KIT/PDGFRA 野生型胃肠道间质瘤的分子亚型：来自美国国立卫生研究院胃肠道间质瘤临床中心的报告。

Molecular Subtypes of KIT/PDGFRA Wild-Type Gastrointestinal Stromal Tumors: A Report From the National Institutes of Health Gastrointestinal Stromal Tumor Clinic.

机构信息

Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland2now with Sarcoma and Rare Tumors Program, Division of Hematology, Oncology, and Palliative Care, Massey Cancer Center, Virginia Commonwealth University, R.

Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee.

出版信息

JAMA Oncol. 2016 Jul 1;2(7):922-8. doi: 10.1001/jamaoncol.2016.0256.

DOI:10.1001/jamaoncol.2016.0256

PMID:27011036

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5472100/

Abstract

IMPORTANCE

Wild-type (WT) gastrointestinal stromal tumors (GISTs), which lack KIT and PDGFRA gene mutations, are the primary form of GIST in children and occasionally occur in adults. They respond poorly to standard targeted therapy. Better molecular and clinical characterization could improve management.

OBJECTIVE

To evaluate the clinical and tumor genomic features of WT GIST.

DESIGN, SETTING, AND PARTICIPANTS: Patients enrolled in an observational study at the National Institutes of Health starting in 2008 and were evaluated in a GIST clinic held once or twice yearly. Patients provided access to existing medical records and tumor specimens. Self-referred or physician-referred patients younger than 19 years with GIST or 19 years or older with known WT GIST (no mutations in KIT or PDGFRA) were recruited; 116 patients with WT GIST were enrolled, and 95 had adequate tumor specimen available. Tumors were characterized by immunohistochemical analysis (IHC) for succinate dehydrogenase (SDH) subunit B, sequencing of SDH genes, and determination of SDHC promoter methylation. Testing of germline SDH genes was offered to consenting patients and families.

MAIN OUTCOMES AND MEASURES

For classification, tumors were characterized by SDHA, B, C, or D (SDHX) mutations and other genetic and epigenetic alterations, including presence of mutations in germline. Clinical characteristics were categorized.

RESULTS

Wild-type GIST specimens from 95 patients (median age, 23 [range, 7-78] years; 70% female) were classified into 3 molecular subtypes: SDH-competent (n = 11), defined by detection of SDHB by IHC; and 2 types of SDH-deficient GIST (n = 84). Of SDH-deficient tumors, 63 (67%) had SDH mutations, and in 31 of 38 (82%), the SDHX mutation was also present in germline. Twenty-one (22%) SDH-deficient tumors had methylation of the SDHC promoter leading to silencing of expression. Mutations in known cancer-associated pathways were identified in 9 of 11 SDH-competent tumors. Among patients with SDH-mutant tumors, 62% were female (39 of 63), median (range) age was 23 (7-58) years, and approximately 30% presented with metastases (liver [12 of 58], peritoneal [6 of 58], lymph node [15 of 23]). SDHC-epimutant tumors mostly affected young females (20 of 21; median [range] age, 15 [8-50] years), and approximately 40% presented with metastases (liver [7 of 19], peritoneal [1 of 19], lymph node [3 of 8]). SDH-deficient tumors occurred only in the stomach and had an indolent course.

CONCLUSIONS AND RELEVANCE

An observational study of WT GIST permitted the evaluation of a large number of patients with this rare disease. Three molecular subtypes with implications for prognosis and clinical management were identified.

摘要

重要性

野生型（WT）胃肠道间质瘤（GIST）缺乏 KIT 和 PDGFRA 基因突变，是儿童 GIST 的主要形式，偶尔也会发生在成年人中。它们对标准靶向治疗反应不佳。更好的分子和临床特征描述可以改善管理。

目的

评估 WT GIST 的临床和肿瘤基因组特征。

设计、地点和参与者：从 2008 年开始，患者在国立卫生研究院（NIH）的一项观察性研究中登记，并在每年举行一次或两次的 GIST 诊所进行评估。患者提供了现有病历和肿瘤标本的访问权限。招募了年龄在 19 岁以下患有 GIST 或 19 岁及以上患有已知 WT GIST（无 KIT 或 PDGFRA 突变）的自我推荐或医生推荐的患者；共纳入 116 例 WT GIST 患者，其中 95 例有足够的肿瘤标本。通过琥珀酸脱氢酶（SDH）亚基 B 的免疫组织化学分析（IHC）、SDH 基因测序和 SDHC 启动子甲基化测定来对肿瘤进行特征描述。向同意的患者和家属提供了对种系 SDH 基因的检测。

主要结果和测量

为了进行分类，肿瘤的特征是 SDHA、B、C 或 D（SDHX）突变和其他遗传和表观遗传改变，包括种系中存在突变。对临床特征进行了分类。

结果

从 95 名患者（中位年龄 23 岁[范围 7-78 岁]；70%为女性）的 WT GIST 标本中，分为 3 种分子亚型：SDH 功能正常（n=11），通过 IHC 检测到 SDHB；和 2 种 SDH 缺陷型 GIST（n=84）。在 SDH 缺陷型肿瘤中，有 63 个（67%）有 SDH 突变，在 38 个中的 31 个（82%）中，SDHX 突变也存在于种系中。21 个（22%）SDH 缺陷型肿瘤的 SDHC 启动子发生甲基化，导致表达沉默。在 11 个 SDH 功能正常的肿瘤中，有 9 个识别出了已知的癌症相关途径的突变。在 SDH 突变型肿瘤患者中，62%为女性（63 例中的 39 例），中位（范围）年龄为 23 岁（7-58 岁），约 30%出现转移（肝脏[58 例中的 12 例]，腹膜[58 例中的 6 例]，淋巴结[23 例中的 15 例]）。SDHC 表观突变型肿瘤主要影响年轻女性（21 例中的 20 例；中位[范围]年龄为 15 岁[8-50 岁]），约 40%出现转移（肝脏[19 例中的 7 例]，腹膜[19 例中的 1 例]，淋巴结[8 例中的 3 例]）。SDH 缺陷型肿瘤仅发生在胃中，且具有惰性病程。