RESUMO
BACKGROUND: The presence of single nucleotide polymorphisms (SNPs) in the REarranged during Transfection (RET) gene has been investigated with regard to their potential role in the development or progression of medullary thyroid cancer or pheochromocytomas (PHEO) in patients with the multiple endocrine neoplasia type 2 (MEN2) syndrome. The aim of this study was to evaluate the spectrum of RET variants in France between 2003 and 2013, and to evaluate the impact of SNPs on the MEN2 A phenotype. METHODS: In this retrospective cohort study, RET variants were screened in 5109 index cases, and RET pathogenic variants were screened in 2214 relatives. Exons 5, 8, 10, 11, 13, 14, 15, and 16 were characterized by Sanger sequencing. RET pathogenic variants, RET variants with unknown functional significance (VUS), and four RET SNP variants-G691S (rs1799939), L769L (rs1800861), S836S (rs1800862), and S904S (rs1800863)-were characterized and are reported in index cases. In silico analysis and classification following the recommendation of the American College of Medical Genetics and Genomics was performed for RET VUS. Each patient's age at the time of diagnosis, sex, and the endocrine neoplasias present at molecular diagnosis were recorded. RESULTS: Twenty-six single VUS in RET without any well-defined risk profiles were found in 33 patients. Nine of these were considered probably pathogenic, 11 of uncertain significance, and six as probably benign. Three double pathogenic variants found in three patients were classified as pathogenic. A study of the entire cohort showed that patients carrying pathogenic variants or VUS in RET together with PHEO were diagnosed earlier than the others. The presence of the G691S SNP, or a combination of SNPs, increased the risk of developing PHEO but did not modify the date of the diagnosis. No association was found between SNPs and medullary thyroid cancer or hyperparathyroidism. CONCLUSIONS: The findings propose a classification of 15 of the 26 VUS in RET without any well-defined risk profiles and suggest that the G691S SNP, or a combination of SNPs, may be associated with the development of PHEO.
Assuntos
Neoplasias das Glândulas Suprarrenais/genética , Carcinoma Medular/genética , Neoplasia Endócrina Múltipla Tipo 2a/genética , Feocromocitoma/genética , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas c-ret/genética , Neoplasias da Glândula Tireoide/genética , Neoplasias das Glândulas Suprarrenais/patologia , Adulto , Idoso , Carcinoma Medular/patologia , Éxons , Feminino , França , Frequência do Gene , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasia Endócrina Múltipla Tipo 2a/patologia , Feocromocitoma/patologia , Estudos Retrospectivos , Neoplasias da Glândula Tireoide/patologiaRESUMO
Between January 1994 and December 2004, 696 patients with localized endometrial carcinoma have been treated at the Institute Jean-Godinot. Patients were selected on the following criteria: histologically proven adenocarcinoma of the endometrium; age at onset under 60 years; patient not deceased at the time of the study. One hundred twelve patients met these criteria and received a mailed specific questionnaire to establish their pedigree. Thirty-one patients (35.5%) were eventually found eligible for a genetic counselling but only 13 patients agreed to be informed later on. According to the obtained pedigrees and MSI test results, 7 genetic tests have been carried out and so far, 3 MMR mutations were detected. This study suggested the feasibility of a step by step screening of endometrial cancers to select patients at risk for Lynch syndrome and for whom a genetic test would be recommended. Authors suggest that either Amsterdam or Bethesda criteria should be systematically used prospectively in every newly diagnosed endometrial cancer and retrospectively using clinical databases available on endometrial cancers.
Assuntos
Adenocarcinoma/radioterapia , Braquiterapia/métodos , Neoplasias Colorretais Hereditárias sem Polipose/radioterapia , Neoplasias do Endométrio/radioterapia , Proteínas Adaptadoras de Transdução de Sinal/genética , Adenocarcinoma/diagnóstico , Adenocarcinoma/genética , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo do DNA/genética , Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/genética , Feminino , Humanos , Proteína 1 Homóloga a MutL , Proteína 2 Homóloga a MutS/genética , Mutação , Proteínas Nucleares/genética , Avaliação de Resultados em Cuidados de Saúde , Inquéritos e QuestionáriosRESUMO
Expression of three major resistance genes MDR1, MRP1 and LRP was investigated in small cell lung cancer, non-small cell lung cancer and metastasis. Single biopsies of bronchoscopy from 73 patients were performed to investigate expression of these three resistance genes by reverse transcriptase-polymerase chain reaction. Relations between gene expression and patient age, smoking status, histology, and chemotherapy were evaluated. A more frequent expression of MDR1 (77 versus 66%), MRP1 (91 versus 72%) and LRP (77 versus 63%) genes was detected in the malignant biopsies than in the non-malignant, respectively. In the metastasis biopsies, expression of these genes was markedly increased. No significant difference was observed between specimens before and after chemotherapy. Biopsies from progressing cancer showed higher MDR1, MRP1 and LRP gene expression. In conclusion, these data reveal a major role of MRP1 in intrinsic resistance and the high gene expression of MDR1 and MRP1 in relapsed diseases.
