Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, NY 12208, USA.
Gynecol Oncol. 2013 Sep;130(3):554-9. doi: 10.1016/j.ygyno.2013.06.019. Epub 2013 Jun 20.
Targeted next generation sequencing (NGS) was evaluated for its ability to identify unanticipated targetable genomic alterations (GA) for patients with relapsed ovarian epithelial carcinoma (OC).
DNA sequencing was performed for 3320 exons of 182 cancer-related genes and 37 introns of 14 genes frequently rearranged in cancer on indexed, adaptor ligated, hybridization-captured libraries using DNA isolated from FFPE sections from 48 histologically verified relapsed OC specimens. The original primary tumor was sequenced in 26 (54%) of the cases and recurrent/metastatic tumor site biopsies were sequenced in 22 (46%) of the cases. Actionability was defined as: GA that predict sensitivity or resistance to approved or standard therapies or are inclusion or exclusion criteria for specific experimental therapies in NCI registered clinical trials.
There were 38 (80%) serous, 5 (10%) endometrioid, 3 (6%) clear cell, 1 mucinous (2%) and 1 (2%) undifferentiated carcinomas. 141 GA were identified with an average of 2.9 GA (range 0-8) per tumor, of which 67 were actionable for an average of 1.4 actionable GA per patient (range 0-5). 33/48 (69%) of OC patient samples harbored at least one actionable GA. Most common GA were TP53 (79%); MYC (25%); BRCA1/2 (23%); KRAS (16.6%) and NF1 (14.5%). One tumor featured an ERBB2 point mutation. One of 3 (33%) of clear cell tumors featured cMET amplification validated by both FISH and IHC.
NGS assessment of therapy resistant OC identifies an unexpectedly high frequency of GA that could influence targeted therapy selection for the disease.
评估靶向下一代测序（NGS）在鉴定复发性卵巢上皮癌（OC）患者中意外可靶向基因组改变（GA）的能力。
从 48 例经组织学证实的复发性 OC 标本的 FFPE 切片中提取 DNA，对 182 个癌症相关基因的 3320 个外显子和 14 个基因的 37 个内含子进行靶向 NGS 测序，这些基因的 DNA 与索引、衔接子连接、杂交捕获文库连接。在 26 例（54%）病例中对原始原发性肿瘤进行了测序，在 22 例（46%）病例中对复发性/转移性肿瘤部位活检进行了测序。可操作性定义为：GA 预测对批准或标准治疗的敏感性或耐药性，或为 NCI 注册临床试验中特定实验治疗的纳入或排除标准。
有 38 例（80%）为浆液性，5 例（10%）为子宫内膜样，3 例（6%）为透明细胞，1 例（2%）为黏液性和 1 例（2%）为未分化癌。发现 141 个 GA，每个肿瘤平均有 2.9 个 GA（范围 0-8），其中 67 个对患者平均 1.4 个可操作 GA（范围 0-5）有作用。48 例 OC 患者样本中有 33/48（69%）至少存在一个可操作的 GA。最常见的 GA 是 TP53（79%）；MYC（25%）；BRCA1/2（23%）；KRAS（16.6%）和 NF1（14.5%）。一个肿瘤有 ERBB2 点突变。3 个透明细胞肿瘤中有 1 个（33%）存在 cMET 扩增，该扩增被 FISH 和 IHC 均证实。
对耐药 OC 的 NGS 评估鉴定了意外高频率的 GA，这可能影响该疾病的靶向治疗选择。
