Gastric cancer is one of the deadliest cancer entities worldwide. While surgery is the only curative treatment option in early tumors, for locally advanced and metastatic patients further therapeutic targets are needed. Several studies not only reported mutations but also amplifications of the KRAS locus in different cancer entities. More recently, KRAS amplification was discussed as a new therapeutic target. Little is known about the (prognostic) relevance and (heterogenic) distribution of KRAS amplification in gastric adenocarcinomas, especially in Non-Asian patients. Amplification of the KRAS locus and corresponding protein expression was analyzed in 582 gastric adenocarcinomas employing fluorescence in-situ hybridization (FISH) and immunohistochemistry. Amplification status was correlated with clinico-pathological features, clinical outcome and molecular tumor data including a correlation to the TCGA subtypes of gastric carcinoma. KRAS amplification was detected in 27 out of 470 analysable tumors (5.7%) and correlated with protein expression of KRAS in all amplified tumors. Within the KRAS amplified gastric tumors 14/27 (51.9%) showed a heterogeneous distribution with also KRAS non-amplified tumor parts. According to TCGA 24 tumors (88.8%) were related to chromosomal instable tumors (CIN). The survival analysis of the entire patient cohort did not show any difference in overall survival in dependence on the KRAS status. However, a significant survival difference with a worse outcome for patients with KRAS amplified tumors was identified when analysing patients without neoadjuvant pre-treatment. We confirm the unfavorable prognosis of KRAS amplified tumors reported by other studies in (Asian) patient groups, at least in patients without neoadjuvant pre-treatment. Within KRAS amplified tumors we revealed intratumoral heterogeneity that may define a (more aggressive) tumor cell population which is more frequently observed in patients with lymph node metastases. Despite the heterogeneous distribution of KRAS amplified tumor clones, KRAS amplified locally advanced or metastasized gastric adenocarcinomas represent a therapeutically highly relevant tumor subgroup.

中文翻译：

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KRAS 的扩增及其在非亚洲胃腺癌中的异质性。

胃癌是全世界最致命的癌症之一。虽然手术是早期肿瘤唯一的治疗选择，但对于局部晚期和转移性患者，需要进一步的治疗目标。一些研究不仅报告了不同癌症实体中 KRAS 基因座的突变，还报告了扩增。最近，KRAS 扩增被讨论为新的治疗靶点。关于胃腺癌中 KRAS 扩增的（预后）相关性和（异质性）分布知之甚少，尤其是在非亚洲患者中。采用荧光原位杂交 (FISH) 和免疫组织化学分析了 582 例胃腺癌中 KRAS 基因座的扩增和相应的蛋白表达。扩增状态与临床病理特征、临床结果和分子肿瘤数据相关，包括与胃癌 TCGA 亚型的相关性。在 470 个可分析肿瘤中的 27 个（5.7%）中检测到 KRAS 扩增，并与所有扩增肿瘤中 KRAS 的蛋白表达相关。在 KRAS 扩增的胃肿瘤中，14/27 (51.9%) 与 KRAS 未扩增的肿瘤部分表现出异质分布。根据 TCGA，24 个肿瘤（88.8%）与染色体不稳定肿瘤（CIN）相关。整个患者队列的生存分析并未显示总生存率因 KRAS 状态而存在任何差异。然而，在分析未经新辅助预处理的患者时，发现 KRAS 扩增肿瘤患者的生存率存在显着差异，且预后较差。我们证实了其他研究报告的（亚洲）患者组中 KRAS 扩增肿瘤的不良预后，至少在未经新辅助预处理的患者中是这样。在 KRAS 扩增的肿瘤中，我们揭示了肿瘤内异质性，这可能定义了（更具侵袭性）肿瘤细胞群，这种肿瘤细胞群在淋巴结转移患者中更常见。尽管 KRAS 扩增的肿瘤克隆分布不均匀，但 KRAS 扩增的局部晚期或转移性胃腺癌代表了治疗上高度相关的肿瘤亚组。