Valero Vicente, Saunders Tyler J, He Jin, Weiss Matthew J, Cameron John L, Dholakia Avani, Wild Aaron T, Shin Eun Ji, Khashab Mouen A, O'Broin-Lennon Anne Marie, Ali Syed Z, Laheru Daniel, Hruban Ralph H, Iacobuzio-Donahue Christine A, Herman Joseph M, Wolfgang Christopher L
*Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD †Department of Pathology ‡Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD §Department of Radiation Oncology and Molecular Radiation Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD ¶Department of Gastroenterology and Hepatology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD.
Ann Surg. 2016 Jan;263(1):153-61. doi: 10.1097/SLA.0000000000001156.
To determine the feasibility of genotyping pancreatic tumors via fine needle aspirates (FNAs).
FNA is a common method of diagnosis for pancreatic cancer, yet it has traditionally been considered inadequate for molecular studies due to the limited quantity of DNA derived from FNA specimens and tumor heterogeneity.
In vitro mixing studies were performed to deduce the minimum cellularity needed for genetic analysis. DNA from both simulated FNAs and clinical FNAs was sequenced. Mutational concordance was determined between simulated FNAs and that of the resected specimen.
Limiting dilution studies indicated that mutations present at allele frequencies as low as 0.12% are detectable. Comparison of simulated FNAs and matched tumor tissue exhibited a concordance frequency of 100% for all driver genes present. In FNAs obtained from 17 patients with unresectable disease, we identified at least 1 driver gene mutation in all patients including actionable somatic mutations in ATM and MTOR. The constellation of mutations identified in these patients was different than that reported for resectable pancreatic cancers, implying a biologic basis for presentation with locally advanced pancreatic cancer.
FNA sequencing is feasible and subsets of patients may harbor actionable mutations that could potentially impact therapy. Moreover, preoperative FNA sequencing has the potential to influence the timing of surgery relative to systemic therapy. FNA sequencing opens the door to clinical trials in which patients undergo neoadjuvant or a surgery-first approach based on their tumor genetics with the goal of utilizing cancer genomics in the clinical management of pancreatic cancer.
确定通过细针穿刺抽吸物（FNA）对胰腺肿瘤进行基因分型的可行性。
FNA是胰腺癌的一种常见诊断方法，但由于FNA标本获取的DNA数量有限以及肿瘤异质性，传统上认为其不适用于分子研究。
进行体外混合研究以推断基因分析所需的最低细胞数量。对模拟FNA和临床FNA的DNA进行测序。确定模拟FNA与切除标本之间的突变一致性。
有限稀释研究表明，等位基因频率低至0.12%的突变也可被检测到。模拟FNA与匹配的肿瘤组织比较显示，所有存在的驱动基因的一致性频率均为100%。在从17例不可切除疾病患者获取的FNA中，我们在所有患者中均鉴定出至少1个驱动基因突变，包括ATM和MTOR中的可操作体细胞突变。这些患者中鉴定出的突变组合与可切除胰腺癌报道的不同，这意味着局部晚期胰腺癌存在生物学基础。
FNA测序是可行的，部分患者可能携带可影响治疗的可操作突变。此外，术前FNA测序有可能影响相对于全身治疗的手术时机。FNA测序为临床试验打开了大门，在这些试验中，患者根据其肿瘤遗传学接受新辅助治疗或先行手术治疗，目标是在胰腺癌的临床管理中利用癌症基因组学。
