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Rajesh C Rao, Andi K. Cani, Daniel H. Hovelson, Hakan Demirci, Mark W Johnson, Scott A Tomlins; Precision medicine for vitreoretinal lymphomas: new routes to targeted therapies from liquid biopsies. Invest. Ophthalmol. Vis. Sci. 2017;58(8):1251.
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© ARVO (1962-2015); The Authors (2016-present)
The purpose of this study is to elucidate the actionable cancer genome of vitreoretinal lymphoma (VRL).
In this retrospective study, we collected diluted vitreous biopsies from 4 patients with a high suspicion for VRL. Following cytological confirmation of lymphoma, we subjected genomic DNA from the biopsies to targeted next generation sequencing (NGS), using a panel containing 126 genes (3,435 amplicons), which was modified from that of the NCI MATCH Trial. Using a validated bioinformatics pipeline, we assessed for the presence of actionable mutations and copy number alterations.
In all four small-volume, intraocular liquid biopsies, we obtained sufficient genomic DNA for analysis. Using NGS, we found targetable heterozygous gain-of-function mutations in the MYD88 oncogene, and confirmed in our cohort the presence the L265 mutations, previously described using PCR-based assays. For the first time in VRL, we also identified the MYD88 S243N mutation. We also identified two-copy copy number losses in the tumor suppressor CDK2NA in all four cases, and one copy loss of the tumor suppressor PTEN in one sample. In one case, in which vitreous biopsies were originally read as cytologically negative, but which was confirmed as lymphoma when a lesion appeared in the brain two years later, our NGS-based approach detected tumoral DNA in the banked, original liquid biopsy.
We performed the first systematic exploration of the actionable cancer genome in VRL. Our NGS-based approach identified exploitable genomic alterations in all cases, such as gain-of-function MYD88 oncogene mutations and loss of the tumor suppressor CDK2NA, and thus illuminates new routes to biologically targeted therapies for VRL, a cancer with a dismal prognosis. This precision medicine strategy could be used to nominate novel, targeted therapies in lymphomas and other blinding and deadly ocular, orbital, and ocular adnexal diseases for which few treatments exist.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
Figure. Workflow of determining driver and potentially actionable genomic alterations. Genomic DNA from intraocular liquid biopsies is subjected to targeted next generation sequencing using a cancer gene panel. Bioinformatics analysis yields candidate point mutations and copy number alterations that potentially drive tumor growth and development in vitreoretinal lymphomas. Potentially actionable therapeutic targets are prioritized and reported.
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