RESUMO
Germline DNA alterations affecting homologous recombination pathway genes have been associated with pancreatic cancer (PC) risk. BRCA2 is the most studied gene and affects the management of PC patients and their families. Even though recent reports have suggested a similar role of germline ATM pathogenic variants (PV) in familial PC, there is still a disagreement between experts on how it could affect patient management given the lack of proper PC risk estimates. We retrospectively analyzed the germline data of 257 PC patients among whom nearly 50% were sporadic cases. We showed similar frequencies of BRCA2 (4.9%) and ATM (4.4%) PV or likely pathogenic variants, which were not related to familial history. Based on our findings and that of the literature, we suggest including ATM gene among the panel of genes analyzed in PC patients pending the publication of prospective studies.
Assuntos
Predisposição Genética para Doença , Neoplasias Pancreáticas , Humanos , Estudos Retrospectivos , Estudos Prospectivos , Mutação em Linhagem Germinativa , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologiaRESUMO
BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) syndrome is a childhood cancer predisposition syndrome involving biallelic germline mutations of MMR genes, poorly recognised by clinicians so far. METHODS: Retrospective review of all 31 patients with CMMRD diagnosed in French genetics laboratories in order to describe the characteristics, treatment and outcome of the malignancies and biological diagnostic data. RESULTS: 67 tumours were diagnosed in 31 patients, 25 (37%) Lynch syndrome-associated malignancies, 22 (33%) brain tumours, 17 (25%) haematological malignancies and 3 (5%) sarcomas. The median age of onset of the first tumour was 6.9â years (1.2-33.5). Overall, 22 patients died, 9 (41%) due to the primary tumour. Median survival after the diagnosis of the primary tumour was 27â months (0.26-213.2). Failure rate seemed to be higher than expected especially for T-cell non-Hodgkin's lymphoma (progression/relapse in 6/12 patients). A familial history of Lynch syndrome was identified in 6/23 families, and consanguinity in 9/23 families. PMS2 mutations (n=18) were more frequent than other mutations (MSH6 (n=6), MLH1 (n=4) and MSH2 (n=3)). CONCLUSIONS: In conclusion, this unselected series of patients confirms the extreme severity of this syndrome with a high mortality rate mostly related to multiple childhood cancers, and highlights the need for its early detection in order to adapt treatment and surveillance.
Assuntos
Neoplasias Encefálicas/diagnóstico , Neoplasias Colorretais/diagnóstico , Síndromes Neoplásicas Hereditárias/diagnóstico , Proteínas Adaptadoras de Transdução de Sinal/genética , Adenosina Trifosfatases/genética , Adolescente , Adulto , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Criança , Pré-Escolar , Neoplasias Colorretais/genética , Neoplasias Colorretais/terapia , Enzimas Reparadoras do DNA/genética , Proteínas de Ligação a DNA/genética , Feminino , Humanos , Lactente , Masculino , Endonuclease PMS2 de Reparo de Erro de Pareamento , Proteína 1 Homóloga a MutL , Proteína 2 Homóloga a MutS/genética , Mutação , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/terapia , Proteínas Nucleares/genética , Resultado do Tratamento , Adulto JovemRESUMO
Cutaneous melanoma is a multifactorial disease resulting from both environmental and genetic factors. Five susceptibility genes have been identified over the past years, comprising high-risk susceptibility genes (CDKN2A, CDK4, and BAP1 genes) and intermediate-risk susceptibility genes (MITF, and MC1R genes). The aim of this expert consensus was to define clinical contexts justifying genetic analyses, to describe the conduct of these analyses, and to propose surveillance recommendations. Given the regulatory constraints, it is recommended that dermatologists work in tandem with a geneticist. Genetic analysis may be prescribed when at least two episodes of histologically proven invasive cutaneous melanoma have been diagnosed before the age of 75 years in two 1st or 2nd degree relatives or in the same individual. The occurrence in the same individual or in a relative of invasive cutaneous melanoma with ocular melanoma, pancreatic cancer, renal cancer, mesothelioma or a central nervous system tumour are also indications for genetic testing. Management is based upon properly managed photoprotection and dermatological monitoring according to genetic status. Finally, depending on the mutated gene and the familial history, associated tumour risks require specific management (e.g. ocular melanoma, pancreatic cancer). Due to the rapid progress in genetics, these recommendations will need to be updated regularly.
Assuntos
Predisposição Genética para Doença , Testes Genéticos , Melanoma/genética , Neoplasias Cutâneas/genética , Quinase 4 Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Genótipo , Humanos , Fator de Transcrição Associado à Microftalmia/genética , Mutação , Receptor Tipo 1 de Melanocortina/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genéticaRESUMO
The BRCA1-associated protein 1 (BAP1) gene encodes a nuclear deubiquitin enzyme which acts as a tumour suppressor. Loss of function germline mutations of BAP1 have been associated with an enhanced risk of uveal and cutaneous melanomas, mesothelioma, clear cell renal cancer and atypical cutaneous melanocytic proliferations. In two independent BAP1 families, we noticed an unusual frequency of basal cell carcinomas (BCCs). Indeed, 19 BCCs were diagnosed in four patients, either of superficial (13/19) or nodular (6/19) subtype; they were all located in chronic sun-exposed areas (limbs, head or neck). Immunohistochemistry (IHC) identified in the 19 tumours, complete or partial loss of BAP1 protein nuclear expression, restricted to the BCC nests. A control study was conducted in 22 sporadic BCCs in 22 subjects under 65 without known associated BAP1 tumours: no loss of BAP1 expression was found. Overall, our observations suggest that BCCs are part of the BAP1 cancer syndrome, perhaps in relation with chronic sun exposure and melanocortin 1 receptor (MC1R) variants. In conclusion, cutaneous follow-up of BAP1 carriers should not only aim to detect melanocytic neoplasms but also BCCs.
Assuntos
Carcinoma Basocelular/genética , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Síndrome do Hamartoma Múltiplo/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Adulto , Carcinoma Basocelular/diagnóstico , Estudos de Casos e Controles , Feminino , Genótipo , Síndrome do Hamartoma Múltiplo/diagnóstico , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Receptor Tipo 1 de Melanocortina , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina Tiolesterase/metabolismoRESUMO
Lynch syndrome (LS) is an autosomal dominant disorder caused by a defect in one of the DNA mismatch repair genes: MLH1, MSH2, MSH6 and PMS2. In the last 15 years, an increasing number of patients have been described with biallelic mismatch repair gene mutations causing a syndrome referred to as 'constitutional mismatch repair-deficiency' (CMMR-D). The spectrum of cancers observed in this syndrome differs from that found in LS, as about half develop brain tumours, around half develop digestive tract cancers and a third develop haematological malignancies. Brain tumours and haematological malignancies are mainly diagnosed in the first decade of life, and colorectal cancer (CRC) and small bowel cancer in the second and third decades of life. Surveillance for CRC in patients with LS is very effective. Therefore, an important question is whether surveillance for the most common CMMR-D-associated cancers will also be effective. Recently, a new European consortium was established with the aim of improving care for patients with CMMR-D. At a workshop of this group held in Paris in June 2013, one of the issues addressed was the development of surveillance guidelines. In 1968, criteria were proposed by WHO that should be met prior to the implementation of screening programmes. These criteria were used to assess surveillance in CMMR-D. The evaluation showed that surveillance for CRC is the only part of the programme that largely complies with the WHO criteria. The values of all other suggested screening protocols are unknown. In particular, it is questionable whether surveillance for haematological malignancies improves the already favourable outcome for patients with these tumours. Based on the available knowledge and the discussions at the workshop, the European consortium proposed a surveillance protocol. Prospective collection of all results of the surveillance is needed to evaluate the effectiveness of the programme.
Assuntos
Neoplasias Encefálicas/diagnóstico , Distúrbios no Reparo do DNA/genética , Neoplasias do Sistema Digestório/diagnóstico , Neoplasias/diagnóstico , Neoplasias Encefálicas/etiologia , Neoplasias Colorretais/genética , Neoplasias Colorretais Hereditárias sem Polipose/tratamento farmacológico , Neoplasias Colorretais Hereditárias sem Polipose/genética , Distúrbios no Reparo do DNA/complicações , Humanos , Leucemia/diagnóstico , Mutação , Neoplasias/etiologia , Vigilância da PopulaçãoRESUMO
Oral, but not transdermal, estrogen therapy increases the risk of venous thromboembolism (VTE) in women who are past menopause. Data from the Estrogen and Thromboembolism Risk (ESTHER) study were used to investigate the effects of the genetic polymorphism of NFE2L2 rs6721961, which may impair Nrf2-dependent hepatic conjugation of estrogen metabolites. As compared with nonusers, the odds ratio (OR) for VTE in current users of oral estrogens was 2.5 (95% confidence interval (CI): 1.3-4.8) in patients with wild-type NFE2L2 and 17.9 (95% CI: 3.7-85.7) in those with the polymorphism (interaction, P = 0.01).
Assuntos
Terapia de Reposição de Estrogênios/efeitos adversos , Fator 2 Relacionado a NF-E2/genética , Polimorfismo de Nucleotídeo Único , Pós-Menopausa , Tromboembolia Venosa/genética , Administração Cutânea , Administração Oral , Idoso , Estudos de Casos e Controles , Estradiol/administração & dosagem , Estradiol/efeitos adversos , Estradiol/farmacocinética , Estradiol/uso terapêutico , Estrogênios/administração & dosagem , Estrogênios/efeitos adversos , Estrogênios/farmacocinética , Estrogênios/uso terapêutico , Feminino , Estudos de Associação Genética , Humanos , Desintoxicação Metabólica Fase II/genética , Pessoa de Meia-Idade , Razão de Chances , Embolia Pulmonar/epidemiologia , Embolia Pulmonar/genética , Fatores de Risco , Tromboembolia Venosa/epidemiologia , Trombose Venosa/epidemiologia , Trombose Venosa/genéticaRESUMO
PCR analysis in two unusual occurrences of trichomoniasis, trichomonal empyema due to Trichomonas tenax and Trichomonas vaginalis in an infant urine sample, allowed us to obtain rapid and accurate trichomonad species identification. The weak sensitivity of wet preparations and the low viability of the flagellates can be remedied by the PCR method.
Assuntos
Tricomoníase/diagnóstico , Trichomonas vaginalis , Trichomonas , Adulto , Animais , Feminino , Humanos , Lactente , Reação em Cadeia da PolimeraseRESUMO
The antimalarial trioxaquine derivative DU-1102, synthesized by covalent linkage between aminoquinoline and trioxane moieties, was highly active against Cameroonian isolates (mean 50% inhibitory concentration of 43 nmol/liter) of Plasmodium falciparum. There was no correlation between the responses to DU-1102 and chloroquine and only a low correlation between the responses to DU-1102 and pyrimethamine, suggesting an independent mode of action of the trioxaquine against the parasites.