RB1 gene mutations in Argentine retinoblastoma patients. Implications for genetic counseling.
RB1 gene mutations in Argentine retinoblastoma patients. Implications for genetic counseling.
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DOI：
10.1371/journal.pone.0189736
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Szijan I
中科院分区：
文献类型：
--
作者：
Parma D;Ferrer M;Luce L;Giliberto F;Szijan I
视网膜母细胞瘤（RB）是一种遗传性儿童眼部癌症，由肿瘤抑制基因RB 1突变引起。RB 1突变的鉴定对于评估患者亲属发生视网膜母细胞瘤的风险至关重要。视网膜母细胞瘤是一种潜在的可治愈的癌症，早期诊断对生存和眼睛保护至关重要。单侧视网膜母细胞瘤大多数是非遗传性的，由两个体细胞突变引起，而双侧视网膜母细胞瘤是遗传性的，由一个生殖系和一个体细胞突变引起，两者都具有90%的高遗传率。本研究的目的是确定RB患者不同临床表现的致病RB 1突变。采用综合方法对34例单侧、双侧和三侧视网膜母细胞瘤患者进行研究。通过测序和多重连接依赖性探针扩增（MLPA）测定分析血液和肿瘤DNA。通过克隆PCR产物来验证插入突变。我们队列中的大多数患者患有单侧RB，8例患者患有双侧RB，1例患者患有眼和鞍上/鞍位置的三侧肿瘤。在受影响的家庭中还发现了视网膜母细胞瘤以外的其他肿瘤。一名患者有两种综合征，视网膜母细胞瘤和神经鞘瘤病，另一名RB患者的父亲患有视网膜瘤。25例单侧RB患者中有5例（20%）携带gerbB基因突变，主要为错义突变。双侧和三侧患者携带剪接位点，无义和移码突变以及整个RB 1基因缺失。错义突变与轻度表型相关：单侧视网膜母细胞瘤、视网膜瘤或无肿瘤。在这项研究中，我们确定了大多数双侧RB患者和一些单侧RB患者的致病RB 1突变，包括5个新的突变。这些数据对于遗传咨询至关重要，并证实需要对体质和肿瘤组织中的RB 1突变进行完整的遗传筛查。
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.
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