Abstract
Retinoblastoma (RB) is an inherited childhood ocular cancer caused by mutations in the tumor suppressor RB1 gene. Identification of RB1 mutations is essential to assess the risk of developing retinoblastoma in the patients´ relatives. Retinoblastoma is a potentially curable cancer and an early diagnosis is critical for survival and eye preservation. Unilateral retinoblastoma is mostly non-heritable and results from two somatic mutations whereas bilateral retinoblastoma is heritable and results from one germline and one somatic mutation, both have high penetrance, 90%. The purpose of this study was to identify causative RB1 mutations in RB patients with different clinical presentations. A comprehensive approach was used to study a cohort of 34 patients with unilateral, bilateral and trilateral retinoblastoma. Blood and tumor DNA was analyzed by sequencing and multiplex ligation-dependent probe amplification (MLPA) assay. Validation of an insertion mutation was performed by cloning the PCR product. Most of the patients in our cohort had unilateral RB, eight patients had bilateral RB and one patient had a trilateral tumor with ocular and suprasellar/sellar locations. Other tumors in addition to retinoblastoma were also found in the affected families. One patient had two syndromes, retinoblastoma and schwannomatosis, and another RB patient had a father with a retinoma. Five out of the 25 unilateral RB patients carried germinal mutations (20%), which were mostly missense mutations. The bilateral and trilateral patients carried splice-site, nonsense and frameshift mutations as well as a whole RB1 gene deletion. Missense mutations were associated with mild phenotype: unilateral retinoblastoma, retinoma or no tumor. In this study we identified causative RB1 mutations in most bilateral RB patients and in some unilateral RB patients, including five novel mutations. These data are crucial for genetic counseling and confirm the need to perform complete genetic screening for RB1 mutations in both constitutional and tumor tissues.
Highlights
Seventy four percent of patients studied had unilateral RB and the remainder had bilateral RB except one patient who had trilateral RB with a suprasellar/sellar neuroectodermal tumor in addition to bilateral RB. This patient was diagnosed at two months of age, enucleated and treated by chemotherapy, but despite the intensive treatments he died at two years of age. Another rare patient presented with two syndromes, unilateral RB and schwannomatosis
Alterations in the promoter proximal splice-site lead to a significant reduction in nascent transcription [28]. This splice-site mutation is rare and has only been reported three times in http://rb1-lovd.d-lohmann.de), we identified it in two bilateral RB patients
Two rare RB1 mutations associated with bilateral RB and included the donor splice-site mutation and the large deletion of RB1 gene along with several centromeric and telomeric genes
Summary
Retinoblastoma develops as a result of inactivation of the tumor suppressor RB1 gene, 40% of RBs are heritable tumors and 60% are non heritable tumors. In heritable RB the first RB1 mutation is germline and the second mutation is somatic. In non-heritable RBs two somatic RB1 mutations occur in the developing retina. Ten percent of heritable RBs are inherited and 30% arise “de novo”. 75–80% of heritable RBs are bilateral in which both eyes are affected and 15–25% are unilateral in which, only one eye is affected. Heritable RB can be diagnosed at approximately one year of age, whereas, non-heritable RB is always unilateral and develops at approximately two years of age or older [2,3]
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