De Novo RB1 Germline Variant in Retinoblastoma with Two Subsequent Independent Neoplasms: Case Report and Literature Review

Variants in the gene are associated with retinoblastoma (RB) development, and their presence in germline cells considerably increases the risk of subsequent malignant neoplasms (SMNs) in RB survivors. We report a female patient with bilateral RB who developed two SMNs in less than ten years, with a de novo pathogenic nonsense variant in [NM_000321.3:c.306T>A, p.(Cys102*)] in heterozygosity. The updated literature review of similar cases of SMN in patients with a previous diagnosis of RB reveals a wide range in both the type of subsequent malignancy and the age at which these SMNs develop. In addition, we identified only three cases with two SMNs following RB diagnosis, with at least one of these being an EWS. This case broadens the clinical and genetic landscape of RB, demonstrates the importance of a multidisciplinary approach in these patients, and highlights genetic diagnosis as a mandatory feature for management.

References

Ferris I Tortajada J, Berbel Tornero O, Ortega Garcia J, Claudio-Morales L, Garcia I Castell J, Marti Perales V . [Risk factors for pediatric malignant bone tumors]. An Pediatr (Barc). 2005; 63(6):537-47. DOI: 10.1016/s1695-4033(05)70254-x. View

Henderson T, Moskowitz C, Chou J, Bradbury A, Neglia J, Dang C . Breast Cancer Risk in Childhood Cancer Survivors Without a History of Chest Radiotherapy: A Report From the Childhood Cancer Survivor Study. J Clin Oncol. 2015; 34(9):910-8. PMC: 4871997. DOI: 10.1200/JCO.2015.62.3314. View

KITCHIN F, Ellsworth R . Pleiotropic effects of the gene for retinoblastoma. J Med Genet. 1974; 11(3):244-6. PMC: 1013134. DOI: 10.1136/jmg.11.3.244. View

Okeda R, Kanazawa A, Yamada M, Ohkawa Y, Kawabata K, Yoshida M . A 14-year-old patient with Ewing's sarcoma presenting at autopsy with multiple neurofibrillary tangles and Lewy bodies in addition to hemiatrophy of the central nervous system. Clin Neuropathol. 1997; 16(2):77-84. View

Aerts I, Pacquement H, Doz F, Mosseri V, Desjardins L, Sastre X . Outcome of second malignancies after retinoblastoma: a retrospective analysis of 25 patients treated at the Institut Curie. Eur J Cancer. 2004; 40(10):1522-9. DOI: 10.1016/j.ejca.2004.03.023. View

Schifter S, Vendelbo L, JENSEN O, Kaae S . Ewing's tumor following bilateral retinoblastoma. A case report. Cancer. 1983; 51(9):1746-9. DOI: 10.1002/1097-0142(19830501)51:9<1746::aid-cncr2820510930>3.0.co;2-g. View

Abramson D, Servodidio C . Retinoblastoma. Optom Clin. 1993; 3(3):49-61. View

Thompson S, Ritz B, Cockburn M, Heck J . Prenatal ambient pesticide exposure and childhood retinoblastoma. Int J Hyg Environ Health. 2022; 245:114025. PMC: 9901366. DOI: 10.1016/j.ijheh.2022.114025. View

Abramson D, Melson M, Dunkel I, FRANK C . Third (fourth and fifth) nonocular tumors in survivors of retinoblastoma. Ophthalmology. 2001; 108(10):1868-76. DOI: 10.1016/s0161-6420(01)00713-8. View

10.

MacCarthy A, Bayne A, Brownbill P, Bunch K, Diggens N, Draper G . Second and subsequent tumours among 1927 retinoblastoma patients diagnosed in Britain 1951-2004. Br J Cancer. 2013; 108(12):2455-63. PMC: 3694232. DOI: 10.1038/bjc.2013.228. View

11.

Ceha H, Balm A, de Jong D, van t Veer L . Multiple malignancies in a patient with bilateral retinoblastoma. J Laryngol Otol. 1998; 112(2):189-92. DOI: 10.1017/s0022215100140289. View

12.

Hu H, Zielinska-Kwiatkowska A, Munro K, Wilcox J, Wu D, Yang L . EWS/FLI1 suppresses retinoblastoma protein function and senescence in Ewing's sarcoma cells. J Orthop Res. 2008; 26(6):886-93. DOI: 10.1002/jor.20597. View

13.

Kleinerman R, Tucker M, Tarone R, Abramson D, Seddon J, Stovall M . Risk of new cancers after radiotherapy in long-term survivors of retinoblastoma: an extended follow-up. J Clin Oncol. 2005; 23(10):2272-9. DOI: 10.1200/JCO.2005.05.054. View

14.

Marees T, van Leeuwen F, Schaapveld M, Imhof S, de Boer M, Kors W . Risk of third malignancies and death after a second malignancy in retinoblastoma survivors. Eur J Cancer. 2010; 46(11):2052-8. DOI: 10.1016/j.ejca.2010.03.029. View

15.

Marees T, Moll A, Imhof S, de Boer M, Ringens P, van Leeuwen F . Risk of second malignancies in survivors of retinoblastoma: more than 40 years of follow-up. J Natl Cancer Inst. 2008; 100(24):1771-9. DOI: 10.1093/jnci/djn394. View

16.

Chantada G, Fandino A, Schvartzman E, Raslawski E, Schaiquevich P, Manzitti J . Impact of chemoreduction for conservative therapy for retinoblastoma in Argentina. Pediatr Blood Cancer. 2013; 61(5):821-6. DOI: 10.1002/pbc.24857. View

17.

Hoang C, Duong H, Nguyen N, Nguyen S, Nguyen C, Nguyen B . Clinical evaluation of RB1 genetic testing reveals novel mutations in Vietnamese patients with retinoblastoma. Mol Clin Oncol. 2021; 15(3):182. PMC: 8278403. DOI: 10.3892/mco.2021.2344. View

18.

Wong J, Morton L, Tucker M, Abramson D, Seddon J, Sampson J . Risk of subsequent malignant neoplasms in long-term hereditary retinoblastoma survivors after chemotherapy and radiotherapy. J Clin Oncol. 2014; 32(29):3284-90. PMC: 4178525. DOI: 10.1200/JCO.2013.54.7844. View

19.

Kay R, Eckardt J, Mirra J . Osteosarcoma and Ewing's sarcoma in a retinoblastoma patient. Clin Orthop Relat Res. 1996; (323):284-7. DOI: 10.1097/00003086-199602000-00039. View

20.

Fletcher O, Easton D, Anderson K, Gilham C, Jay M, Peto J . Lifetime risks of common cancers among retinoblastoma survivors. J Natl Cancer Inst. 2004; 96(5):357-63. DOI: 10.1093/jnci/djh058. View