysis strongly suggested a French founder variant. Variants c.544G>A and c.314+4_314+7del lead to splice defects. The level of MRE11 in lymphoblastoid cell lines was consistently and dramatically reduced. Functional consequences were evaluated on activation of the ATM pathway via phosphorylation of ATM targets (KAP1 and CHK2), but no consistent defect was observed. However, an S-phase checkpoint activation defect after camptothecin was observed in these patients with ATLD. In conclusion, we report the first three French ATLD patients and a French founder variant, and propose an S-phase checkpoint activation study to evaluate the pathogenicity of MRE11 variants.

10.
Breast ; 45: 29-35, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30822622

RESUMO

Multigene panel testing for breast and ovarian cancer predisposition diagnosis is a useful tool as it makes possible to sequence a considerable number of genes in a large number of individuals. More than 200 different multigene panels in which the two major BRCA1 and BRCA2 breast cancer predisposing genes are included are proposed by public or commercial laboratories. We review the clinical validity and clinical utility of the 26 genes most oftenly included in these panels. Because clinical validity and utility are not established for all genes and due to the heterogeneity of tumour risk levels, there is a substantial difficulty in the routine use of multigene panels if management guidelines and recommendations for testing relatives are not previously defined for each gene. Besides, the classification of variant of unknown significance (VUS) is a particular limitation and challenge. Efforts to classify VUSs and also to identify factors that modify cancer risks are now needed to produce personalised risk estimates. The complexity of information, the capacity to come back to patients when VUS are re-classified as pathogenic, and the expected large increase in the number of individuals to be tested especially when the aim of multigene panel testing is not only prevention but also treatment are challenging both for physicians and patients. Quality of tests, interpretation of results, information and accompaniment of patients must be at the heart of the guidelines of multigene panel testing.

12.
Eur J Hum Genet ; 27(5): 792-800, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30683922

RESUMO

Next-generation sequencing (NGS) is routinely used for constitutional genetic analysis. However, cross-contamination between samples constitutes a major risk that could impact the results of the analysis. We have developed ART-DeCo, a tool using the allelic ratio (AR) of the Single Nucleotide Polymorphisms sequenced with regions of interest. When a sample is contaminated by DNA with a different genotype, unexpected ARs are obtained, which are in turn used for detection of contamination with a screening test, followed by identification and quantification of the contaminant. Following optimization, ART-DeCo was applied to 2222 constitutional DNA samples. The screening test was positive for 191 samples. In 33 cases (contamination percentages: 1.3% to 29.2%), the contaminant was identified and was mostly located in adjacent wells. Three other positive cases were due to barcoding errors or mixture of two DNA samples. Interestingly, the last contaminated sample corresponded to a bone marrow transplant recipient. Lastly, no contaminant was identified in 154 weakly positive ( < 4%) samples that were considered to be irrelevant to constitutional genetic analysis. ART-DeCo lends itself to mandatory quality control procedures, also highlighting the delicate steps of library preparation, resulting in practice improvement. Importantly, ART-DeCo can be implemented in any NGS workflow, from gene panel to genome-wide analyses. https://sourceforge.net/projects/ngs-art-deco/ .

13.
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
14.
J Natl Cancer Inst ; 2018 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-30517737

RESUMO

Background: The BRCA1-associated protein-1 (BAP1) tumor predisposition syndrome (BAP1-TPDS) is a hereditary tumor syndrome caused by germline pathogenic variants in BAP1 encoding a tumor suppressor associated with uveal melanoma, mesothelioma, cutaneous melanoma, renal cell carcinoma, and cutaneous BAP1-inactivated melanocytic tumors. However, the full spectrum of tumors associated with the syndrome is yet to be determined. Improved understanding of the BAP1-TPDS is crucial for appropriate clinical management of BAP1 germline variant carriers and their families, including genetic counseling and surveillance for new tumors. Methods: We collated germline variant status, tumor diagnoses, and information on BAP1 immunohistochemistry or loss of somatic heterozygosity on 106 published and 75 unpublished BAP1 germline variant-positive families worldwide to better characterize the genotypes and phenotypes associated with the BAP1-TPDS. Tumor spectrum and ages of onset were compared between missense and null variants. All statistical tests were two-sided. Results: The 181 families carried 140 unique BAP1 germline variants. The collated data confirmed the core tumor spectrum associated with the BAP1-TPDS and showed that some families carrying missense variants can exhibit this phenotype. A variety of noncore BAP1-TPDS -associated tumors were found in families of variant carriers. Median ages of onset of core tumor types were lower in null than missense variant carriers for all tumors combined (P < .001), mesothelioma (P < .001), cutaneous melanoma (P < .001), and nonmelanoma skin cancer (P < .001). Conclusions: This analysis substantially increases the number of pathogenic BAP1 germline variants and refines the phenotype. It highlights the need for a curated registry of germline variant carriers for proper assessment of the clinical phenotype of the BAP1-TPDS and pathogenicity of new variants, thus guiding management of patients and informing areas requiring further research.

15.
PLoS Genet ; 14(12): e1007752, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30586411

RESUMO

The BRCA Challenge is a long-term data-sharing project initiated within the Global Alliance for Genomics and Health (GA4GH) to aggregate BRCA1 and BRCA2 data to support highly collaborative research activities. Its goal is to generate an informed and current understanding of the impact of genetic variation on cancer risk across the iconic cancer predisposition genes, BRCA1 and BRCA2. Initially, reported variants in BRCA1 and BRCA2 available from public databases were integrated into a single, newly created site, www.brcaexchange.org. The purpose of the BRCA Exchange is to provide the community with a reliable and easily accessible record of variants interpreted for a high-penetrance phenotype. More than 20,000 variants have been aggregated, three times the number found in the next-largest public database at the project's outset, of which approximately 7,250 have expert classifications. The data set is based on shared information from existing clinical databases-Breast Cancer Information Core (BIC), ClinVar, and the Leiden Open Variation Database (LOVD)-as well as population databases, all linked to a single point of access. The BRCA Challenge has brought together the existing international Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium expert panel, along with expert clinicians, diagnosticians, researchers, and database providers, all with a common goal of advancing our understanding of BRCA1 and BRCA2 variation. Ongoing work includes direct contact with national centers with access to BRCA1 and BRCA2 diagnostic data to encourage data sharing, development of methods suitable for extraction of genetic variation at the level of individual laboratory reports, and engagement with participant communities to enable a more comprehensive understanding of the clinical significance of genetic variation in BRCA1 and BRCA2.


Assuntos
Bases de Dados Genéticas , Genes BRCA1 , Genes BRCA2 , Variação Genética , Alelos , Neoplasias da Mama/genética , Bases de Dados Genéticas/ética , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos , Disseminação de Informação/ética , Disseminação de Informação/legislação & jurisprudência , Masculino , Mutação , Neoplasias Ovarianas/genética , Penetrância , Fenótipo , Fatores de Risco
16.
Eur J Cancer ; 106: 45-53, 2018 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-30471647

RESUMO

European Breast Cancer Council manifesto and supporting article on genetic risk prediction testing in breast cancer, presented at the 11th European Breast Cancer Conference in Barcelona, Spain.

18.
Cancers (Basel) ; 10(11)2018 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-30453575

RESUMO

BRCA1 and BRCA2 are major breast cancer susceptibility genes whose pathogenic variants are associated with a significant increase in the risk of breast and ovarian cancers. Current genetic screening is generally limited to BRCA1/2 exons and intron/exon boundaries. Most identified pathogenic variants cause the partial or complete loss of function of the protein. However, it is becoming increasingly clear that variants in these regions only account for a small proportion of cancer risk. The role of variants in non-coding regions beyond splice donor and acceptor sites, including those that have no qualitative effect on the protein, has not been thoroughly investigated. The key transcriptional regulatory elements of BRCA1 and BRCA2 are housed in gene promoters, untranslated regions, introns, and long-range elements. Within these sequences, germline and somatic variants have been described, but the clinical significance of the majority is currently unknown and it remains a significant clinical challenge. This review summarizes the available data on the impact of variants on non-coding regions of BRCA1/2 genes and their role on breast and ovarian cancer predisposition.

19.
Am J Pathol ; 188(10): 2378-2391, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30075151

RESUMO

Medullary breast carcinoma (MBC) is a rare subtype of triple-negative breast cancer with specific genomic features within the spectrum of basal-like carcinoma (BLC). In this study of 19 MBCs and 36 non-MBC BLCs, we refined the transcriptomic and genomic knowledge about this entity. Unsupervised and supervised analysis of transcriptomic profiles confirmed that MBC clearly differs from non-MBC BLC, with 92 genes overexpressed and 154 genes underexpressed in MBC compared with non-MBC BLC. Immunity-related pathways are the most differentially represented pathways in MBC compared with non-MBC BLC. The proapoptotic gene BCLG (official name BCL2L14) is by far the most intensely overexpressed gene in MBC. A quantitative RT-PCR validation study conducted in 526 breast tumors corresponding to all molecular subtypes documented the specificity of BCLG overexpression in MBC, which was confirmed at the protein level by immunohistochemistry. We also found that most MBCs belong to the immunomodulatory triple-negative breast cancer subtype. Using pan-genomic analysis, it was found that MBC harbors more losses of heterozygosity than non-MBC BLC. These observations corroborate the notion that MBC remains a distinct entity that could benefit from specific treatment strategies (such as deescalation or targeted therapy) adapted to this rare tumor type.

20.
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.

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