Wang Kai, Johnson Adrienne, Ali Siraj M, Klempner Samuel J, Bekaii-Saab Tanios, Vacirca Jeffrey L, Khaira Depinder, Yelensky Roman, Chmielecki Juliann, Elvin Julia A, Lipson Doron, Miller Vincent A, Stephens Philip J, Ross Jeffrey S
Foundation Medicine, Inc., Cambridge, Massachusetts, USA; Division of Hematology-Oncology, University of California Irvine, Orange, California, USA; The Ohio State University-James Cancer Hospital, Columbus, Ohio, USA; National Translational Research Group, New York, New York, USA; Albany Medical College, Albany, New York, USA
Foundation Medicine, Inc., Cambridge, Massachusetts, USA; Division of Hematology-Oncology, University of California Irvine, Orange, California, USA; The Ohio State University-James Cancer Hospital, Columbus, Ohio, USA; National Translational Research Group, New York, New York, USA; Albany Medical College, Albany, New York, USA.
Oncologist. 2015 Oct;20(10):1132-9. doi: 10.1634/theoncologist.2015-0156. Epub 2015 Sep 2.
Esophageal squamous cell carcinomas (ESCCs) and esophageal adenocarcinomas (EACs) account for >95% of esophageal malignancies and represent a major global health burden. ESCC is the dominant histology globally but represents a minority of U.S. cases, with EAC accounting for the majority of U.S.
The patient outcomes for advanced ESCC and EAC are poor, and new therapeutic options are needed. Using a sensitive sequencing assay, we compared the genomic profiles of ESCC and EAC with attention to identification of therapeutically relevant genomic alterations.
Next-generation sequencing-based comprehensive genomic profiling was performed on hybridization-captured, adaptor ligation-based libraries to a median coverage depth of >650× for all coding exons of 315 cancer-related genes plus selected introns from 28 genes frequently rearranged in cancer. Results from a single sample were evaluated for all classes of genomic alterations (GAs) including point mutations, short insertions and deletions, gene amplifications, homozygous deletions, and fusions/rearrangements. Clinically relevant genomic alterations (CRGAs) were defined as alterations linked to approved drugs and those under evaluation in mechanism-driven clinical trials.
There were no significant differences by sex for either tumor type, and the median age for all patients was 63 years. All ESCCs and EACs were at an advanced stage at the time of sequencing. All 71 ESCCs and 231 EACs featured GAs on profiling, with 522 GAs in ESCC (7.4 per sample) and 1,303 GAs in EAC (5.6 per sample). The frequency of clinically relevant GAs in ESCC was 94% (2.6 per sample) and 93% in EAC (2.7 per sample). CRGAs occurring more frequently in EAC included KRAS (23% EAC vs. 6% ESCC) and ERBB2 (23% EAC vs. 3% ESCC). ESCC samples were enriched for CRGA in PIK3CA (24% ESCC vs. 10% EAC), PTEN (11% ESCC vs. 4% EAC), and NOTCH1 (17% ESCC vs. 3% EAC). Other GAs that differed significantly between histologic tumor types included SMAD4 (14% EAC vs. 1% ESCC), RB1 (14% ESCC vs. 2% EAC), SOX2 (18% ESCC vs. 1% EAC), and NFE2L2 (24% ESCC vs. 1% EAC).
ESCC and EAC share similarly high frequencies of overall and clinically relevant genomic alterations; however, the profiles of genomic alterations in the two diseases differ widely, with KRAS and ERBB2 far more frequently altered in EAC compared with ESCC and with mammalian target of rapamycin (MTOR) pathway genes (PIK3CA and PTEN) and NOTCH1 more frequently altered in ESCC compared with EAC. Comprehensive genomic profiling highlights the promise of identifying clinically relevant genomic alterations in both ESCC and EAC and suggests new avenues for molecularly directed therapies in esophageal cancer.
食管鳞状细胞癌（ESCC）和食管腺癌（EAC）占食管恶性肿瘤的95%以上，是全球主要的健康负担。ESCC是全球主要的组织学类型，但在美国病例中占少数，EAC占美国病例的大多数。
晚期ESCC和EAC患者的预后较差，需要新的治疗选择。我们使用一种敏感的测序分析方法，比较了ESCC和EAC的基因组图谱，以确定与治疗相关的基因组改变。
基于下一代测序的全面基因组分析是在杂交捕获、基于衔接子连接的文库上进行的，对315个癌症相关基因的所有编码外显子以及28个在癌症中频繁重排的基因的选定内含子进行测序，中位数覆盖深度>650×。对单个样本的结果进行评估，以确定所有类型的基因组改变（GA），包括点突变、短插入和缺失、基因扩增、纯合缺失以及融合/重排。临床相关基因组改变（CRGA）被定义为与已批准药物相关的改变以及在机制驱动的临床试验中正在评估的改变。
两种肿瘤类型在性别上均无显著差异，所有患者的中位年龄为63岁。所有ESCC和EAC在测序时均处于晚期。所有71例ESCC和231例EAC在分析中均有GA，ESCC中有522个GA（每个样本7.4个），EAC中有1303个GA（每个样本5.6个）。ESCC中临床相关GA的频率为94%（每个样本2.6个），EAC中为93%（每个样本2.7个）。EAC中更频繁出现的CRGA包括KRAS（EAC中为23%，ESCC中为6%）和ERBB2（EAC中为23%，ESCC中为3%）。ESCC样本中PIK3CA（ESCC中为24%，EAC中为10%）、PTEN（ESCC中为11%，EAC中为4%）和NOTCH1（ESCC中为17%，EAC中为3%）的CRGA更为丰富。组织学肿瘤类型之间其他显著不同的GA包括SMAD4（EAC中为14%，ESCC中为1%）、RB1（ESCC中为14%，EAC中为2%）、SOX2（ESCC中为18%，EAC中为1%）和NFE2L2（ESCC中为24%，EAC中为1%）。
ESCC和EAC在总体和临床相关基因组改变方面的频率相似；然而，这两种疾病的基因组改变图谱差异很大，与ESCC相比，EAC中KRAS和ERBB2的改变频率更高，与EAC相比，ESCC中雷帕霉素哺乳动物靶标（MTOR）途径基因（PIK3CA和PTEN）和NOTCH1的改变频率更高。全面的基因组分析突出了在ESCC和EAC中识别临床相关基因组改变的前景，并为食管癌的分子靶向治疗提出了新途径。
