Translating Genomics for Precision Cancer Medicine

Roychowdhury, Sameek; Chinnaiyan, Arul M.

doi:10.1146/annurev-genom-090413-025552

Cited by 62 publications

(35 citation statements)

References 116 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In parallel, identifying the genetic causes of Mendelian disorders is required for developing and applying gene-specific treatments. Similar to recent breakthroughs in cancer treatment based on genomic information (reviewed in Sameek and Chinnaiyan), 53 understanding the genetic causes of Mendelian disorders will inform future gene-specific treatments and is a major step towards personalised medicine for affected individuals.…”

Section: Limitationsmentioning

confidence: 94%

Joubert syndrome: a model for untangling recessive disorders with extreme genetic heterogeneity

et al. 2015

View full text Add to dashboard Cite

Background Joubert syndrome (JS) is a recessive neurodevelopmental disorder characterized by hypotonia, ataxia, cognitive impairment, abnormal eye movements, respiratory control disturbances, and a distinctive mid-hindbrain malformation. JS demonstrates substantial phenotypic variability and genetic heterogeneity. This study provides a comprehensive view of the current genetic basis, phenotypic range and gene-phenotype associations in JS. Methods We sequenced 27 JS-associated genes in 440 affected individuals (375 families) from a cohort of 532 individuals (440 families) with JS, using molecular inversion probe-based targeted capture and next generation sequencing. Variant pathogenicity was defined using the Combined Annotation Dependent Depletion (CADD) algorithm with an optimized score cut-off. Results We identified presumed causal variants in 62% of pedigrees, including the first B9D2 mutations associated with JS. 253 different mutations in 23 genes highlight the extreme genetic heterogeneity of JS. Phenotypic analysis revealed that only 34% of individuals have a “pure JS” phenotype. Retinal disease is present in 30% of individuals, renal disease in 25%, coloboma in 17%, polydactyly in 15%, liver fibrosis in 14% and encephalocele in 8%. Loss of CEP290 function is associated with retinal dystrophy, while loss of TMEM67 function is associated with liver fibrosis and coloboma, but we observe no clear-cut distinction between JS-subtypes. Conclusion This work illustrates how combining advanced sequencing techniques with phenotypic data addresses extreme genetic heterogeneity to provide diagnostic and carrier testing, guide medical monitoring for progressive complications, facilitate interpretation of genome-wide sequencing results in individuals with a variety of phenotypes, and enable gene-specific treatments in the future.

show abstract

Section: Limitationsmentioning

confidence: 94%

Joubert syndrome: a model for untangling recessive disorders with extreme genetic heterogeneity

et al. 2015

View full text Add to dashboard Cite

show abstract

“…However, the benefit is short-lived, and resistance to these drugs and treatment side effects usually develops (4,5). There is an urgent need to continue to develop effective and novel strategies to inhibit AR as well as other CaP drivers which contribute to CaP progression (6,7). …”

Section: Introductionmentioning

confidence: 99%

Synergistic Activity with NOTCH Inhibition and Androgen Ablation in ERG-Positive Prostate Cancer Cells

Mohamed

Tan

Xavier

et al. 2017

Molecular Cancer Research

View full text Add to dashboard Cite

The oncogenic activation of the ETS related gene (ERG) due to gene fusions is present in over half of prostate cancer (CaP) in Western countries. Due to its high incidence and oncogenic role, ERG and components of ERG network have emerged as potential drug targets for CaP. Utilizing gene expression datasets, from matched normal and prostate tumor epithelial cells, an association of NOTCH transcription factors with ERG expression status was identified; confirming that NOTCH factors are direct transcriptional targets of ERG. Inhibition of ERG in TMPRSS2-ERG positive VCaP cells led to decreased levels of NOTCH-1 and -2 proteins and downstream transcriptional targets and partially recapitulated the phenotypes associated with ERG inhibition. Regulation of NOTCH-1 and -2 genes by ERG were also noted with ectopic ERG expression in LNCaP (ERG-negative CaP) and RWPE-1 (benign prostate derived immortalized) cells. Furthermore, inhibition of NOTCH by the small molecule gamma-Secretase inhibitor 1, GSI-1, conferred an increased sensitivity to androgen receptor (AR) inhibitors (Bicalutamide, Enzalutamide,) or the androgen biosynthesis inhibitor (Abiraterone) in VCaP cells. Combined treatment with Bicalutamide and GSI-1 showed strongest inhibition of AR, ERG, NOTCH1, NOTCH2, and PSA protein levels along with decreased cell growth, cell survival and enhanced apoptosis. Intriguingly, this effect was not observed in ERG-negative prostate cancer cells or immortalized benign/normal prostate epithelial cells. These data underscore the synergy of AR and NOTCH inhibitors in reducing the growth of ERG-positive CaP cells. Implications Combinational targeting of NOTCH and AR signaling has therapeutic potential in advanced ERG-driven prostate cancers.

show abstract

“…Now, nearly all pregnant women are screened for genetic and chromosomal conditions by their obstetricians, and increased newborn genetic screening will more rapidly identify risks to child and adult health ( Timmermans & Buchbinder, 2013). In oncology, tumor genotyping can predict a patient's chemotherapeutic response and recurrence, and the body's own immune system can be leveraged to fight tumor cells ( Roychowdhury & Chinnaiyan, 2014). Gene therapy using viral vectors and stem cell transplantation is being explored for any number of conditions ( Ginn, Alexander, Edelstein, Abedi, & Wixon, 2013).…”

Section: Implications and Implementation Of Genomics In Social Work Pmentioning

confidence: 99%

Leadership, Literacy, and Translational Expertise in Genomics: Challenges and Opportunities for Social Work

Werner‐Lin

McCoyd²,

Doyle

et al. 2016

Health Social Work

View full text Add to dashboard Cite

Translating Genomics for Precision Cancer Medicine

Cited by 62 publications

References 116 publications

Joubert syndrome: a model for untangling recessive disorders with extreme genetic heterogeneity

Joubert syndrome: a model for untangling recessive disorders with extreme genetic heterogeneity

Synergistic Activity with NOTCH Inhibition and Androgen Ablation in ERG-Positive Prostate Cancer Cells

Leadership, Literacy, and Translational Expertise in Genomics: Challenges and Opportunities for Social Work

Contact Info

Product

Resources

About