Abstract 2247: Genomic heterogeneity in the aqueous humor cell-free DNA in a patient with bilateral retinoblastoma
Elyssa Y. WongLiya XuLi ShenMary E. KimAshley PolskiRishvanth K. PrabakarRachana ShahRima JubranJonathan W. KimJaclyn A. BiegelXiaowu GaiPeter KühnJames HicksJesse L. Berry
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Abstract Purpose: Germline alterations in the RB1 tumor suppressor gene predispose patients to developing retinoblastoma (RB) in both eyes. However, tumors in bilateral RB may not respond identically to treatment. The additional genomic events that occur independently in each eye during tumorigenesis are not well characterized. The aqueous humor (AH) provides a novel source of cell-free tumor-derived DNA (ctDNA) for liquid biopsy, enabling the in vivo study of RB tumors. In this case report, we use our AH liquid biopsy to compare genomic profiles between the right and left eyes of a single patient with heritable RB while also showing that ctDNA longitudinal dynamics correspond to therapeutic response. Methods: One patient with bilateral RB was included. Multiple samples of AH were obtained from each eye during routine intravitreal melphalan therapy and following enucleation of the left eye. Routine clinical blood testing was performed to determine germline RB1 status. CtDNA was isolated from the AH and sequenced on an Illumina platform to assess genome-wide somatic copy number alterations (SCNAs). The same sequencing libraries were used to identify somatic RB1 pathogenic variants using a custom hybridization and next generation sequencing panel targeting RB1. Tumor fraction (TFx) was estimated using ichorCNA software. Results: Five AH samples from both eyes (3 from the right eye and 2 from the left eye) were included. Peripheral blood RB1 testing detected germline 13q and 16p deletions. Targeted RB1 mutational analysis of AH ctDNA identified a different somatic RB1 mutation in each eye. At initial AH sampling, three SCNAs were present in the right eye and these same SCNAs persisted in further samples. Two SCNAs were initially detected in the left eye and were consistently identified in later sampling. Despite the same germline RB1 mutation, the second somatic mutation was different in each eye and there were distinct, non-overlapping patterns of SCNAs in each eye. In addition, the right eye demonstrated a progressive decrease in TFx corresponding with therapeutic responsiveness and ocular salvage. The left eye had persistently larger TFx values and required enucleation due to tumor recurrence. Conclusions: Our AH liquid biopsy detected distinct genomic events between eyes in a patient with bilateral RB and TFx changes corresponding with disease activity. Identifying inter-eye genomic heterogeneity without the need for enucleated tumor tissue may help direct active management of RB, with particular usefulness in bilateral cases. Citation Format: Elyssa Y. Wong, Liya Xu, Lishuang Shen, Mary E. Kim, Ashley Polski, Rishvanth K. Prabakar, Rachana Shah, Rima Jubran, Jonathan W. Kim, Jaclyn A. Biegel, Xiaowu Gai, Peter Kuhn, James Hicks, Jesse L. Berry. Genomic heterogeneity in the aqueous humor cell-free DNA in a patient with bilateral retinoblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2247.Keywords:
Retinoblastoma
Liquid biopsy
Seventy-one eyes of 64 patients with advanced retinoblastoma received 81 cobalt plaques for the treatment of advanced retinoblastoma. Sixty-three of the 64 patients had bilateral retinoblastoma. Fifty of the 63 patients with bilateral retinoblastoma had already had an enucleation of the fellow eye at the time of insertion of the plaque. Of the 64 patients who received a plaque, 60 had already failed prior therapy to the eye. More than half (45-81) of the tumors were larger than 10 mm in base diameter and 70 of the 81 tumors were either in the ciliary body, anterior chamber, or seeded into the vitreous. Eight of the 64 patients died of metastatic retinoblastoma (12.5%), and four of the survivors developed second nonocular tumors. In 44 of the 71 eyes, enucleation was prevented by the plaque. Of the 27 who required enucleation, 21 did so because of continued tumor growth.
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To evaluate the enucleation rate for children with unilateral sporadic retinoblastoma based on initial external findings detected by the family and the pediatrician.A retrospective, nonrandomized review was performed on 257 consecutive patients with unilateral sporadic retinoblastoma treated at a major ocular oncology center. Data were gathered regarding the initial external clinical finding noted by the family members, pediatrician, and ocular oncologist and then correlated with the final resulted in enucleation in 77%. Specifically, enucleation was necessary in 75% of patients with pediatrician-detected leukocoria, 46% of those with pediatrician-detected strabismus, and 86% of those with pediatrician-detected red eye, heterochromia, decreased visual acuity, or an unspecified eye problem. Enucleation was necessary in 81% of those patients in whom an ocular oncologist detected any external finding such as leukocoria, strabismus, red eye, heterochromia, or buphthalmos and in only 33% of those without external findings.Children with retinoblastoma who present with obvious external findings of leukocoria, strabismus, or red eye detectable by their family or pediatrician most often require enucleation. Children who manifest no obvious external findings can often avoid enucleation.
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Study of BRAF mutations in melanoma and nevi from patients with germline mutation in the CDKN2A gene
10075 Background: Germline mutations in the CDKN2A tumor suppressor gene is a rare condition associated with a high risk of melanoma. Somatic activating mutations of the BRAF gene are frequently observed in cutaneous melanoma (40–60%) but their occurrence vary according to melanoma subtypes (cutaneous, vs mucosal or uveal) and are less frequent in melanoma located on chronically sun-exposed skin. It is thought that melanomas occurring in patients carrier of a CDKN2A germline mutation are associated a second inactivating genetic event in the tumor, facilitating cellular transformation by loss of function this crucial gatekeeper of the G1-S checkpoint. However, the potential role of the MAP-kinase pathway, and more precisely, the involvement of BRAF activation, in this particular population of patients, are still unknown. Thus, our objective was to evaluate the frequency of BRAF somatic mutations in melanoma and nevi developed by patients carrier of a CDKN2A germline mutation. Methods: DNA was extracted from paraffin-embedded tissues of 36 primary melanomas, 9 metastases and 20 nevi from 31 patients with CDKN2A germline mutation. Ten sporadic melanoma from patients harbouring no CDKN2A mutation were also studied as a control population. BRAF mutations were screened by direct sequencing of exon 11 and 15. Results: BRAF mutations (V599E) were found with a significantly lower frequency of 14% (5/36) in melanomas from patients with proven CDKN2A germline mutation, as compared to a frequency of 55% (5/9) in patients with no genetic predisposition (two-sided Fishers exact test, p=0.02). Frequencies of BRAF mutations in metastases and nevi from patients with CDKN2A germline mutation were 33%(3/9) and 10% (2/20) respectively. Conclusions: BRAF mutations seem to be less frequent in melanoma from patients with familial predisposition harbouring CDKN2A germ line mutation than in sporadic melanoma. These results suggest that CDKN2A loss of function gives rise to tumorigenic pathways where genetic events distinct from BRAF activating mutation can induce cell transformation. Additional biological studies are performed on this rare population of melanoma samples in order to better characterize the specificity of cellular transformation in the context of CDKN2A germ line mutation. No significant financial relationships to disclose.
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Conservative Management
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We document here an aggressive carcinoma arising in the conjunctiva of an anophthalmic socket, 41 years after enucleation for a sporadic, non-hereditary unilateral retinoblastoma. This tumor was treated for the first time with proton beam irradiation of the orbit. Investigations revealed an extensive metastatic spread to the loco-regional lymph nodes, requiring complementary parotidectomy, chemotherapy, and radiation therapy.
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Background: Retinal dysplasia is a congenital ocular pathology that can mimic as retinoblastoma caused by abnormal proliferation of retinal tissue. Objective: To present a case of retinal dysplasia misdiagnosed clinically as retinoblastoma and underwent enucleation surgery.Result: A 7 years old female underwent enucleation surgery as she was diagnosed clinically as retinoblastoma. Both of them could present with leucocoria and histologically can show rossettes formation. It is important to differentiate both these entities inorder to avoid enucleation in case of retinal dysplasia.
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ABSTRACT We correlated the pathologic diagnosis with the preoperative clinical diagnosis of retinoblastoma in children treated by enucleation within the United States and Canada between the years 1974 and 1980. In order to avoid inappropriate selectivity and institutional bias, we studied only those cases submitted directly to the Registry of Ophthalmic Pathology in which the enucleated eyes had not been examined initially at the local hospital. Of the 56 eyes removed because of suspected retinoblastoma, 15 (26.8%) did not contain a malignant tumor. In two cases enucleation was delayed because retinoblastoma was not considered initially in the differential diagnosis of spontaneous hyphema. During the same period, two of 268 eyes that were enucleated for reasons other than suspected retinoblastoma were found to contain a retinoblastoma. The diagnostic error rate in our study reflects the persistent difficulty in diagnosing retinoblastoma in eyes with opaque media and retinal detachment.
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Enucleation (eye removal) is often the only curative treatment for the childhood eye cancer retinoblastoma, yet parental refusal of enucleation commonly contributes to treatment delay and poor survival globally.Physicians who treat retinoblastoma were surveyed to glean underlying reasons for treatment refusal.Refusal rates were higher when less time was spent with parents explaining retinoblastoma/enucleation, and where fewer support services were available. Reasons for refusal included parental belief in alternative treatments, culture, and social stigma.We suggest strategies to increase parental compliance with enucleation and save the lives of children with retinoblastoma.
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Despite considerable advances in the treatment of retinoblastoma tumor growths cannot be arrested in a proportion of cases. The consent fro the removal of both eyes constitutes a burdensome decision on the part of the child's parents, so that it is quite frequently refused. A short movie illustrating the behaviour of a 6-year-old boy, who had undergone bilateral enucleation because of retinoblastoma should aid the parents having to face a similar situation.
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