PURPOSE We aimed to investigate genomic correlates underlying extremes of survivorship in metastatic colorectal cancer and their applicability in informing survival in distinct subsets of patients with metastatic colorectal cancer. EXPERIMENTAL DESIGN We examined differences in oncogenic somatic alterations between metastatic colorectal cancer cohorts demonstrating extremes of survivorship following complete metastasectomy: ≤2-year (n = 17) and ≥10-year (n = 18) survivors. Relevant genomic findings, and their association with overall survival (OS), were validated in two independent datasets of 935 stage IV and 443 resected stage I-IV patients. RESULTS In the extremes-of-survivorship cohort, significant co-occurrence of KRAS hotspot mutations and TP53 alterations was observed in ≤2-year survivors (P < 0.001). When validating these findings in the independent cohort of 935 stage IV patients, incorporation of the cumulative effect of any oncogenic Ras/B-raf (i.e., either KRAS, NRAS, or BRAF) and TP53 alteration generated three prognostic clusters: (i) TP53-altered alone (median OS, 132 months); (ii) Ras/B-raf-altered alone (65 months) or Ras/B-raf- and TP53 pan-wild-type (60 months); and (iii) coaltered Ras/B-raf-TP53 (40 months; P < 0.0001). Coaltered Ras/B-raf-TP53 was independently associated with mortality (HR, 2.47; 95% confidence interval, 1.91-3.21; P < 0.001). This molecular profile predicted survival in the second independent cohort of 443 resected stage I-IV patients. Coaltered Ras/B-raf-TP53 was associated with worse OS in patients with liver (n = 490) and lung (n = 172) but not peritoneal surface (n = 149) metastases. Moreover, coaltered Ras/B-raf-TP53 tumors were significantly more likely to involve extrahepatic metastatic sites with limited salvage options. CONCLUSIONS Genomic analysis of extremes of survivorship following colorectal cancer metastasectomy identifies a prognostic role for coaltered Ras/B-raf-TP53 and its association with distinct patterns of colorectal cancer metastasis.

中文翻译：

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联合的Ras / B-raf和TP53与转移性结直肠癌患者的生存率极高和转移的明显模式相关。

目的我们旨在研究与基因组相关的潜在转移性结直肠癌极端生存状况及其在告知转移性结直肠癌患者不同亚组生存情况方面的适用性。实验设计我们检查了转移性结直肠癌队列之间的致癌体细胞变化的差异，这些证据表明完全转移术后患者的生存极限：≤2年（n = 17）和≥10年（n = 18）的幸存者。在935个IV期和443个切除的I-IV期患者的两个独立数据集中，验证了相关的基因组发现及其与总生存期（OS）的关联。结果在极端生存队列中，在≤2年生存者中观察到KRAS热点突变和TP53改变的显着同时发生（P <0.001）。在935例IV期患者的独立队列中验证这些发现时，将任何致癌性Ras / B-raf（即KRAS，NRAS或BRAF）和TP53改变的累积作用结合起来，产生了三个预后指标：（i）TP53 -单独更改（操作系统的中位数，132个月）；（ii）单独的Ras / B-raf-改变型（65个月）或Ras / B-raf-和TP53泛野生型（60个月）；（iii）联合的Ras / B-raf-TP53（40个月； P <0.0001）。联合的Ras / B-raf-TP53与死亡率独立相关（HR，2.47； 95％置信区间，1.91-3.21； P <0.001）。该分子谱预测了443例切除的I-IV期患者的第二个独立队列中的存活率。肝（n = 490）和肺（n = 172）但腹膜表面（n = 149）转移的患者中，联合的Ras / B-raf-TP53与较差的OS相关。而且，合并的Ras / B-raf-TP53肿瘤更有可能涉及肝外转移部位，挽救手段有限。结论结直肠癌转移切除术后极端生存的基因组分析确定了联合的Ras / B-raf-TP53的预后作用及其与结直肠癌转移的不同模式的关联。