Molecular profiling of neuroendocrine malignancies to identify prognostic and therapeutic markers: a Fox Chase Cancer Center Pilot Study.
Molecular profiling of neuroendocrine malignancies to identify prognostic and therapeutic markers: a Fox Chase Cancer Center Pilot Study.
复制标题
DOI：
10.1038/bjc.2016.229
复制
发表时间：
2016-08-23
影响因子：
8.8
通讯作者：
Engstrom PF
中科院分区：
文献类型：
--
作者：
Vijayvergia N;Boland PM;Handorf E;Gustafson KS;Gong Y;Cooper HS;Sheriff F;Astsaturov I;Cohen SJ;Engstrom PF
神经内分泌恶性肿瘤的罕见性限制了开发新疗法的能力，因此更好地了解潜在的生物学至关重要。通过一项前瞻性的IRB批准的方案，神经内分泌恶性肿瘤患者接受了下一代肿瘤测序，以检测50种癌症相关基因的体细胞突变（SM）。低分化神经内分泌癌（NEC/低分化组织学和Ki-67> 20%）与胰腺神经内分泌肿瘤（PanNET/Ki-67> 20%）和非胰腺神经内分泌肿瘤（NP-NET/Ki-67> 20%）之间存在临床病理相关性。共有77名患者入组，63名患者获得了下一代测序结果。低分化NEC中SM的发生率为83%（23例中的19例），PanNET中为45%（11例中的5例），NP-NET中为14%（29例中的4例）。TP53是低分化NEC中最常见的突变（57%），KRAS（30%）、PIK3CA/PTEN（22%）和BRAF（13%）也存在突变，小肠神经内分泌肿瘤（Ki67 <2%/n = 9）未发现突变。突变的患病率与前一年内进展风险较高相关（32%（低风险）vs 11%（高风险），P = 0.01），TP53突变与生存率较差相关（2年生存率66% vs 97%，P = 0.003）。分化差的NEC具有高突变负荷，具有潜在的靶向突变。TP53突变与神经内分泌恶性肿瘤的生存率低相关。这些发现对治疗的选择和预后分层具有临床试验意义，并值得证实。
The rarity of neuroendocrine malignancies limits the ability to develop new therapies and thus a better understanding of the underlying biology is critical. Through a prospective, IRB-approved protocol, patients with neuroendocrine malignancies underwent next-generation sequencing of their tumours to detect somatic mutations (SMs) in 50 cancer-related genes. Clinicopathologic correlation was made among poorly differentiated neuroendocrine carcinomas (NECs/poorly differentiated histology and Ki-67 >20%) and pancreatic neuroendocrine tumours (PanNETs/Ki67 ⩽20%) and non-pancreatic neuroendocrine tumours (NP-NETs/Ki67 ⩽20%). A total of 77 patients were enrolled, with next-generation sequencing results available on 63 patients. Incidence of SMs was 83% (19 out of 23) in poorly differentiated NECs, 45% (5 out of 11) in PanNETs and 14% (4 out of 29) in NP-NETs. TP53 was the most prevalent mutation in poorly differentiated NECs (57%), and KRAS (30%), PIK3CA/PTEN (22%) and BRAF (13%) mutations were also found. Small intestinal neuroendocrine tumours (Ki67 <2%/n=9) did not harbour any mutations. Prevalence of mutations correlated with higher risk of progression within the previous year (32% (low risk) vs 11% (high risk), P=0.01) and TP53 mutation correlated with worse survival (2-year survival 66% vs 97%, P=0.003). Poorly differentiated NECs have a high mutation burden with potentially targetable mutations. The TP53 mutations are associated with poor survival in neuroendocrine malignancies. These findings have clinical trial implications for choice of therapy and prognostic stratification and warrant confirmation.