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1.
J Med Genet ; 61(3): 284-288, 2024 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-37748860

RESUMO

PURPOSE: Mosaic BRCA1 promoter methylation (BRCA1meth) increases the risk of early-onset breast cancer, triple-negative breast cancer and ovarian cancer. As mosaic BRCA1meth are believed to occur de novo, their role in family breast/ovarian cancer has not been assessed. PATIENTS: Blood-derived DNA from 20 unrelated affected cases from families with aggregation of breast/ovarian cancer, but with no germline pathogenic variants in BRCA1/2, PALB2 or RAD51C/D, were screened by methylation-sensitive high-resolution melting. CpG analysis was performed by pyrosequencing on blood and buccal swab. Two probands carried a pathogenic variant in a moderate-penetrance gene (ATM and BARD1), and 8 of 18 others (44%) carried BRCA1meth (vs none of the 20 age-matched controls). Involvement of BRCA1 in tumourigenesis in methylated probands was demonstrated in most tested cases by detection of a loss of heterozygosity and a homologous recombination deficiency signature. Among the eight methylated probands, two had relatives with breast cancer with detectable BRCA1meth in blood, including one with high methylation levels in two non-tumour tissues. CONCLUSIONS: The high prevalence of mosaic BRCA1meth in patients with breast/ovarian cancer with affected relatives, as well as this first description of a family aggregation of mosaic BRCA1meth, shows how this de novo event can contribute to hereditary breast/ovarian cancer pedigrees.


Assuntos
Neoplasias da Mama , Neoplasias Ovarianas , Humanos , Feminino , Proteína BRCA1/genética , Linhagem , Proteína BRCA2/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Metilação , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/diagnóstico , Mutação em Linhagem Germinativa/genética , Predisposição Genética para Doença , Metilação de DNA/genética
2.
Am J Hum Genet ; 108(10): 1907-1923, 2021 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-34597585

RESUMO

Up to 80% of BRCA1 and BRCA2 genetic variants remain of uncertain clinical significance (VUSs). Only variants classified as pathogenic or likely pathogenic can guide breast and ovarian cancer prevention measures and treatment by PARP inhibitors. We report the first results of the ongoing French national COVAR (cosegregation variant) study, the aim of which is to classify BRCA1/2 VUSs. The classification method was a multifactorial model combining different associations between VUSs and cancer, including cosegregation data. At this time, among the 653 variants selected, 101 (15%) distinct variants shared by 1,624 families were classified as pathogenic/likely pathogenic or benign/likely benign by the COVAR study. Sixty-six of the 101 (65%) variants classified by COVAR would have remained VUSs without cosegregation data. Of note, among the 34 variants classified as pathogenic by COVAR, 16 remained VUSs or likely pathogenic when following the ACMG/AMP variant classification guidelines. Although the initiation and organization of cosegregation analyses require a considerable effort, the growing number of available genetic tests results in an increasing number of families sharing a particular variant, and thereby increases the power of such analyses. Here we demonstrate that variant cosegregation analyses are a powerful tool for the classification of variants in the BRCA1/2 breast-ovarian cancer predisposition genes.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/patologia , Predisposição Genética para Doença , Variação Genética , Neoplasias Ovarianas/patologia , Neoplasias da Mama/classificação , Neoplasias da Mama/genética , Feminino , Testes Genéticos , Genótipo , Humanos , Neoplasias Ovarianas/classificação , Neoplasias Ovarianas/genética
3.
J Med Genet ; 61(1): 78-83, 2023 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-37541786

RESUMO

About half of the human genome is composed of repeated sequences derived from mobile elements, mainly retrotransposons, generally without pathogenic effect. Familial forms of retinoblastoma are caused by germline pathogenic variants in RB1 gene. Here, we describe a family with retinoblastoma affecting a father and his son. No pathogenic variant was identified after DNA analysis of RB1 gene coding sequence and exon-intron junctions. However, RB1 mRNA analysis showed a chimeric transcript with insertion of 114 nucleotides from HPF1 gene inside RB1 gene. This chimeric transcript led to an insertion of 38 amino acids in functional domain of retinoblastoma protein. Subsequent DNA analysis in RB1 intron 17 revealed the presence of a full-length HPF1 retrogene insertion in opposite orientation. Functional assay shows that this insertion has a deleterious impact on retinoblastoma protein function. This is the first report of a full-length retrogene insertion involved in human Mendelian disease leading to a chimeric transcript and a non-functional chimeric protein. Some retrogene insertions may be missed by standard diagnostic genetic testing, so contribution of retrogene insertions to human disease may be underestimated. The increasing use of whole genome sequencing in diagnostic settings will help to get a more comprehensive view of retrogenes.


Assuntos
Neoplasias da Retina , Retinoblastoma , Humanos , Retinoblastoma/genética , Retinoblastoma/diagnóstico , Retinoblastoma/patologia , Proteína do Retinoblastoma/genética , Genes do Retinoblastoma , Suscetibilidade a Doenças , Neoplasias da Retina/diagnóstico , Neoplasias da Retina/genética , Neoplasias da Retina/patologia , DNA , Análise Mutacional de DNA , Ubiquitina-Proteína Ligases/genética , Proteínas de Ligação a Retinoblastoma/genética , Proteínas de Transporte/genética , Proteínas Nucleares/genética
4.
J Med Genet ; 60(12): 1198-1205, 2023 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-37402566

RESUMO

BACKGROUND: The MSH3 gene is part of the DNA mismatch repair system, but has never been shown to be involved in Lynch syndrome. A first report of four patients from two families, bearing biallelic MSH3 germline variants, with a phenotype of attenuated colorectal adenomatous polyposis raised the question of its involvement in hereditary cancer predisposition. The patients' tumours exhibited elevated microsatellite alterations at selected tetranucleotide repeats (EMAST), a hallmark of MSH3 deficiency. METHODS: We report five new unrelated patients with MSH3-associated polyposis. We describe their personal and familial history and study the EMAST phenotype in various normal and tumour samples, which are relevant findings based on the rarity of this polyposis subtype so far. RESULTS: All patients had attenuated colorectal adenomatous polyposis, with duodenal polyposis in two cases. Both women had breast carcinomas. EMAST phenotype was present at various levels in different samples of the five patients, confirming the MSH3 deficiency, with a gradient of instability in polyps depending on their degree of dysplasia. The negative EMAST phenotype ruled out the diagnosis of germline MSH3 deficiency for two patients: one homozygous for a benign variant and one with a monoallelic large deletion. CONCLUSION: This report lends further credence to biallelic MSH3 germline pathogenic variants being involved in colorectal and duodenal adenomatous polyposis. Large-scale studies may help clarify the tumour spectrum and associated risks. Ascertainment of EMAST may help with the interpretation of variants of unknown significance. We recommend adding MSH3 to dedicated diagnostic gene panels.


Assuntos
Polipose Adenomatosa do Colo , Neoplasias Colorretais Hereditárias sem Polipose , Neoplasias Colorretais , Humanos , Feminino , Polipose Adenomatosa do Colo/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Repetições de Microssatélites/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Predisposição Genética para Doença , Proteína 3 Homóloga a MutS/genética , Proteína 3 Homóloga a MutS/metabolismo
5.
J Med Genet ; 60(12): 1206-1209, 2023 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-37263769

RESUMO

BRCA1 and BRCA2 are tumour suppressor genes that have been characterised as predisposition genes for the development of hereditary breast and ovarian cancers among other malignancies. The molecular diagnosis of this predisposition syndrome is based on the detection of inactivating variants of any type in those genes. But in the case of structural variants, functional consequences can be difficult to assess using standard molecular methods, as the precise resolution of their sequence is often impossible with short-read next generation sequencing techniques. It has been recently demonstrated that Oxford Nanopore long-read sequencing technology can accurately and rapidly provide genetic diagnoses of Mendelian diseases, including those linked to pathogenic structural variants. Here, we report the accurate resolution of a germline duplication event of exons 18-20 of BRCA1 using Nanopore sequencing with adaptive sampling target enrichment. This allowed us to classify this variant as pathogenic within a short timeframe of 10 days. This study provides a proof-of-concept that nanopore adaptive sampling is a highly efficient technique for the investigation of structural variants of tumour suppressor genes in a clinical context.


Assuntos
Neoplasias da Mama , Sequenciamento por Nanoporos , Feminino , Humanos , Virulência , Predisposição Genética para Doença , Proteína BRCA1/genética , Proteína BRCA2/genética , Genes BRCA2 , Éxons , Neoplasias da Mama/genética , Mutação em Linhagem Germinativa/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos
6.
J Med Genet ; 60(5): 460-463, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36270768

RESUMO

APC germline pathogenic variants result in predisposition to familial adenomatous polyposis and extraintestinal tumours such as desmoid fibromatosis, medulloblastomas and thyroid cancers. They have also been recently involved in ovarian microcystic stromal tumours. APC inactivation has been described at the tumour level in epithelial ovarian cancers (EOCs). Here, we report the identification of APC germline pathogenic variants in two patients diagnosed with premenopausal EOC in early 30s, with no other pathogenic variant detected in the known ovarian cancer predisposing genes. Subsequent tumour analysis showed neither a second hit of APC inactivation nor ß-catenin activation. Both tumours did not have a homologous recombination (HR) deficiency, pointing towards the implication of other genes than those involved in HR. APC may contribute to the carcinogenesis of EOC in a multifactorial context. Further studies are required to clarify the role of APC in predisposition to EOC.


Assuntos
Carcinoma Epitelial do Ovário , Genes APC , Neoplasias Ovarianas , Adulto , Feminino , Humanos , Carcinoma Epitelial do Ovário/genética , Predisposição Genética para Doença/genética , Células Germinativas/patologia , Mutação em Linhagem Germinativa/genética , Neoplasias Ovarianas/genética , Pré-Menopausa , beta Catenina/genética
7.
Lancet Oncol ; 24(1): 91-106, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36436516

RESUMO

BACKGROUND: Truncating pathogenic or likely pathogenic variants of CDH1 cause hereditary diffuse gastric cancer (HDGC), a tumour risk syndrome that predisposes carrier individuals to diffuse gastric and lobular breast cancer. Rare CDH1 missense variants are often classified as variants of unknown significance. We conducted a genotype-phenotype analysis in families carrying rare CDH1 variants, comparing cancer spectrum in carriers of pathogenic or likely pathogenic variants (PV/LPV; analysed jointly) or missense variants of unknown significance, assessing the frequency of families with lobular breast cancer among PV/LPV carrier families, and testing the performance of lobular breast cancer-expanded criteria for CDH1 testing. METHODS: This genotype-first study used retrospective diagnostic and clinical data from 854 carriers of 398 rare CDH1 variants and 1021 relatives, irrespective of HDGC clinical criteria, from 29 institutions in ten member-countries of the European Reference Network on Tumour Risk Syndromes (ERN GENTURIS). Data were collected from Oct 1, 2018, to Sept 20, 2022. Variants were classified by molecular type and clinical actionability with the American College of Medical Genetics and Association for Molecular Pathology CDH1 guidelines (version 2). Families were categorised by whether they fulfilled the 2015 and 2020 HDGC clinical criteria. Genotype-phenotype associations were analysed by Student's t test, Kruskal-Wallis, χ2, and multivariable logistic regression models. Performance of HDGC clinical criteria sets were assessed with an equivalence test and Youden index, and the areas under the receiver operating characteristic curves were compared by Z test. FINDINGS: From 1971 phenotypes (contributed by 854 probands and 1021 relatives aged 1-93 years), 460 had gastric and breast cancer histology available. CDH1 truncating PV/LPVs occurred in 176 (21%) of 854 families and missense variants of unknown significance in 169 (20%) families. Multivariable logistic regression comparing phenotypes occurring in families carrying PV/LPVs or missense variants of unknown significance showed that lobular breast cancer had the greatest positive association with the presence of PV/LPVs (odds ratio 12·39 [95% CI 2·66-57·74], p=0·0014), followed by diffuse gastric cancer (8·00 [2·18-29·39], p=0·0017) and gastric cancer (7·81 [2·03-29·96], p=0·0027). 136 (77%) of 176 families carrying PV/LPVs fulfilled the 2015 HDGC criteria. Of the remaining 40 (23%) families, who did not fulfil the 2015 criteria, 11 fulfilled the 2020 HDGC criteria, and 18 had lobular breast cancer only or lobular breast cancer and gastric cancer, but did not meet the 2020 criteria. No specific CDH1 variant was found to predispose individuals specifically to lobular breast cancer, although 12 (7%) of 176 PV/LPV carrier families had lobular breast cancer only. Addition of three new lobular breast cancer-centred criteria improved testing sensitivity while retaining high specificity. The probability of finding CDH1 PV/LPVs in patients fulfilling the lobular breast cancer-expanded criteria, compared with the 2020 criteria, increased significantly (AUC 0·92 vs 0·88; Z score 3·54; p=0·0004). INTERPRETATION: CDH1 PV/LPVs were positively associated with HDGC-related phenotypes (lobular breast cancer, diffuse gastric cancer, and gastric cancer), and no evidence for a positive association with these phenotypes was found for CDH1 missense variants of unknown significance. CDH1 PV/LPVs occurred often in families with lobular breast cancer who did not fulfil the 2020 HDGC criteria, supporting the expansion of lobular breast cancer-centred criteria. FUNDING: European Reference Network on Genetic Tumour Risk Syndromes, European Regional Development Fund, Fundação para a Ciência e a Tecnologia (Portugal), Cancer Research UK, and European Union's Horizon 2020 research and innovation programme.


Assuntos
Neoplasias da Mama , Carcinoma Lobular , Neoplasias Gástricas , Feminino , Humanos , Antígenos CD/genética , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Caderinas/genética , Predisposição Genética para Doença , Genótipo , Células Germinativas/patologia , Mutação em Linhagem Germinativa , Linhagem , Fenótipo , Estudos Retrospectivos , Neoplasias Gástricas/epidemiologia , Neoplasias Gástricas/genética , Mutação de Sentido Incorreto
8.
Neuropathol Appl Neurobiol ; 49(4): e12929, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37524406

RESUMO

AIMS: The mutY DNA glycosylase encoded by the MUTYH gene prevents G:C → T:A transversions through the base excision repair DNA repair system. Germline biallelic pathogenic variants in MUTYH cause an adenomatous polyposis called MUTYH-associated polyposis (MAP), an autosomal recessive disease (OMIM: 608456), with an increased risk of colorectal cancer. Digestive lesions in this context show an excess of G:C → T:A transversions, individualising a specific mutational signature associated with MUTYH deficiency called signature SBS36. Predisposition to other tumours in patients with germline biallelic pathogenic variants in MUTYH is suspected but remains unclear. We report the first case of medulloblastoma in a patient with MAP, carrying the homozygous pathogenic variant c.1227_1228dup, p.(Glu410Glyfs*43) in MUTYH. METHODS: Whole exome sequencing was performed on the medulloblastoma to enlighten single nucleotide variants of interest, microsatellite status and mutational signature. The objective was to determine the involvement of MUTYH deficiency in the oncogenesis of this medulloblastoma. RESULTS: The medulloblastoma has the mutational signature SBS36 and driver pathogenic variants in CTNNB1, PTCH1 and KDM6A corresponding to G:C → T:A transversions, suggesting a role of MUTYH deficiency in oncogenesis. CONCLUSIONS: Therefore, medulloblastoma could be a rare manifestation associated with germline biallelic pathogenic variants in MUTYH.


Assuntos
Polipose Adenomatosa do Colo , Neoplasias Cerebelares , Neoplasias Colorretais , Meduloblastoma , Humanos , Meduloblastoma/genética , Predisposição Genética para Doença , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/patologia , Mutação , Neoplasias Cerebelares/genética , Carcinogênese , Neoplasias Colorretais/genética
9.
Clin Genet ; 104(1): 107-113, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-36974006

RESUMO

In breast or ovarian cancer (BC/OC) patients with evocative personal and/or family history, multigene panel sequencing is performed on blood to diagnose hereditary predispositions. Additionally, BRCA1/BRCA2 testing can be performed on tumor sample for therapeutic purpose. The accuracy of multigene panel tumor analysis on BC/OC to detect predisposing germline pathogenic variants (gPV) has not been precisely assessed. By comparing sequencing data from blood and fresh-frozen tumor we show that tumor genomic instability causes pitfalls to consider when performing tumor testing to detect gPV. Even if loss of heterozygosity increases germline signal in most cases, somatic copy number variants (CNV) can mask germline CNV and collapse point gPV variant allele frequency (VAF). Moreover, VAF does not allow an accurate distinction between germline and somatic pathogenic variants.


Assuntos
Neoplasias da Mama , Neoplasias Ovarianas , Feminino , Humanos , Predisposição Genética para Doença , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/genética , Proteína BRCA1/genética , Proteína BRCA2/genética , Genes BRCA2 , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Mutação em Linhagem Germinativa/genética
10.
J Med Genet ; 59(12): 1189-1195, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36038258

RESUMO

BACKGROUND: Pathogenic variants (PV) of CTNNA1 are found in families fulfilling criteria for hereditary diffuse gastric cancer (HDGC) but no risk estimates were available until now. The aim of this study is to evaluate diffuse gastric cancer (DGC) risks for carriers of germline CTNNA1 PV. METHODS: Data from published CTNNA1 families were updated and new families were identified through international collaborations. The cumulative risk of DGC by age for PV carriers was estimated with the genotype restricted likelihood (GRL) method, taking into account non-genotyped individuals and conditioning on all observed phenotypes and genotypes of the index case to obtain unbiased estimates. A non-parametric (NP) and the Weibull functions were used to model the shape of penetrance function with the GRL. Kaplan-Meier incidence curve and standardised incidence ratios were also computed. A 'leave-one-out' strategy was used to evaluate estimate uncertainty. RESULTS: Thirteen families with 46 carriers of PV were included. The cumulative risks of DGC at 80 years for carriers of CTNNA1 PV are 49% and 57%, respectively with the Weibull GRL and NP GRL methods. Risk ratios to population incidence reach particularly high values at early ages and decrease with age. At 40 years, they are equal to 65 and 833, respectively with the Weibull GRL and NP GRL. CONCLUSION: This is the largest series of CTNNA1 families that provides the first risk estimates of GC. These data will help to improve management and surveillance for these patients and support inclusion of CTNNA1 in germline testing panels.


Assuntos
Neoplasias Gástricas , Humanos , Neoplasias Gástricas/epidemiologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Caderinas/genética , Predisposição Genética para Doença , Heterozigoto , Células Germinativas/patologia , Mutação em Linhagem Germinativa/genética , alfa Catenina/genética
11.
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
12.
Breast Cancer Res Treat ; 192(2): 375-383, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34994879

RESUMO

PURPOSE: A personalized approach to prevention and early detection based on known risk factors should contribute to early diagnosis and treatment of breast cancer. We initiated a risk assessment clinic for all women wishing to undergo an individual breast cancer risk assessment. METHODS: Women underwent a complete breast cancer assessment including a questionnaire, mammogram with evaluation of breast density, collection of saliva sample, consultation with a radiologist, and a breast cancer specialist. Women aged 40 or older, with 0 or 1 first-degree relative with breast cancer diagnosed after the age of 40 were eligible for risk assessment using MammoRisk, a machine learning-based tool that provides an individual 5-year estimated risk of developing breast cancer based on the patient's clinical data and breast density, with or without polygenic risk scores (PRSs). DNA was extracted from saliva samples for genotyping of 76 single-nucleotide polymorphisms. The individual risk was communicated to the patient, with individualized screening and prevention recommendations. RESULTS: A total of 290 women underwent breast cancer assessment, among which 196 women (68%) were eligible for risk assessment using MammoRisk (median age 52, range 40-72). When PRS was added to MammoRisk, 40% (n = 78) of patients were assigned a different risk category, with 28% (n = 55) of patients changing from intermediate to moderate or high risk. CONCLUSION: Individual risk assessment is feasible in the general population. Screening recommendations could be given based on individual risk. The use of PRS changed the risk score and screening recommendations in 40% of women.


Assuntos
Neoplasias da Mama , Adulto , Densidade da Mama , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Detecção Precoce de Câncer/métodos , Estudos de Viabilidade , Feminino , Humanos , Mamografia , Pessoa de Meia-Idade , Medição de Risco/métodos , Fatores de Risco
13.
Clin Chem ; 68(2): 322-331, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-34928333

RESUMO

BACKGROUND: DICER1 syndrome is an autosomal dominant inherited syndrome predisposing to various benign and malignant tumors, mainly occurring in children and young adults, requiring broad surveillance starting at birth with repeated irradiating imaging exams and sedations for young patients. It is caused by monoallelic germline pathogenic variants in the DICER1 gene. More than 90% of tumors bear an additional somatic DICER1 missense hotspot mutation, as a second hit, involving 1 of 6 codons clustered in exons 24 and 25. We designed and in vitro validated a drop-off droplet digital PCR (ddPCR) system to scan all DICER1 hotspot codons, allowing for a liquid biopsy test, an alternative to sedation and radiation exposure. METHODS: Three drop-off ddPCR assays were designed, with 2 TaqMan probes per assay, 1 complementary to the wild-type sequence of the region containing hotspots and another 1 used as a reference. Eight tumor-derived DNAs and 5 synthetic oligonucleotides bearing DICER1 hotspot mutations were tested. RESULTS: All tested mutations were detected, with a limit of detection ranging from 0.07% to 0.31% for codons p. E1705, p. D1709, and p. D1713 in exon 24 and from 0.06% to 0.15% for codons p. G1809, p. D1810, and p. E1813 in exon 25. CONCLUSIONS: The high sensitivity of this method is compatible with its use for plasma circulating tumor DNA (ctDNA) analysis for early tumor detection in DICER1 syndrome patients. It may reduce the need for radiation exposure and sedation in surveillance protocols and may also improve patient prognosis. Clinical trials are needed to evaluate ctDNA analysis in these patients.


Assuntos
DNA Tumoral Circulante , Neoplasias , Criança , Códon , RNA Helicases DEAD-box/genética , Humanos , Recém-Nascido , Mutação , Neoplasias/genética , Reação em Cadeia da Polimerase/métodos , Ribonuclease III/genética , Adulto Jovem
14.
J Med Genet ; 58(6): 357-361, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-32576655

RESUMO

INTRODUCTION: We report a very rare case of familial breast cancer and diffuse gastric cancer, with germline pathogenic variants in both BRCA1 and CDH1 genes. To the best of our knowledge, this is the first report of such an association.Family description: The proband is a woman diagnosed with breast cancer at the age of 52 years. She requested genetic counselling in 2012, at the age of 91 years, because of a history of breast cancer in her daughter, her sister, her niece and her paternal grandmother and was therefore concerned about her relatives. Her sister and maternal aunt also had gastric cancer. She was tested for several genes associated with hereditary breast cancer. RESULTS: A large deletion of BRCA1 from exons 1 to 7 and two CDH1 pathogenic cis variants were identified. CONCLUSION: This complex situation is challenging for genetic counselling and management of at-risk individuals.


Assuntos
Antígenos CD/genética , Neoplasias da Mama/genética , Caderinas/genética , Genes BRCA1 , Mutação em Linhagem Germinativa , Neoplasias Primárias Múltiplas/genética , Neoplasias Gástricas/genética , Idoso de 80 Anos ou mais , Neoplasias da Mama/complicações , Feminino , Humanos , Anamnese , Linhagem , Neoplasias Gástricas/complicações
15.
Clin Genet ; 99(5): 662-672, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33454955

RESUMO

Biallelic pathogenic variants in the NTHL1 (Nth like DNA glycosylase 1) gene cause a recently identified autosomal recessive hereditary cancer syndrome predisposing to adenomatous polyposis and colorectal cancer. Half of biallelic carriers also display multiple colonic or extra-colonic primary tumors, mainly breast, endometrium, urothelium, and brain tumors. Published data designate NTHL1 as an important contributor to hereditary cancers but also underline the scarcity of available informations. Thanks to the French oncogenetic consortium (Groupe Génétique et Cancer), we collected NTHL1 variants from 7765 patients attending for hereditary colorectal cancer or polyposis (n = 3936) or other hereditary cancers (n = 3829). Here, we describe 10 patients with pathogenic biallelic NTHL1 germline variants, that is, the second largest NTHL1 series. All carriers were from the "colorectal cancer or polyposis" series. All nine biallelic carriers who underwent colonoscopy presented adenomatous polyps. For digestive cancers, average age at diagnosis was 56.2 and we reported colorectal, duodenal, caecal, and pancreatic cancers. Extra-digestive malignancies included sarcoma, basal cell carcinoma, breast cancer, urothelial carcinoma, and melanoma. Although tumor risks remain to be precisely defined, these novel data support NTHL1 inclusion in diagnostic panel testing. Colonic surveillance should be conducted based on MUTYH recommendations while extra-colonic surveillance has to be defined.


Assuntos
Desoxirribonuclease (Dímero de Pirimidina)/genética , Síndromes Neoplásicas Hereditárias/genética , Neoplasias Ovarianas/genética , Polipose Adenomatosa do Colo/genética , Adulto , Idoso , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Neoplasias Colorretais/genética , Feminino , Mutação em Linhagem Germinativa , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Reação em Cadeia da Polimerase Via Transcriptase Reversa
16.
Gynecol Oncol ; 156(2): 377-386, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31753525

RESUMO

BACKGROUND: Carriers of pathogenic variants in both BRCA1 and BRCA2 genes as a double mutation (BRCA1/2 DM) have been rarely reported in women with epithelial ovarian cancer (EOC). METHODS: We reviewed the English literature and interrogated three repositories reporting EOC patients carrying BRCA1/2 DM. The clinicopathological parameters of 36 EOC patients carrying germline BRCA1/2 DM were compared to high-grade serous EOC women of the COEUR cohort with known germline BRCA1/BRCA2 mutation carrier status (n = 376 non-carriers, n = 65 BRCA1 and n = 38 BRCA2). Clinicopathological parameters evaluated were age at diagnosis, stage of disease, loss of heterozygosity, type of mutation, immunohistochemistry profile, progression occurrence and survival. RESULTS: Median age at diagnosis of BRCA1/2 DM patients was 51.9 years, similar to BRCA1 mutation carriers (49.7 years, p = .58) and younger than BRCA2 mutation carriers (58.1 years, p = .02). Most patients were diagnosed at advanced stage (III-IV; 82%) and were carriers of founder/frequent mutations (69%). Tissue immunostainings revealed no progesterone receptor expression and low intraepithelial inflammation. The 5-year survival rate (60%) was significantly lower than that of BRCA2 mutation carriers (76%, p = .03) but not of BRCA1 mutation carriers (51%, p = .37). CONCLUSIONS: Our data suggests some co-dominant effect of both mutations but the outcome of these patients more closely resembled that of BRCA1 mutation carriers with poor prognosis factors.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Carcinoma Epitelial do Ovário/genética , Neoplasias Ovarianas/genética , Adulto , Idoso , Carcinoma Epitelial do Ovário/patologia , Feminino , Genes BRCA1 , Genes BRCA2 , Mutação em Linhagem Germinativa , Heterozigoto , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Receptores de Progesterona/biossíntese , Receptores de Progesterona/genética
17.
Gynecol Oncol ; 155(2): 262-269, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31604666

RESUMO

OBJECTIVE: To investigate clinical factors associated with prolonged progression-free survival (PFS) and overall survival (OS) in relapsing epithelial ovarian cancer (EOC) patients with BRCA mutations and receiving olaparib as maintenance therapy in daily practice. METHODS: Multicenter (8 hospitals) European retrospective study of relapsing EOC patients having germline or somatic mutations of BRCA1/BRCA2 genes and treated with olaparib as maintenance therapy after platinum-based chemotherapy. RESULTS: One hundred and fifteen patients were included. Median age was 54 years. There were 90 BRCA1 carriers, 24 BRCA2 carriers and one patient had germline mutation of BRCA1 and BRCA2. Six patients had somatic mutations (all BRCA1) and 109 had germline mutations. Ninety percent had serous carcinomas and were platinum-sensitive. Following ultimate platinum-based chemotherapy, 69% of the patients had normalization of CA-125 levels and 87% had RECIST objective responses, either partial (53%) or complete (34%). After a median follow-up of 21 months, median PFS was 12.7 months and median OS was 35.4 months. In multivariate analysis, factors associated with prolonged PFS under olaparib were: platinum-free interval (PFI) ≥ 12 months, RECIST complete response (CR) or partial response (PR) and normalization of CA-125 upon ultimate platinum-based chemotherapy. Factors associated with prolonged OS were PFI ≥ 12 months, CR and normalization of CA-125. CONCLUSIONS: Platinum-free interval ≥ 12 months, complete response and normalized CA-125 levels after ultimate platinum-based chemotherapy are associated with prolonged PFS and OS in relapsing BRCA1/BRCA2 mutated ovarian cancer patients who received olaparib as maintenance therapy.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Ftalazinas/uso terapêutico , Piperazinas/uso terapêutico , Antígeno Ca-125/metabolismo , Intervalo Livre de Doença , Feminino , Genes BRCA1/fisiologia , Genes BRCA2/fisiologia , Mutação em Linhagem Germinativa/genética , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/mortalidade , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/mortalidade , Estudos Retrospectivos , Resultado do Tratamento
18.
Pharmacol Res ; 136: 56-61, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30142421

RESUMO

Δ4-abiraterone (Δ4A) is an activemetabolite of abiraterone (ABI), which is approved in the treatment of metastatic castration resistant prostate cancer (mCRPC). The contribution of Δ4A to the clinical antitumor activity of ABI remains unknown. The aim of this study was to explore the relationship between plasma Δ4A concentration and survival in 36 mCRPC patients treated with abiraterone acetate (1000 mg/day) plus prednisone (10 mg/day). Plasma trough ABI and Δ4A concentrations were monthly assayed using liquid chromatography during the first 3 months of treatment. ABI and Δ4A Cmin were defined as the mean of trough concentrations measured for each patient. Predictive factors regarding progression-free survival (PFS) and overall survival (OS) were explored using univariate Cox model. Mean plasma ABI and Δ4A Cmin were 12.6 ± 6.8 ng/mL and 1.6 ± 1.3 ng/mL, respectively. The mean metabolic ratio Δ4A/ABI was of 0.18 ± 0.25. In regard with in vitro pharmacodynamic data, effective plasma concentrations for ABI and Δ4A were reached in 30 patients (83.3%) and only 2 patients (5.6%), respectively. Higher Δ4A Cmin was associated with shorter OS (Hazard ratio, HR 1.54; CI95% 1.06-2.22; p = 0.022) but not with PFS. The HR associated with the metabolic Δ4A/ABI ratio for PFS and OS were 7.80 (CI 95% 1.63-37.38; p = 0.010) and 12.52 (CI 95% 1.95-80.47, p = 0.0078), respectively. The present study shows Δ4A is unlikely to have meaningful contribution to pharmacodynamic activity of ABI in mCPRC, rather that higher plasma Δ4A concentration is associated with worse clinical outcomes. A high Δ4A/ABI metabolic ratio could help to identify mCRPC patients with poorer survival.


Assuntos
Acetato de Abiraterona/farmacocinética , Acetato de Abiraterona/uso terapêutico , Antagonistas de Receptores de Andrógenos/farmacocinética , Antagonistas de Receptores de Andrógenos/uso terapêutico , Androstenos/sangue , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Acetato de Abiraterona/sangue , Idoso , Idoso de 80 Anos ou mais , Antagonistas de Receptores de Andrógenos/sangue , Humanos , Masculino , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Análise de Sobrevida
19.
Pediatr Blood Cancer ; 65(6): e27005, 2018 06.
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.


Assuntos
RNA Helicases DEAD-box/genética , Mutação em Linhagem Germinativa , Bócio Nodular/genética , Íntrons/genética , Pneumopatias/genética , Neoplasias Ovarianas/genética , Ribonuclease III/genética , Tumor de Células de Sertoli-Leydig/genética , Adolescente , Idoso , Criança , Feminino , Bócio Nodular/patologia , Humanos , Pneumopatias/patologia , Masculino , Neoplasias Ovarianas/patologia , Linhagem , Prognóstico , Tumor de Células de Sertoli-Leydig/patologia
20.
Int J Cancer ; 138(4): 891-900, 2016 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-26317927

RESUMO

Therapeutic strategies targeting Homologous Recombination Deficiency (HRD) in breast cancer requires patient stratification. The LST (Large-scale State Transitions) genomic signature previously validated for triple-negative breast carcinomas (TNBC) was evaluated as biomarker of HRD in luminal (hormone receptor positive) and HER2-overexpressing (HER2+) tumors. The LST genomic signature related to the number of large-scale chromosomal breakpoints in SNP-array tumor profile was applied to identify HRD in in-house and TCGA sets of breast tumors, in which the status of BRCA1/2 and other genes was also investigated. In the in-house dataset, HRD was predicted in 5% (20/385) of sporadic tumors luminal or HER2+ by the LST genomic signature and the inactivation of BRCA1, BRCA2 or RAD51C confirmed this prediction in 75% (12/16) of the tested cases. In 14% (6/43) of tumors occurring in BRCA1/2 mutant carriers, the corresponding wild-type allele was retained emphasizing the importance of determining the tumor status. In the TCGA luminal and HER2+ subtypes HRD incidence was estimated at 5% (18/329, 95%CI: 5-8%) and 2% (1/59, 95%CI: 2-9%), respectively. In TNBC cisplatin-based neo-adjuvant clinical trials, HRD is shown to be a necessary condition for cisplatin sensitivity. This analysis demonstrates the high performance of the LST genomic signature for HRD detection in breast cancers, which suggests its potential as a biomarker for genetic testing and patient stratification for clinical trials evaluating platinum salts and PARP inhibitors.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Carcinoma/genética , Reparo de DNA por Recombinação/genética , Transcriptoma/genética , Neoplasias da Mama/patologia , Carcinoma/patologia , Quebra Cromossômica , Feminino , Genes BRCA2 , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Receptor ErbB-2/genética
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