Evolutionary Action Score of <i>TP53</i> Coding Variants Is Predictive of Platinum Response in Head and Neck Cancer Patients

Osman, Abdullah A.; Neskey, David M.; Katsonis, Panagiotis; Patel, Ameeta A.; Ward, Alexandra M.; Hsu, Teng-Kuei; Hicks, Stephanie C.; McDonald, Thomas O.; Ow, Thomas J.; Alves, Marcus Ortega; Pickering, Curtis R.; Skinner, Heath D.; Zhao, Mei; Sturgis, Erich M.; Kies, Merrill S.; El‐Naggar, Adel K.; Perrone, Francesco; Licitra, Lisa; Bossi, Paolo; Kimmel, Marek; Frederick, Mitchell J.; Lichtarge, Olivier; Myers, Jeffrey N.

doi:10.1158/0008-5472.can-14-2729

Cited by 79 publications

(115 citation statements)

References 36 publications

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“…The Evolutionary Action Eq. 2 is thus generally solvable for coding mutation of proteins and quantifies the effect of mutations over multiple scales, spanning molecular, clinical, and population genetics effects (21)(22)(23)(24). Here, for each residue identified in Fig.…”

Section: Resultsmentioning

confidence: 99%

Elucidation of G-protein and β-arrestin functional selectivity at the dopamine D2 receptor

Peterson¹,

Pack²,

Wilkins

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The neuromodulator dopamine signals through the dopamine D2 receptor (D 2 R) to modulate central nervous system functions through diverse signal transduction pathways. D 2 R is a prominent target for drug treatments in disorders where dopamine function is aberrant, such as schizophrenia. D 2 R signals through distinct G-protein and β-arrestin pathways, and drugs that are functionally selective for these pathways could have improved therapeutic potential. How D 2 R signals through the two pathways is still not well defined, and efforts to elucidate these pathways have been hampered by the lack of adequate tools for assessing the contribution of each pathway independently. To address this, Evolutionary Trace was used to produce D 2 R mutants with strongly biased signal transduction for either the G-protein or β-arrestin interactions. These mutants were used to resolve the role of G proteins and β-arrestins in D 2 R signaling assays. The results show that D 2 R interactions with the two downstream effectors are dissociable and that G-protein signaling accounts for D 2 R canonical MAP kinase signaling cascade activation, whereas β-arrestin only activates elements of this cascade under certain conditions. Nevertheless, when expressed in mice in GABAergic medium spiny neurons of the striatum, the β-arrestin-biased D 2 R caused a significant potentiation of amphetamine-induced locomotion, whereas the G proteinbiased D 2 R had minimal effects. The mutant receptors generated here provide a molecular tool set that should enable a better definition of the individual roles of G-protein and β-arrestin signaling pathways in D 2 R pharmacology, neurobiology, and associated pathologies.

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Section: Resultsmentioning

confidence: 99%

Elucidation of G-protein and β-arrestin functional selectivity at the dopamine D2 receptor

Peterson¹,

Pack²,

Wilkins

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…This is a key issue for genetic counseling, as the use of NGS has led to the discovery of very rare novel germline TP53 variants of unknown significance (VUS) in the normal population (27). Multiple methodologies have been developed to assess the functional effect of TP53 variants, but their specificities and sensitivities remain low for uncommon variants (28)(29)(30).…”

Section: Heterogeneity Of Tp53 Variantsmentioning

confidence: 99%

“…Although some of these classifications have improved the clinical value of TP53 status for head and neck cancer (30), breast carcinoma (41), or diffuse large B-cell lymphoma (42), no clear rationale to definitively score TP53 variants has yet been defined.…”

Section: Somatic Tp53 Mutation In Human Tumorsmentioning

confidence: 99%

Recommended Guidelines for Validation, Quality Control, and Reporting of TP53 Variants in Clinical Practice

et al. 2017

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Accurate assessment of TP53 gene status in sporadic tumors and in the germline of individuals at high risk of cancer due to Li-Fraumeni Syndrome (LFS) has important clinical implications for diagnosis, surveillance, and therapy. Genomic data from more than 20,000 cancer genomes provide a wealth of information on cancer gene alterations and have confirmed TP53 as the most commonly mutated gene in human cancer. Analysis of a database of 70,000 TP53 variants reveals that the two newly discovered exons of the gene, exons 9b and 9g, generated by alternative splicing, are the targets of inactivating mutation events in breast, liver, and head and neck tumors. Furthermore, germline rearrangements in intron 1 of TP53 are associated with LFS and are frequently observed in sporadic osteosarcoma. In this context of constantly growing genomic data, we discuss how screening strategies must be improved when assessing TP53 status in clinical samples. Finally, we discuss how TP53 alterations should be described by using accurate nomenclature to avoid confusion in scientific and clinical reports.

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“…For these types of cancers, TP53 is the most varied gene, with between 60 and 80% having a mutation. In one study that used an evolutionary action score to assess the mutations, it was found that a subset of high-risk TP53 mutations demonstrated significantly reduced in vitro and in vivo drug efficacy, making the gene a potential prognostic marker for selection of cisplatin in treatment of head and neck cancers (Osman et al 2015). In another study, the predictive efficacy of cisplatin and carboplatin was examined in triple negative breast cancer.…”

Section: Predicting Drug Efficacymentioning

confidence: 99%

The state-of-play and future of platinum drugs

Apps

Choi

Wheate

2015

Endocrine-Related Cancer

224

140

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The year 2015 marks the 50th anniversary since the discovery of the anticancer potential of cisplatin and it remains just as useful now as it did back then, especially for the treatment of some endocrine-related cancers like ovarian and testicular carcinomas. Since its discovery, five other platin drugs have received approval in various countries. While several new platin drugs are in preclinical development, in the last decade only two new platin drugs have entered clinical trials, LA-12 and dicycloplatin, reflecting a shift in research focus from new drug design to improved formulations of already approved platin drugs. These formulations include their encapsulation with macrocycles to slow and prevent their degradation by proteins and peptides; their attachment to nanoparticles to passively target solid tumours through the enhanced permeability and retention effect and their coordination to important nutrients, proteins, antibodies and aptamers for active tumour targeting. These formulation methods have all shown potential but none have yet yielded a new marketable medicine containing a platin drug. The reasons for this are problems of consistent drug loading, controlling the location and timing of drug release and the inherent toxicity of some of the drug delivery vehicles. In addition to drug delivery, functional genomics is now playing an increasing role in predicting patients' responses to platin chemotherapy and their likelihood of experiencing severe side effects.

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Evolutionary Action Score of TP53 Coding Variants Is Predictive of Platinum Response in Head and Neck Cancer Patients

Cited by 79 publications

References 36 publications

Elucidation of G-protein and β-arrestin functional selectivity at the dopamine D2 receptor

Elucidation of G-protein and β-arrestin functional selectivity at the dopamine D2 receptor

Recommended Guidelines for Validation, Quality Control, and Reporting of TP53 Variants in Clinical Practice

The state-of-play and future of platinum drugs

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