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1.
Sci Rep ; 11(1): 5307, 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33674644

RESUMO

Up to 10% of pediatric cancer patients harbor pathogenic germline variants in one or more cancer susceptibility genes. A recent study from the US reported pathogenic variants in 22 out of 60 analyzed autosomal dominant cancer susceptibility genes, implicating 8.5% of pediatric cancer patients. Here we aimed to assess the prevalence of germline pathogenic variants in these 22 genes in a population-based Swedish cohort and to compare the results to those described in other populations. We found pathogenic variants in 10 of the 22 genes covering 3.8% of these patients. The prevalence of TP53 mutations was significantly lower than described in previous studies, which can largely be attributed to differences in tumor diagnosis distributions across the three cohorts. Matched family history for relatives allowed assessment of familial cancer incidence, however, no significant difference in cancer incidence was found in families of children carrying pathogenic variants compared to those who did not.

2.
N Engl J Med ; 384(5): 428-439, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33471991

RESUMO

BACKGROUND: Genetic testing for breast cancer susceptibility is widely used, but for many genes, evidence of an association with breast cancer is weak, underlying risk estimates are imprecise, and reliable subtype-specific risk estimates are lacking. METHODS: We used a panel of 34 putative susceptibility genes to perform sequencing on samples from 60,466 women with breast cancer and 53,461 controls. In separate analyses for protein-truncating variants and rare missense variants in these genes, we estimated odds ratios for breast cancer overall and tumor subtypes. We evaluated missense-variant associations according to domain and classification of pathogenicity. RESULTS: Protein-truncating variants in 5 genes (ATM, BRCA1, BRCA2, CHEK2, and PALB2) were associated with a risk of breast cancer overall with a P value of less than 0.0001. Protein-truncating variants in 4 other genes (BARD1, RAD51C, RAD51D, and TP53) were associated with a risk of breast cancer overall with a P value of less than 0.05 and a Bayesian false-discovery probability of less than 0.05. For protein-truncating variants in 19 of the remaining 25 genes, the upper limit of the 95% confidence interval of the odds ratio for breast cancer overall was less than 2.0. For protein-truncating variants in ATM and CHEK2, odds ratios were higher for estrogen receptor (ER)-positive disease than for ER-negative disease; for protein-truncating variants in BARD1, BRCA1, BRCA2, PALB2, RAD51C, and RAD51D, odds ratios were higher for ER-negative disease than for ER-positive disease. Rare missense variants (in aggregate) in ATM, CHEK2, and TP53 were associated with a risk of breast cancer overall with a P value of less than 0.001. For BRCA1, BRCA2, and TP53, missense variants (in aggregate) that would be classified as pathogenic according to standard criteria were associated with a risk of breast cancer overall, with the risk being similar to that of protein-truncating variants. CONCLUSIONS: The results of this study define the genes that are most clinically useful for inclusion on panels for the prediction of breast cancer risk, as well as provide estimates of the risks associated with protein-truncating variants, to guide genetic counseling. (Funded by European Union Horizon 2020 programs and others.).


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença/genética , Variação Genética , Mutação de Sentido Incorreto , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Razão de Chances , Risco , Análise de Sequência de DNA , Adulto Jovem
3.
J Clin Virol ; 42(2): 129-34, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18304864

RESUMO

BACKGROUND: In recent years an increase of the incidence of nosocomial outbreaks caused by noroviruses has been observed throughout Sweden, with high peaks noted in the winter seasons 2002/2003 and 2004/2005, respectively. OBJECTIVES: To phylogenetically characterize norovirus strains causing nosocomial outbreaks from 1997 to 2005 and estimate the impact of norovirus-like disease on the Swedish health care system during the peak season 2002/2003 when a new variant of norovirus occurred. STUDY DESIGN: Stool samples from 115 randomly selected nosocomial outbreaks occurring during 1997--2005 throughout Sweden were studied by RT-PCR and sequencing. In addition, to investigate the impact on the health-care system, a questionnaire was distributed to infection control units (n=90) serving all Swedish hospitals, nursing homes and other health-care institutions during the largest epidemic of nosocomial outbreaks. RESULTS: Sequencing of 279 nucleotides of the norovirus RNA polymerase gene in stools containing norovirus RNA showed that strains belonging to the GII.4 genotype dominated. Each of the two large epidemics was due to a new variant within this cluster. The questionnaire revealed that 30,000-35,000 episodes of nosocomial norovirus-like infections occurred in 80 of 82 major Swedish hospitals affected in 2002/2003. CONCLUSION: New norovirus variants within the cluster GGII.4 may have a major impact on the health-care system.


Assuntos
Infecções por Caliciviridae/epidemiologia , Infecção Hospitalar/epidemiologia , Surtos de Doenças , Gastroenterite/epidemiologia , Variação Genética , Norovirus/classificação , Infecções por Caliciviridae/virologia , Infecção Hospitalar/virologia , Fezes/virologia , Gastroenterite/virologia , Genótipo , Humanos , Epidemiologia Molecular , Norovirus/genética , Filogenia , Vigilância da População , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estações do Ano , Análise de Sequência de DNA , Inquéritos e Questionários , Suécia/epidemiologia
4.
J Med Virol ; 79(8): 1169-75, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17596834

RESUMO

In order to evaluate three common human papillomavirus (HPV) DNA tests for key performance indices in population-based cervical screening, we sampled 12,527 women aged 32-38 years who attended invitational, population-based screening and followed them for 4 years with comprehensive registry linkages. Three different HPV DNA tests (GP5+/6+ general primer PCR (using either AmpliTaq or AmpliTaq Gold DNA polymerase), Amplicor PCR and Hybrid Capture II were evaluated using baseline samples from women who on follow-up developed cervical intraepithelial neoplasia grade 2 or worse (CINII+) (n = 197) as well as a representative subsample of the women in the cohort (n = 794). The population-based HPV prevalence, sensitivity for future cervical intraepithelial neoplasia grade 2 or worse (CINII+), and absolute risk of CINII+ was 7.1%, 87.1%, and 23.2% for AmpliTaq GP5+/6+ PCR, 11.9%, 88.9%, and 11.0% for AmpliTaq Gold GP5+/6+ PCR, 15.7%, 93.4%, and 9.8% for Amplicor, 10.0%, 92.9%, and 15.3% for Amplicor with raised cut-off, and 7.8%, 79.7%, and 16.9% for Hybrid Capture II. In conclusion, AmpliTaq GP5+/6+ PCR and Amplicor with raised cut-off value have adequate performance indices for primary screening.


Assuntos
Alphapapillomavirus/isolamento & purificação , DNA Viral/isolamento & purificação , Infecções por Papillomavirus/epidemiologia , Feminino , Humanos , Programas de Rastreamento , Infecções por Papillomavirus/virologia , Reação em Cadeia da Polimerase/métodos , Vigilância da População , Suécia/epidemiologia
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