Mutation-positive and mutation-negative patients with Cowden and Bannayan-Riley-Ruvalcaba syndromes associated with distinct 10q haplotypes
Mutation-positive and mutation-negative patients with Cowden and Bannayan-Riley-Ruvalcaba syndromes associated with distinct 10q haplotypes
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DOI：
10.1086/508943
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发表时间：
2006-11-01
影响因子：
9.8
通讯作者：
Eng, Charis
中科院分区：
文献类型：
--
作者：
Pezzolesi, Marcus G.;Li, Yan;Eng, Charis
10号染色体缺失的磷酸酶和张力蛋白同源物（PTEN）编码一种在散发性和遗传性人类癌症中经常突变的肿瘤抑制磷酸酶。生殖系突变与许多可遗传的癌症综合征相关，这些综合征共同被称为“PTEN错构瘤肿瘤综合征”（PHTS），并且包括Cowden综合征、Bannayan-Riley-Ruvalcaba综合征、Proteus综合征和Proteus样综合征。生殖系PTEN突变已被确定在一个显着比例的PHTS患者，然而，仍然有许多人的经典诊断特征的突变尚未确定。为了解决这一问题，我们采取了基于单体型的方法，并研究了PTEN基因座的特定基因组区域与PHTS的关联。我们发现这个位点的特点是由三个不同的单倍型块33 kb，65 kb，和43 kb的长度。在PHTS患者和对照组中，所有三个区块的单倍型分布的比较差异显著（区块1、2和3分别为P = 0.0098、P <0.0001和P <0.0001）。“稀有”单倍型块和扩展单倍型占PHTS染色体的两到三倍比控制染色体。PTEN突变阴性患者与跨越PTEN上游区域和基因第一内含子的单倍型块密切相关（P = 0.0027）。此外，等位基因组合有助于这种综合征的表型复杂性。总之，这些数据表明，特定的单倍型和罕见的等位基因是这些样本人群中疾病病因的基础;构成低突变率，修饰基因座;并且，特别是在传统突变尚未被鉴定的PHTS患者的情况下，可能含有通过标准PTEN突变扫描方法逃避检测的致病性变体。
Phosphatase and tensin homolog deleted on chromosome 10 ( PTEN) encodes a tumor-suppressor phosphatase frequently mutated in both sporadic and heritable forms of human cancer. Germline mutations are associated with a number of heritable cancer syndromes that are jointly referred to as the "PTEN hamartoma tumor syndrome" (PHTS) and include Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, and Proteus-like syndrome. Germline PTEN mutations have been identified in a significant proportion of patients with PHTS; however, there are still many individuals with classic diagnostic features for whom mutations have yet to be identified. To address this, we took a haplotype-based approach and investigated the association of specific genomic regions of the PTEN locus with PHTS. We found this locus to be characterized by three distinct haplotype blocks 33 kb, 65 kb, and 43 kb in length. Comparisons of the haplotype distributions for all three blocks differed significantly among patients with PHTS and controls (P = .0098, P < .0001, and P < .0001 for blocks 1, 2, and 3, respectively). "Rare" haplotype blocks and extended haplotypes account for two-to-threefold more PHTS chromosomes than control chromosomes. PTEN mutation-negative patients are strongly associated with a haplotype block spanning a region upstream of PTEN and the gene's first intron (P = .0027). Furthermore, allelic combinations contribute to the phenotypic complexity of this syndrome. Taken together, these data suggest that specific haplotypes and rare alleles underlie the disease etiology in these sample populations; constitute low-penetrance, modifying loci; and, specifically in the case of patients with PHTS for whom traditional mutations have yet to be identified, may harbor pathogenic variant(s) that have escaped detection by standard PTEN mutation-scanning methodologies.