From the Cancer Research Institute, Beth Israel Deaconess Cancer Center (Y.-R.L., T.K., J.Z., N.P., J.L., W.W., P.P.P.), and the Departments of Medicine (Y.-R.L., T.K., N.P., P.P.P.) and Pathology (J.Z., J.L., W.W., P.P.P.), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston; the Genomic Medicine Institute (L.Y., Y.N., B.L., C.E.) and the Department of Quantitative Health Sciences (Y.N.), Lerner Research Institute, Cleveland Clinic, the Taussig Cancer Institute (C.E.), the Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine (C.E.), and the Germline High Risk Cancer Focus Group, Case Comprehensive Cancer Center, Case Western Reserve University (C.E.) - all in Cleveland; the Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University (J.Z.), and the Medical Research Institute, Wuhan University (J.Z.) - both in Wuhan, China; and the Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy (P.P.P.).
N Engl J Med. 2020 May 28;382(22):2103-2116. doi: 10.1056/NEJMoa1914919.
Patients with hamartoma tumor syndrome (PHTS) have germline mutations in the tumor-suppressor gene encoding phosphatase and tensin homologue (). Such mutations have been associated with a hereditary predisposition to multiple types of cancer, including the Cowden syndrome. However, a majority of patients who have PHTS-related phenotypes have tested negative for mutations. In a previous study, we found that the E3 ubiquitin ligase WWP1 negatively regulates the function of PTEN.
In a prospective cohort study conducted from 2005 through 2015, we enrolled 431 patients with wild-type who met at least the relaxed diagnostic criteria of the International Cowden Consortium. Patients were scanned for germline variants. We used the Cancer Genome Atlas (TCGA) data set as representative of apparently sporadic cancers and the Exome Aggregation Consortium data set excluding TCGA (non-TCGA ExAC) and the noncancer Genome Aggregation Database (gnomAD) as representative of population controls without a reported cancer diagnosis. We established both in vitro and murine in vivo models to functionally characterize representative variants.
The existence of germline variants was first established in a family with wild-type who had oligopolyposis and early-onset colon cancers. A validation series indicated that germline variants occurred in 5 of 126 unrelated patients (4%) with oligopolyposis as a predominant phenotype. Germline variants, particularly the K740N and N745S alleles, were enriched in patients who did not have PHTS but had prevalent sporadic cancers, including related cancer types in TCGA (odds ratio, 1.5; 95% confidence interval, 1.1 to 2.1; P = 0.01). The prioritized variants resulted in gain-of-function effects, which led to aberrant enzymatic activation with consequent PTEN inactivation, thereby triggering hyperactive growth-promoting PI3K signaling in cellular and murine models.
In this study involving patients with disorders resulting in a predisposition to the development of multiple malignant neoplasms without germline mutations, we confirmed the function of as a cancer-susceptibility gene through direct aberrant regulation of the PTEN-PI3K signaling axis. (Funded by the National Institutes of Health and others.).
患有错构瘤肿瘤综合征（PHTS）的患者在肿瘤抑制基因编码磷酸酶和张力蛋白同源物（）中存在种系突变。此类突变与多种类型的癌症（包括考登综合征）的遗传易感性相关。然而，大多数具有 PHTS 相关表型的患者检测到突变呈阴性。在之前的一项研究中，我们发现 E3 泛素连接酶 WWPl 负调控 PTEN 的功能。
在 2005 年至 2015 年期间进行的一项前瞻性队列研究中，我们招募了 431 名符合国际考登综合征联合会放宽诊断标准的野生型患者。对患者进行种系突变检测。我们使用癌症基因组图谱（TCGA）数据集作为明显散发癌症的代表，以及排除 TCGA 的外显子组聚合联盟数据集（非 TCGA ExAC）和无癌症基因组聚合数据库（gnomAD）作为无报告癌症诊断的人群对照的代表。我们建立了体外和鼠体内模型来对代表性的变体进行功能表征。
首先在一个具有野生型但具有寡聚性和早发性结肠癌的家族中确立了种系的存在。验证系列表明，在以寡聚性为主要表型的 126 名无关患者中，有 5 名患者存在种系变体。种系变体，特别是 K740N 和 N745S 等位基因，在没有 PHTS 但具有普遍散发癌症的患者中更为丰富，包括 TCGA 中的相关癌症类型（比值比，1.5；95%置信区间，1.1 至 2.1；P = 0.01）。优先变体导致获得性功能效应，导致异常酶激活，从而导致 PTEN 失活，从而在细胞和鼠模型中触发过度活跃的促进生长的 PI3K 信号传导。
在这项涉及因多种恶性肿瘤发生倾向而导致疾病的患者的研究中，我们在没有突变的情况下，通过直接对 PTEN-PI3K 信号轴的异常调节，证实了作为癌症易感性基因的功能。（由美国国立卫生研究院等资助）。
