Identification of six new susceptibility loci for invasive epithelial ovarian cancer

Embrace,; Hebon,; Investigators, kConFab; Study, Australian Cancer; Brca,

doi:10.1038/ng.3185

Cited by 227 publications

(198 citation statements)

References 60 publications

(67 reference statements)

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“…For genetic studies, the major benefit has been access to all variants in an individual for association testing. That benefit has been predominantly realized by using whole-genome sequences of related populations to impute the alleles of variants that have not been directly genotyped (The 1000 Genomes Project Consortium 2012; Delaneau and Marchini 2014;Gudbjartsson et al 2015;Horikoshi et al 2015;Kuchenbaecker et al 2015;Surakka et al 2015) and by whole-exome sequencing (for examples and reviews, see Bamshad et al 2011;Chong et al 2015;de Bruin and Dauber 2015). Meanwhile, the first association studies that replace targeted genotyping with whole-genome sequencing are now starting to appear (Gaulton et al 2013;Morrison et al 2013;Taylor et al 2015).…”

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confidence: 99%

Genomic approaches for understanding the genetics of complex disease

Lowe

Reddy

2015

Genome Res.

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There are thousands of known associations between genetic variants and complex human phenotypes, and the rate of novel discoveries is rapidly increasing. Translating those associations into knowledge of disease mechanisms remains a fundamental challenge because the associated variants are overwhelmingly in noncoding regions of the genome where we have few guiding principles to predict their function. Intersecting the compendium of identified genetic associations with maps of regulatory activity across the human genome has revealed that phenotype-associated variants are highly enriched in candidate regulatory elements. Allele-specific analyses of gene regulation can further prioritize variants that likely have a functional effect on disease mechanisms; and emerging high-throughput assays to quantify the activity of candidate regulatory elements are a promising next step in that direction. Together, these technologies have created the ability to systematically and empirically test hypotheses about the function of noncoding variants and haplotypes at the scale needed for comprehensive and systematic follow-up of genetic association studies. Major coordinated efforts to quantify regulatory mechanisms across genetically diverse populations in increasingly realistic cell models would be highly beneficial to realize that potential.

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confidence: 99%

Genomic approaches for understanding the genetics of complex disease

Lowe

Reddy

2015

Genome Res.

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“…Pese a que la mayoría de las mutaciones asociadas a los casos son esporádicas, "los avances de la genética han demostrado la relación con una base hereditaria, para un subgrupo de formas de cáncer" (Narod y Rodriguez, 2011, p. 420). Aproximadamente del 5 al 10 % del CGM y CO presenta una historia familiar de herencia autosómica, dominante que incluye los genes BRCA 1 y BRCA 2 de alta penetrancia, caracterizada por la aparición del cáncer de generación en generación y la presencia de la mutación heredada en el 50% de los individuos susceptibles (Kuchenbaecker et al, 2015;Schlebusch et al, 2010;Torres et al, 2007). Con base en estudios poblacionales, "la enfermedad se manifiesta en edades tempranas, de forma bilateral en el CGM y asociada simultáneamente a CO" (Sanabria et al 2009, p. 67).…”

Section: Discussionunclassified

Frecuencia de las mutaciones en los genes BRCA en mujeres con agregación familiar de cáncer de glándula mamaria/ovario

Benavides-Cerquera

Bohorquez-Lozano

Quiroga

et al. 2016

PSM

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 RESUMEN: Objetivo: Reunir evidencias de la variación en la frecuencia de las mutaciones de BRCA1 y BRCA2 y la historia familiar en pacientes con cáncer de glándula mamaria (CGM) y cáncer de ovario (CO) de diferentes orígenes geográficos. Método: En este trabajo se realizó una revisión sistemática, siguiendo los parámetros del protocolo PRISMA, para estimar la prevalencia de mutaciones en los genes BRCA 1/2 en pacientes con CGM y CO, la incidencia de la historia familiar y la prevalencia observada en casos esporádicos en este tipo de cáncer. Resultados: Se observa una heterogeneidad en la frecuencia de las mutaciones de estos genes en los estudios de historia familiar, con una variación entre 0.0 y 0.48 en pacientes y familiares con CGM y CO similares a los previamente reportados. Discusión: Este amplio rango de la frecuencia se debe al origen de la población estudiada, el número de individuos analizados y la metodología de genotipificación utilizada. La revisión revela que el CGM y CO familiar es dos veces más frecuente, en comparación con los casos de esta misma patología con origen esporádico. Conclusiones: Este tipo de estudios moleculares les permite a las personas que presentan historia familiar con CGM y CO realizarse análisis precoces y chequeos para prevenir en un futuro el desarrollo de alguna de estas neoplasias. Palabras Clave: neoplasias de la mama, neoplasias ováricas, gen BRCA1, gen BRCA2, mutación, herencia. ABSTRACT: Objective: Collect evidence about the frequency variation of BRCA1 and BRCA2 mutations and family history in patients with mammary gland cancer (MGC) and ovarian cancer (OC) from different geographical backgrounds. Method: This paper presents a systematic review using the PRISMA protocol parameters to estimate the prevalence of mutations in BRCA 1/2 genes in patients with MGC and OC, the incidence of family history and the observed prevalence in sporadic cases with this type of cancer. Results: Heterogeneity is observed in the frequency of mutations of these genes in studies of family history ranging between 0.0 and 0.48 in patients and families with MGC and OC similar to those previously reported. Discussion: This wide range of frequency is due to the origin of the studied population, the number of individuals analyzed and genotyping methodology used. The review reveals that the family MGC and OC is twice as common compared with cases of the same disease of a sporadic origin. Conclusions: This type of molecular studies allows other people who have family history of MGC and OC to perform early analysis and tests to prevent the future development of this neoplasia.

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“…15 It has also been found to be a prominent susceptibility locus in ovarian cancer. 16 Further Rspo1 has been identified as common insertion site in murine forward genetic tumor screens and the T2/Onc insertions are oriented consistent with transcriptional activation of Rspo1.…”

Section: Increased Rspo1 Expression In Human Breast Cancer With High mentioning

confidence: 95%

MYCandPVT1synergize to regulate RSPO1 levels in breast cancer

et al. 2016

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Copy number gain of the 8q24 region including the v-myc avian myelocytomatosis viral oncogene homolog (MYC) oncogene has been observed in many different cancers and is associated with poor outcomes. While the role of MYC in tumor formation has been clearly delineated, we have recently shown that co-operation between adjacent long non-coding RNA plasmacytoma variant transcription 1 (PVT1) and MYC is necessary for tumor promotion. Chromosome engineered mice containing an increased copy of Myc-Pvt1 (Gain Myc-Pvt1) accelerates mammary tumors in MMTV-Neu mice, while single copy increase of each is not sufficient. In addition, mammary epithelium from the Gain Myc-Pvt1 mouse show precancerous phenotypes, notably increased DNA replication, elevated Y-H2AX phosphorylation and increased ductal branching. In an attempt to capture the molecular signatures in pre-cancerous cells we utilized RNA sequencing to identify potential targets of supernumerary Myc-Pvt1 cooperation in mammary epithelial cells. In this extra view we show that an extra copy of both Myc and Pvt1 leads to increased levels of Rspo1, a crucial regulator of canonical b-catenin signaling required for female development. Human breast cancer tumors with high levels of MYC transcript have significantly more PVT1 transcript and RSPO1 transcript than tumors with low levels of MYC showing that the murine results are relevant to a subset of human tumors. Thus, this work identifies a key mechanism in precancerous and cancerous tissue by which a main player in female differentiation is transcriptionally activated by supernumerary MYC and PVT1, leading to increased premalignant features, and ultimately to tumor formation.

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Identification of six new susceptibility loci for invasive epithelial ovarian cancer

Cited by 227 publications

References 60 publications

Genomic approaches for understanding the genetics of complex disease

Genomic approaches for understanding the genetics of complex disease

Frecuencia de las mutaciones en los genes BRCA en mujeres con agregación familiar de cáncer de glándula mamaria/ovario

MYCandPVT1synergize to regulate RSPO1 levels in breast cancer

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