Relevance of circulating mutant BRAF DNA in melanoma

循环突变 BRAF DNA 与黑色素瘤的相关性

• 批准号: 7140119
• 负责人: DAVID POLSKY
• 金额: $ 14.19万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7140119
• 关键词: alleles; clinical research; gene frequency; gene mutation; genotype; human subject; laser capture microdissection; longitudinal human study; melanoma; metastasis; method development; neoplasm /cancer genetics; oncogenes; polymerase chain reaction; serine threonine protein kinase

DESCRIPTION (provided by applicant): The high frequency of BRAF oncogene mutations coupled with the critical role of its gene product in the pathogenesis of metastatic melanoma have led to the development of BRAF inhibitor therapies that are currently undergoing clinical trials. We are participating in two such trials, (one at our institution testing BAY 43-9006, and the other collaborating with Memorial Sloan-Kettering Cancer Center testing 17-AAG) which require that the patients undergo biopsy of their metastatic lesion for sequencing of the BRAF gene to be eligible for participation. As a result, many patients are ineligible for BRAF inhibitors due to inaccessibility of their metastases. Thus, there is an urgent need to develop a simple mechanism for BRAF genotyping to improve selection of patients who are eligible for anti-BRAF therapies. We have developed a new, sensitive, specific, DNA-based, fluorescent assay to detect mutant BRAF alleles in the peripheral blood and tumor specimens of melanoma patients. In our preliminary analyses, we were able to detect mutant BRAF alleles in 13/23 (57%) patient blood specimens. The objective of our proposal is to define the clinical utility of this innovative assay in well-defined patient cohorts. In Aim 1, we will compare the frequency of detection of mutant BRAF alleles in the peripheral blood of melanoma patients with lymph node metastases (Stage III) to those with metastases to visceral sites (Stage IV). In addition, we will determine the association between detection of mutant BRAF alleles in the blood and disease burden based on well-established, standard clinical measures such as pattern of tumor spread and the number of metastatic sties. In Aim 2, we will determine the level of concordance between mutational BRAF status in the blood and corresponding tumor tissues from the patients analyzed in Aim 1. We foresee our project as a critical step in establishing the utility of this peripheral blood assay in selecting melanoma patients eligible to receive BRAF inhibitor therapy, and, potentially, in monitoring response to treatment.

描述（由申请人提供）：BRAF癌基因突变的高频率及其基因产物在转移性黑色素瘤发病机制中的关键作用导致了BRAF抑制剂疗法的开发，目前正在进行临床试验。我们正在参与两项此类试验（一项在我们的机构测试 BAY 43-9006，另一项与纪念斯隆-凯特琳癌症中心合作测试 17-AAG），这些试验要求患者对其转移性病变进行活检以进行 BRAF 基因测序，才有资格参与。因此，许多患者由于无法接近转移灶而没有资格使用 BRAF 抑制剂。因此，迫切需要开发一种简单的 BRAF 基因分型机制，以改善对适合接受抗 BRAF 治疗的患者的选择。我们开发了一种新的、灵敏的、特异的、基于 DNA 的荧光检测方法，用于检测黑色素瘤患者外周血和肿瘤标本中的突变 BRAF 等位基因。在我们的初步分析中，我们能够在 13/23 (57%) 患者血液样本中检测到突变 BRAF 等位基因。我们提案的目的是确定这种创新测定在明确的患者群体中的临床效用。在目标 1 中，我们将比较淋巴结转移（III 期）和内脏转移（IV 期）黑色素瘤患者外周血中突变 BRAF 等位基因的检测频率。此外，我们将根据完善的标准临床指标（例如肿瘤扩散模式和转移性麦粒肿数量）确定血液中突变 BRAF 等位基因的检测与疾病负担之间的关联。在目标 2 中，我们将确定血液中突变 BRAF 状态与目标 1 中分析的患者的相应肿瘤组织之间的一致性水平。我们预计我们的项目将成为建立这种外周血测定在选择有资格接受 BRAF 抑制剂治疗的黑色素瘤患者方面的效用的关键一步，并可能监测对治疗的反应。

项目成果

Intra- and inter-tumor heterogeneity of BRAF(V600E))mutations in primary and metastatic melanoma.

• DOI: 10.1371/journal.pone.0029336
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Yancovitz M;Litterman A;Yoon J;Ng E;Shapiro RL;Berman RS;Pavlick AC;Darvishian F;Christos P;Mazumdar M;Osman I;Polsky D
• 通讯作者: Polsky D