TY - JOUR
T1 - Chromosome 6p amplification in aqueous humor cell-free DNA is a prognostic biomarker for retinoblastoma ocular survival
AU - Xu, Liya
AU - Polski, Ashley
AU - Prabakar, Rishvanth K.
AU - Reid, Mark W.
AU - Chevez-Barrios, Patricia
AU - Jubran, Rima
AU - Kim, Jonathan W.
AU - Kuhn, Peter
AU - Cobrinik, David
AU - Hicks, James
AU - Berry, Jesse L.
N1 - Funding Information:
The authors would like to thank Subramanian Krishnan, Dilshad Contractor, Brianne Brown, Mitali Singh, Kayla Stepanian, and Mark Reid for their technical support and expertise. This research was also supported by the following sources: NCI of the NIH Award K08CA232344 (to J.L. Berry); Hyundai Hope on Wheels RGA012351 (to J.L. Berry); Childhood Eye Cancer Trust (to J.L. Berry); American Cancer Society IRG-16-181-57 (to J.L. Berry); Wright Foundation (to J.L. Berry and A. Polski); Knights Templar Eye Foundation (to J.L. Berry); The Larry and Celia Moh Foundation (to J.L. Berry); The Institute for Families, Inc., Children's Hospital Los Angeles (J.L. Berry); an unrestricted departmental grant from Research to Prevent Blindness (all); The NIH P30EY029220 (all); The NCI P30CA014089 (all); Vicky Joseph Research Fund (to P. Kuhn); Carol Vassiliadis Research Fund (to P. Kuhn); and USC Dornsife College of Letters, Arts and Sciences (to P. Kuhn).
Funding Information:
The authors would like to thank Subramanian Krishnan, Dilshad Contractor, Brianne Brown, Mitali Singh, Kayla Stepanian, and Mark Reid for their technical support and expertise. This research was also supported by the following sources: NCI of the NIH Award K08CA232344 (to J.L. Berry); Hyundai Hope on Wheels RGA012351 (to J.L. Berry); Childhood Eye Cancer Trust (to J.L. Berry); American Cancer Society IRG-16-181-57 (to J.L. Berry); Wright Foundation (to J.L. Berry and A. Polski); Knights Templar Eye Foundation (to J.L. Berry); The Larry and Celia Moh Foundation (to J.L. Berry); The Institute for Families, Inc., Children's Hospital Los Angeles (J.L. Berry); an unrestricted departmental grant from Research to Prevent Blindness (all); The NIH P30EY029220 (all); The NCI P30CA014089 (all); Vicky
Funding Information:
L. Xu reports a patent for Aqueous humor cell-free DNA and ophthalmic disease pending. P. Chevez-Barrios reports grants from NASA outside the submitted work. J. Hicks reports grants from Carol Vassiliadis Research Fund and grants from Vicky Joseph Research Fund during the conduct of the study; other from Epic Sciences, Inc outside the submitted work; and provisional patent application entitled Aqueous humor cell free DNA for diagnostic and Prognostic evaluation of Ophthalmic Disease. J.L. Berry reports grants from National Cancer Institute of the National Institute of Health Award Number K08CA232344, grants from Hyundai Hope on Wheels, grants from Childhood Eye Cancer Trust, grants from American Cancer Society #IRG-16-181-57, grants from Wright Foundation, grants from Knights Templar Eye Foundation, grants from The Larry and Celia Moh Foundation, grants from The Institute for Families, Inc., Children's Hospital Los Angeles, grants from Research to Prevent Blindness, grants from The National Institute of Health P30EY029220, and grants from The National Cancer Institute P30CA014089 during the conduct of the study; in addition, J.L. Berry has a provisional patent application entitled Aqueous Humor Cell Free DNA for Diagnostic and Prognostic Evaluation of Ophthalmic Disease pending. No potential conflicts of interest were disclosed by the other authors.
Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2020/8/1
Y1 - 2020/8/1
N2 - Aqueous humor contains tumor-derived cell-free DNA (cfDNA) and can serve as a liquid biopsy for retinoblastoma. We previously associated somatic copy-number alteration (SCNA) 6p gain with a 10-fold increased risk of enucleation. Here we provide a 2-year update to further explore 6p gain as a prognostic biomarker for ocular survival. Patients diagnosed with retinoblastoma from December 2014 to July 2019 from whom aqueous humor was sampled were included. cfDNA was extracted and shallow whole-genome sequencing performed to identify highly recurrent retinoblastoma SCNAs (gain of 1q, 2p, 6p, loss of 13q, 16q). 116 aqueous humor samples from 50 eyes of 46 patients were included: 27 eyes were salvaged, 23 were enucleated. Highly recurrent retinoblastoma SCNAs were found in 66% eyes. 6p gain was the most prevalent SCNA (50% eyes). It was particularly more prevalent in enucleated eyes (73.9%) than in salvaged eyes (29.6%;
P = 0.004). 6p gain in aqueous humor cfDNA portended nearly 10-fold increased odds of enucleation (OR = 9.87; 95% confidence interval = 1.75-55.65;
P = 0.009). In the enucleated eyes, 6p gain was associated with aggressive histopathologic features, including necrosis, higher degrees of anaplasia, and focal invasion of ocular structures. With extended follow-up and nearly double the aqueous humor samples, we continue to demonstrate 6p gain as a potential prognostic biomarker for retinoblastoma. IMPLICATIONS: Aqueous humor is a high-yield source of tumor-derived DNA in retinoblastoma eyes. Detection of 6p gain in the aqueous humor allows for targeted, patient-centered therapies based on this molecular prognostic marker. Prospective, multicenter studies with aqueous humor sampled from all eyes at diagnosis are warranted to validate these findings.
AB - Aqueous humor contains tumor-derived cell-free DNA (cfDNA) and can serve as a liquid biopsy for retinoblastoma. We previously associated somatic copy-number alteration (SCNA) 6p gain with a 10-fold increased risk of enucleation. Here we provide a 2-year update to further explore 6p gain as a prognostic biomarker for ocular survival. Patients diagnosed with retinoblastoma from December 2014 to July 2019 from whom aqueous humor was sampled were included. cfDNA was extracted and shallow whole-genome sequencing performed to identify highly recurrent retinoblastoma SCNAs (gain of 1q, 2p, 6p, loss of 13q, 16q). 116 aqueous humor samples from 50 eyes of 46 patients were included: 27 eyes were salvaged, 23 were enucleated. Highly recurrent retinoblastoma SCNAs were found in 66% eyes. 6p gain was the most prevalent SCNA (50% eyes). It was particularly more prevalent in enucleated eyes (73.9%) than in salvaged eyes (29.6%;
P = 0.004). 6p gain in aqueous humor cfDNA portended nearly 10-fold increased odds of enucleation (OR = 9.87; 95% confidence interval = 1.75-55.65;
P = 0.009). In the enucleated eyes, 6p gain was associated with aggressive histopathologic features, including necrosis, higher degrees of anaplasia, and focal invasion of ocular structures. With extended follow-up and nearly double the aqueous humor samples, we continue to demonstrate 6p gain as a potential prognostic biomarker for retinoblastoma. IMPLICATIONS: Aqueous humor is a high-yield source of tumor-derived DNA in retinoblastoma eyes. Detection of 6p gain in the aqueous humor allows for targeted, patient-centered therapies based on this molecular prognostic marker. Prospective, multicenter studies with aqueous humor sampled from all eyes at diagnosis are warranted to validate these findings.
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UR - http://www.scopus.com/inward/citedby.url?scp=85086264366&partnerID=8YFLogxK
U2 - 10.1158/1541-7786.MCR-19-1262
DO - 10.1158/1541-7786.MCR-19-1262
M3 - Article
C2 - 32434859
AN - SCOPUS:85086264366
SN - 1541-7786
VL - 18
SP - 1166
EP - 1175
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 8
ER -