FISH assay identifying oral cancer patients at low risk of lymph node metastasis

描述（由申请人提供）：在美国，死于口腔鳞状细胞癌（SCC）的人比死于黑色素瘤、宫颈癌或卵巢癌的人要多，而且这种疾病的发病率，尤其是年轻人的发病率正在上升。颈部转移是主要死亡原因；然而，并非所有的口腔SCCs都会转移。由于目前在原发癌手术切除前通过临床或影像学检查检测转移的准确性较差，颈部清扫术，根据目前的风险评估能力，如果转移风险为bb0 - 20%，则行手术切除颈（颈）淋巴结。因此，几乎所有的口腔鳞状细胞癌患者都要进行颈部清扫，这增加了患者的发病率。我们实验室最近的研究区分了两种具有不同分子特征和转移率的口服SCC亚型。其中一个亚型是3q8pq20亚型，其特征是存在一个或多个反复出现的拷贝数畸变，+3q, - 8p， +8q和/或+20。另一种亚型（非3q8pq20）缺乏这些拷贝数改变。与3q8pq20亚型46%的转移率相比，非3q8pq20亚型的转移风险较低（7%）。这一观察结果在一个独立的口腔SCC队列中得到了重复。因此，一个或多个这些位点的DNA拷贝数改变是识别转移风险低的患者的生物标志物，这些患者可以避免可能不必要的颈部淋巴结切除手术。针对PA-09-158，我们建议开发我们的DNA拷贝数签名（+3q, -8p, +8q, +20）作为临床测试，以识别低转移风险患者的非3q8pq20亚群。为此，我们将开发并验证一种基于fish的检测方法，以检测染色体3q， 8p， 8q和20的DNA拷贝数，该方法适用于术前收集的病变刷活检分析。工作将集中在样本收集（目标1）和FISH的拷贝数检测（目标2）。我们寻求最适合临床实施的标本采集技术和分析技术的结合。经过验证和优化的检测将在随后的多机构前瞻性试验中用于评估3q8pq20的状态，以确定该生物标志物在识别不需要颈部解剖的患者中的效用。

DESCRIPTION (provided by applicant): In the USA, more people die from oral squamous cell carcinoma (SCC) than melanoma, cervical or ovarian cancer and the incidence, particularly in young people, is increasing. Neck metastasis is the primary cause of death; however, not all oral SCCs metastasize. Due to the current poor accuracy in detecting metastasis by clinical or radiographic examination prior to surgical removal of the primary cancer, neck dissection, surgery to remove the cervical (neck) lymph nodes is performed if the metastatic risk is >20% based on current risk assessment capability. Therefore, almost all oral SCC patients undergo a neck dissection which increases patient morbidity. Recent studies in our laboratories have discriminated two oral SCC subtypes with distinct molecular signatures and metastatic rates. One subtype, the 3q8pq20 subtype, is characterized by the presence of one or more of the recurrent copy number aberrations, +3q, - 8p, +8q and/or +20. The other subtype (non-3q8pq20) lacks these copy number alterations. The non-3q8pq20 subtype is associated with a low risk of metastasis (7%) compared to the 46% rate of metastasis in the 3q8pq20 subtype. This observation has been replicated in an independent oral SCC cohort. Thus, DNA copy number alterations at one or more of these loci is a biomarker identifying a group of patients at low risk for metastasis, who could be spared the potentially unnecessary major surgery required for removal of the cervical lymph nodes. In response to PA-09-158, we are proposing to develop our DNA copy number signature (+3q, -8p, +8q, +20) as a clinical test to identify the non-3q8pq20 subset of patients at low risk for metastasis. To this end, we will develop and validate a FISH-based assay to detect DNA copy number for chromosomes 3q, 8p, 8q and 20 that is suitable for analysis of lesional brush biopsies collected prior to surgery. Work will focus on sample collection (Aim 1) and copy number detection by FISH (Aim 2). We seek the combination of specimen collection technique and analysis technology that would be best suited for clinical implementation. The validated and optimized assay will be used to assess 3q8pq20 status in a subsequent multi-institutional prospective trial to establish the utility of this biomarker to identify patients who do not require a neck dissection. PUBLIC HEALTH RELEVANCE: Neck metastasis is the primary determinant for prognosis of oral cancer patients. Here, an assay for a recently identified molecular signature for tumors with low risk of metastasis will be validated and developed into a clinical test. The assay format will be suitable for analysis of patient samples collected during the period of patient evaluation prior to surgery in order to allow clinicians to confidently identify those patients at low risk for neck metastasis, who, at the time of surgical removal of their tumors, could be spared the additional major surgery required to remove the neck lymph nodes.