Beside P53 and PTEN: Identification of molecular alterations of the RAS/MAPK and PI3K/AKT signaling pathways in high-grade serous ovarian carcinomas to determine potential novel therapeutic targets.
Beside P53 and PTEN: Identification of molecular alterations of the RAS/MAPK and PI3K/AKT signaling pathways in high-grade serous ovarian carcinomas to determine potential novel therapeutic targets.
复制标题
DOI：
10.3892/ol.2016.5083
复制
发表时间：
2016-11
期刊：
影响因子：
2.9
通讯作者：
Harlé A
中科院分区：
文献类型：
--
作者：
Chen S;Cavazza E;Barlier C;Salleron J;Filhine-Tresarrieu P;Gavoilles C;Merlin JL;Harlé A
尽管组织学和分子异质性很大，高级别卵巢癌的临床治疗仍然是非专业化的。作为一个主要的亚组，高级别浆液性卵巢癌（HGSOC）需要新的治疗方法。除了利用传统的组织学预后标志物和进行致癌研究外，还进行了下一代测序（NGS）的分子诊断方法，以确定可以提供创新治疗的“可药物化”靶点。本研究在45例经组织学证实的HGSOC患者（平均年龄59.1岁;范围25-87岁）中进行。乳腺癌1/2（BRCA 1/2）生殖细胞突变筛查17例家族或个人癌症史，这是合理的肿瘤遗传学研究。肿瘤蛋白53（P53）和磷酸酶和张力蛋白同源物（PTEN）的表达进行了评估，在福尔马林固定的石蜡包埋的组织，使用免疫组化。使用NGS对诊断时获得的冷冻肿瘤标本的DNA提取物筛选Kirsten大鼠肉瘤病毒癌基因同源物、神经母细胞瘤RAS病毒癌基因同源物（NRAS）、B-Raf原癌基因、丝氨酸/苏氨酸激酶、磷脂酰肌醇-4，5-二磷酸3-激酶催化亚基α（PIK 3CA）和MET原癌基因、受体酪氨酸激酶（MET）的体细胞突变。中位随访时间为38个月（范围6-93个月），20例患者存活，10例患者无疾病，14例患者在铂类药物治疗后6个月内进展。67%的患者检测到P53过表达，38%的患者检测到PTEN缺失。突变型P53的过度表达与较长的无进展生存期和总生存期相关。总共检测到2个NRAS（外显子3）、3个PIK 3CA（外显子5和10）和5个MET突变（外显子14和18）。在HGSOC中，除了P53和PTEN改变之外，还可以使用NGS检测体细胞遗传异常，并为靶向治疗提供分子基础，可能为患者提供新的治疗机会。
Despite great histological and molecular heterogeneity, the clinical management of high-grade ovarian carcinomas remains unspecialized. As a major subgroup, high-grade serous ovarian carcinomas (HGSOCs) require novel therapies. In addition to utilizing conventional histological prognostic markers and performing oncogenetic investigations, the molecular diagnostic method of next generation sequencing (NGS) was performed to identify ‘druggable’ targets that could provide access to innovative therapy. The present study was performed in 45 HGSOC patients (mean age, 59.1 years; range, 25–87 years) with histologically proven HGSOC. Breast cancer 1/2 (BRCA1/2) germline mutations were screened in 17 patients with a familial or personal history of cancer, which was justified by oncogenetic investigations. Tumor protein 53 (P53) and phosphatase and tensin homolog (PTEN) expression were assessed in formalin-fixed paraffin-embedded tissues using immunohistochemistry. Somatic mutations of Kirsten rat sarcoma viral oncogene homolog, neuroblastoma RAS viral oncogene homolog (NRAS), B-Raf proto-oncogene, serine/threonine kinase, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA) and MET proto-oncogene, receptor tyrosine kinase (MET) were screened using NGS on DNA extracts from frozen tumor specimens obtained at diagnosis. With a median follow-up of 38 months (range, 6–93 months), 20 patients are alive, 10 patients are disease-free and 14 patients progressed within 6 months following platinum-based therapy. P53 overexpression was detected in 67% of patients and PTEN loss was detected in 38% of the patients. The overexpression of mutant P53 was found to be associated with a longer progression-free and overall survival. In total, 2 NRAS (exon 3), 3 PIK3CA (exon 5 and 10) and 5 MET mutations (exons 14 and 18) were detected. In HGSOCs, in addition to P53 and PTEN alterations, somatic genetic abnormalities can be detected using NGS and provide molecular rationale for targeted therapies, potentially offering novel therapeutic opportunities to patients.
登录
查看更多内容
影响因子：
4.7
作者：
Aghajanian C;Goff B;Nycum LR;Wang YV;Husain A;Blank SV
通讯作者：
Blank SV
DOI：
10.1038/nrc2644
发表时间：
2009-06
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
影响因子：
51.1
作者：
Ascierto, Paolo A.;Schadendorf, Dirk;Dummer, Reinhard
通讯作者：
Dummer, Reinhard
影响因子：
8.8
作者：
Arriola, E.;Canadas, I.;Arumi-Uria, M.;Domine, M.;Lopez-Vilarino, J. A.;Arpi, O.;Salido, M.;Menendez, S.;Grande, E.;Hirsch, F. R.;Serrano, S.;Bellosillo, B.;Rojo, F.;Rovira, A.;Albanell, J.
通讯作者：
Albanell, J.
影响因子：
45.3
作者：
Choueiri, Toni K.;Vaishampayan, Ulka;Srinivasan, Ramaprasad
通讯作者：
Srinivasan, Ramaprasad