Abstract：
Most metastatic colorectal cancer (mCRC) patients succumb to refractory disease due to secondary chemotherapy resistance. To elucidate the molecular changes associated with secondary resistance, we recruited 64 patients with mCRC and hepatic metastases before standard first-line chemotherapy between 2014 and 2018. We subjected DNA from primary tumor specimens (P), hepatic metastasis specimens after treatment (M), and liquid biopsies (L) taken prior to (pre), during (intra), and after (post) treatment to next generation sequencing. We performed Nanostring expression analysis in P and M specimens. Comparative bioinformatics and statistical analysis revealed typical mutational patterns with frequent alterations in TP53, APC, and KRAS in P specimens (n = 48). P and pre-L (n = 42), as well as matched P and M (n = 30), displayed a similar mutation spectrum. In contrast, gene expression profiles classified P (n = 31) and M (n = 23), distinguishable by up-regulation of immune/cytokine receptor and autophagy programs. Switching of consensus molecular subtypes from P to M occurred in 58.3% of cases. M signature genes SFRP2 and SPP1 associated with inferior survival, as validated in an independent cohort. Molecular changes during first-line treatment were detectable by expression profiling rather than by mutational tumor and liquid biopsy analyses. SFRP2 and SPP1 may serve as biomarkers and/or actionable targets.
摘要：
大多数转移性结直肠癌（mCRC）患者由于继发性化疗耐药而死于难治性疾病。为了阐明与次级抗性相关的分子变化，我们招募了2014年至2018年标准一线化疗前64例mCRC和肝转移患者.我们从原发肿瘤标本（P）的DNA，治疗后肝转移标本（M），和液体活检（L）之前（前），在(内)期间，以及在(后处理)至下一代测序之后。我们在P和M标本中进行了Nanostring表达分析。比较生物信息学和统计分析揭示了TP53，APC，和P标本中的KRAS(n=48)。P和pre-L（n=42），以及匹配的P和M(n=30)，显示出相似的突变谱。相比之下,基因表达谱分为P(n=31)和M(n=23)，通过免疫/细胞因子受体和自噬程序的上调来区分。58.3％的病例将共有分子亚型从P转换为M。M标记基因SFRP2和SPP1与低生存率相关，在独立队列中验证。一线治疗期间的分子变化可通过表达谱分析而不是通过突变肿瘤和液体活检分析来检测。SFRP2和SPP1可以用作生物标志物和/或可操作靶标。
