PTEN mutation spectrum and genotype-phenotype correlations in Bannayan-Riley-Ruvalcaba syndrome suggest a single entity with Cowden syndrome
PTEN mutation spectrum and genotype-phenotype correlations in Bannayan-Riley-Ruvalcaba syndrome suggest a single entity with Cowden syndrome
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DOI：
10.1093/hmg/8.8.1461
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发表时间：
1999-08-01
影响因子：
3.5
通讯作者：
Eng, C
中科院分区：
文献类型：
--
作者：
Marsh, DJ;Kum, JB;Eng, C
肿瘤抑制基因 PTEN 的种系突变与两种表现出一些临床重叠的错构瘤综合征有关：考登综合征 (CS) 和 Bannayan-Riley-Ruvalcaba 综合征 (BRR)。 PTEN 定位于 10q23，编码双特异性磷酸酶，其底物是磷脂酰肌醇 3,4,5-三磷酸，磷脂酰肌醇 3-激酶途径中的一种磷脂。 CS 的特点是多发性错构瘤以及乳腺、甲状腺和中枢神经系统良性和恶性疾病的风险增加，而癌症的存在尚未在 ERR 中得到正式记录。这两种综合征的部分临床重叠体现在 ERR 的标志性特征上：大头畸形和多发性脂肪瘤，后者发生在少数 CS 患者中。在 ERR 中观察到的其他特征（也可能发生在少数 CS 患者中）包括桥本氏甲状腺炎、血管畸形和智力低下。仅在 ERR 中才会注意到龟头色素斑、运动发育迟缓以及新生儿或婴儿发病。在这项研究中，对来自 43 名 ERR 个体（包括 16 名散发病例和 27 名家族病例，其中 11 名同时患有 CS 和 ERR 的家庭）的组成型 DNA 样本进行了 PTEN 突变筛查。 43 例 ERR 病例中，有 26 例 (60%) 发现了突变。 ERR 组内的基因型-表型分析表明了许多相关性，包括 PTEN 突变与任何给定 CS、ERR 或 BRR/CS 重叠家族中癌症或乳腺纤维腺瘤的关联 (P = 0.014)，特别是截短突变与给定家族中癌症和乳腺纤维腺瘤的存在相关 (P = 0.024)。此外，ERR 患者中脂肪瘤的存在与 PTEN 突变的存在相关（P = 0.028）。与之前的报告相比，家族性 ERR 病例与散发性 ERR 病例的突变状态没有显着差异（P = 0.113）。 ERR 与先前研究的 37 个 CS 家族组之间的比较表明，与单独的 ERR 相比，在仅具有 CS 或同时具有 CS 和 ERR 的家族中发现种系 PTEN 突变的可能性更高 (P = 0.002)。在 PTEN 突变阳性的 CS、ERR 和 BRR/CS 重叠家族中，突变谱相似。因此，PTEN 突变阳性 CS 和 ERR 可能是单一综合征的不同表现，因此，在癌症监测方面，两者应受到同等重视。
Germline mutations in the tumour suppressor gene PTEN have been implicated in two hamartoma syndromes that exhibit some clinical overlap, Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRR). PTEN maps to 10q23 and encodes a dual specificity phosphatase, a substrate of which is phosphatidylinositol 3,4,5-triphosphate, a phospholipid in the phosphatidylinositol 3-kinase pathway. CS is characterized by multiple hamartomas and an increased risk of benign and malignant disease of the breast, thyroid and central nervous system, whilst the presence of cancer has not been formally documented in ERR. The partial clinical overlap in these two syndromes is exemplified by the hallmark features of ERR: macrocephaly and multiple lipomas, the latter of which occur in a minority of individuals with CS. Additional features observed in ERR, which may also occur in a minority of CS patients, include Hashimoto's thyroiditis, vascular malformations and mental retardation. Pigmented macules of the glans penis, delayed motor development and neonatal or infant onset are noted only in ERR. In this study, constitutive DNA samples from 43 ERR individuals comprising 16 sporadic and 27 familial cases, 11 of which were families with both CS and ERR, were screened for PTEN mutations. Mutations were identified in 26 of 43 (60%) ERR cases. Genotype-phenotype analyses within the ERR group suggested a number of correlations, including the association of PTEN mutation and cancer or breast fibroadenoma in any given CS, ERR or BRR/CS overlap family (P = 0.014), and, in particular, truncating mutations were associated with the presence of cancer and breast fibroadenoma in a given family (P = 0.024). Additionally, the presence of lipomas was correlated with the presence of PTEN mutation in ERR patients (P = 0.028). In contrast to a prior report, no significant difference in mutation status was found in familial versus sporadic cases of ERR (P = 0.113). Comparisons between ERR and a previously studied group of 37 CS families suggested an increased likelihood of identifying a germline PTEN mutation in families with either CS alone or both CS and ERR when compared with ERR alone (P = 0.002). Among CS, ERR and BRR/CS overlap families that are PTEN mutation positive, the mutation spectra appear similar. Thus, PTEN mutation-positive CS and ERR may be different presentations of a single syndrome and, hence, both should receive equal attention with respect to cancer surveillance.