Pezzolesi Marcus G, Li Yan, Zhou Xiao-Ping, Pilarski Robert, Shen Lei, Eng Charis
Genomic Medicine Institute, Cleveland Clinic Lerner Research Institute, Cleveland, OH, 44195, USA.
Am J Hum Genet. 2006 Nov;79(5):923-34. doi: 10.1086/508943. Epub 2006 Sep 29.
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.
10号染色体缺失的磷酸酶及张力蛋白同源物（PTEN）编码一种肿瘤抑制磷酸酶，在散发性和遗传性人类癌症中经常发生突变。种系突变与多种遗传性癌症综合征相关，这些综合征统称为“PTEN错构瘤肿瘤综合征”（PHTS），包括考登综合征、巴纳扬-莱利-鲁瓦尔卡巴综合征、变形综合征和类变形综合征。在相当比例的PHTS患者中已鉴定出种系PTEN突变；然而，仍有许多具有典型诊断特征的个体尚未鉴定出突变。为了解决这个问题，我们采用了基于单倍型的方法，研究了PTEN基因座的特定基因组区域与PHTS的关联。我们发现该基因座的特征是有三个不同的单倍型块，长度分别为33 kb、65 kb和43 kb。PHTS患者和对照组中所有三个块的单倍型分布比较差异显著（第1、2和3块分别为P = 0.0098、P < 0.0001和P < 0.0001）。“罕见”单倍型块和扩展单倍型在PHTS染色体中所占比例比对照染色体多两到三倍。PTEN突变阴性患者与跨越PTEN上游区域和该基因第一个内含子的单倍型块密切相关（P = 0.0027）。此外，等位基因组合导致了该综合征的表型复杂性。综上所述，这些数据表明特定的单倍型和罕见等位基因是这些样本群体中疾病病因的基础；构成低外显率的修饰基因座；特别是对于尚未鉴定出传统突变的PHTS患者，可能含有通过标准PTEN突变扫描方法未检测到的致病变体。
