Tumor-specific DNA can be safely “biopsied” from drops of aqueous humor and may ultimately enable the diagnosis of retinoblastoma, as well as prognosis and therapeutic response, according to the first study of this novel approach.
Dr. Jesse Berry of the University of Southern California, Los Angeles, told Reuters Health, “The most exciting aspect of this research is to finally have access to retinoblastoma tumor DNA in eyes that have not been enucleated.”
“While we know a significant amount about the genetic underpinning of this cancer, we have never before been able to harness it without removing the eye,” she explained by email.
“This paper, while early research, demonstrates that the aqueous humor holds tremendous potential to serve as a surrogate tumor biopsy, which is the first step towards offering precision medicine for children suffering from this blinding - and deadly - ocular cancer.”
Dr. Berry and colleagues conducted a case series study from 2014 to 2015 at a retinoblastoma treatment center. They isolated cell-free DNA (cfDNA) in six aqueous humor samples from three children (two boys and one girl diagnosed at ages 7, 20 and 28 months). Two of the children had undergone enucleation, and one was undergoing multiple intravenous injections of melphalan for vitreous seeding.
As reported in JAMA Ophthalmology, online October 12, evaluation of the aqueous humor from enucleated samples showed a corroborative pattern between tumor-derived cfDNA and chromosomal copy number variations (regions of chromosomal gains and losses), which represent changes in the tumor.
In addition, a nonsense RB1 mutation from one child was identified from the aqueous humor samples obtained during intravitreous injection of melphalan, and this matched the postsecondary enucleation tumor sample. Subsequent Sanger sequencing of the aqueous humor cfDNA and tumor DNA showed the same RB1 mutation.
“The results suggest that the aqueous humor can serve as a surrogate tumor biopsy when retinoblastoma tumor tissue is not available,” according to the authors. They conclude that this method “will allow for analyses of tumor-derived DNA in retinoblastoma eyes undergoing salvage therapy that have not been enucleated.”
Dr. J. William Harbour of the University of Miami School of Medicine, author of a related editorial, told Reuters Health, “The most striking finding from this study is that a tiny amount of aqueous fluid from the anterior chamber can yield enough fragments of tumor DNA to accurately determine the chromosomal gains and losses in a retinoblastoma tumor located in the posterior segment of the eye.”
“This ‘liquid biopsy’ technique could allow molecular characterization of retinoblastomas without the risks associated with direct tumor biopsy,” he said by email.
“Further refinement of this technology could dramatically improve the standard of care,” he added, “by identifying objectively which patients may benefit from globe-sparing treatments and which should undergo primary enucleation.”
Dr. Irina Belinsky of NYU Langone Health in New York City, told Reuters Health by email, “While the results are limited by a small sample pool, the conclusion that analysis of aqueous humor in retinoblastoma eyes can offer insight into the behavior of the disease on a molecular level and in vivo is exciting.”
“Perhaps a multicenter investigation might help validate these findings by increasing the number of samples studied and furthering the significant progress made herein,” she suggested.
SOURCES: http://bit.ly/2ifszfL and http://bit.ly/2ynrloY
JAMA Ophthalmol 2017.
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