Comparative Molecular Analyses of Esophageal Squamous Cell Carcinoma, Esophageal Adenocarcinoma, and Gastric Adenocarcinoma

• Published in: The oncologist (Dayton, Ohio) Vol. 23; no. 11; pp. 1319 - 1327
• Main Authors: Salem, Mohamed E., Puccini, Alberto, Xiu, Joanne, Raghavan, Derek, Lenz, Heinz‐Josef, Korn, W. Michael, Shields, Anthony F., Philip, Philip A., Marshall, John L., Goldberg, Richard M.
• Format: Journal Article
• Language: English
• Published: United States AlphaMed Press 01.11.2018
• Subjects: Adenocarcinomas; Gastroesophageal cancers; Gastrointestinal Cancer; Next‐generation sequencing; Squamous cell carcinoma; Squamous cell carcinoma; Gastroesophageal cancers; Adenocarcinomas; Next‐generation sequencing
• ISSN: 1083-7159; 1549-490X; 1549-490X
• DOI: 10.1634/theoncologist.2018-0143

Background Gastroesophageal cancers are often grouped together even though cancers that originate in the esophagus often exhibit different histological features, geographical distribution, risk factors, and clinical characteristics than those originating in the stomach. Herein, we aimed to compare the molecular characteristics of three different gastroesophageal cancer types: esophageal squamous cell carcinoma (ESCC), esophageal adenocarcinoma (EAC), and gastric adenocarcinoma (GAC). Subjects, Materials, and Methods In total, 3,342 gastroesophageal cancers were examined. Next‐generation sequencing was performed on genomic DNA isolated from formalin‐fixed paraffin‐embedded tumor samples using the NextSeq platform. Tumor mutational burden was measured by counting all nonsynonymous missense mutations, and microsatellite instability was examined at over 7,000 target microsatellite loci. Immunohistochemistry and in situ hybridization techniques were also performed. Results When compared with EAC and GAC, ESCC showed significantly lower mutational rates within APC, ARID1A, CDH1, KRAS, PTEN, and SMAD4, whereas more frequent mutations were observed in BAP1, CDKN2A, FOXO3, KMT2D, MSH6, NOTCH1, RB1, and SETD2. Human epidermal growth receptor 2 (HER2) overexpression was observed in 13% of EAC compared with 6% of GAC and 1% of ESCC (p < .0001). Compared with EAC and GAC, ESCC exhibited higher expression of programmed death‐ligand 1 (PD‐L1) (27.7% vs. 7.5% vs. 7.7%, p < .0001). We observed that FGF3, FGF4, FGF19, CCND1 (co‐localized on 11q13), and FGFR1 were significantly more amplified in ESCC compared with EAC and GAC (p < .0001). Conclusion Molecular comparisons between ESCC, EAC, and GAC revealed distinct differences between squamous cell carcinomas and adenocarcinomas in each platform tested. Different prevalence of HER2/neu overexpression and amplification, and immune‐related biomarkers between ESCC, EAC, and GAC, suggests different sensitivity to HER2‐targeted therapy and immune checkpoint inhibition. These findings bring into question the validity of grouping patients with EAC and ESCC together in clinical trials and provide insight into molecular features that may represent novel therapeutic targets. Implications for Practice This study highlights the genomic heterogeneity of gastroesophageal cancers, showing striking molecular differences between tumors originating from different locations. Moreover, this study showed that esophageal squamous cell carcinomas exhibit a unique molecular profile, whereas gastric adenocarcinomas and esophageal adenocarcinomas have some similarities, supporting the fact that adenocarcinomas and squamous cell carcinomas are completely different diseases, irrespective of the tumor location. This raises the question of whether treatment of gastroesophageal tumors should be determined according to histological subtype and molecular targets rather than anatomical site. These findings provide insights that could enable physicians to better select patients and inform therapeutic choices in order to improve clinical outcome. 摘要 背景。 虽然起源于食管的肿瘤与起源于胃部的肿瘤在组织学特征、区域分布、危险因素和临床特征等往往表现不同,但胃食管肿瘤往往被归为一类。在此,我们比较了三种不同类型的胃食管肿瘤的分子特征:食管鳞状细胞癌 (ESCC)、食管腺癌 (EAC) 和胃腺癌 (GAC)。 受试者、材料及方法。 共3 342例胃食管肿瘤患者接受了检查。利用 NextSeq 平台,从福尔马林固定石蜡包埋肿瘤标本中分离出基因组 DNA,进行了下一代测序。通过计数所有非同义错义突变来测量肿瘤突变负担,并在7 000多个靶微卫星位点上检测微卫星不稳定性。同时也使用了免疫组化和原位杂交技术。 结果。 与EAC 和 GAC相比, ESCC在 APC、ARID1A、CDH1、KRAS、PTEN和 SMAD4中的突变率明显降低,而突变更频繁地出现在BAP1、CDKN2A、FOXO3、KMT2D、MSH6、NOTCH1、RB1和 SETD2。观察到 EAC 的人表皮生长因子受体2(HER2) 超表达为13%,而 GAC 为6%,ESCC 为1%(p<0.0001)。与 EAC 和 GAC 相比,ESCC 表现为程序性死亡配体1(PD‐L1)(27.7% vs. 7.5% vs. 7.7%,p<0.000 1)高表达。与 EAC 和 GAC 相比,我们观察到 FGF3、FGF4、FGF19、CCND1 (共定位于11q13)及FGFR1 在 ESCC 中明显扩增 (p<0.0001)。 结论。 通过 ESCC、EAC 和 GAC 的分子比较显示,在每一个平台的测试中,鳞状细胞癌和腺癌之间有明显的差异。ESCC、EAC 和 GAC 之间的 HER2/neu 过表达和扩增以及与免疫相关的生物标记物的不同发生率表明,对 HER2 靶向治疗和免疫检查点抑制剂具有不同的敏感性。这些发现引起了人们对临床试验中将 EAC 和 ESCC 患者归为一组的有效性的质疑,并对可能代表新治疗靶点的分子特征提出了深刻见解。 实践意义: 这项研究突出了胃食管肿瘤的基因组异质性,显示源自不同部位的肿瘤之间有明显的分子差异。此外,本研究还发现食管鳞状细胞癌具有独特的分子特征,而胃腺癌和食管腺癌有一些相似之处,在不考虑肿瘤部位的情况下,这支持了腺癌和鳞状细胞癌是完全不同的疾病这一事实。这就提出了一个问题:是否应该根据组织学亚型和分子靶点而不是解剖部位来确定胃食管肿瘤的治疗方案。这些发现提出的深刻见解使医生能够更好地甄别患者,并告知治疗选项,以改善临床效果。 To improve the precision of targeted and conventional therapy, the molecular profiles of gastroesophageal tumors were assessed, with the aim of comparing the molecular characteristics of esophageal adenocarcinoma, esophageal squamous cell carcinoma, and gastric adenocarcinoma. Results are reported in this article.