Ottaiano Alessandro, Nasti Guglielmo, Santorsola Mariachiara, Altieri Vincenzo, Di Fruscio Giuseppina, Circelli Luisa, Luce Amalia, Cossu Alessia Maria, Scognamiglio Giosuè, Perri Francesco, Correra Marco, Belli Andrea, Delrio Paolo, Botti Gerardo, Caraglia Michele
Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale", Naples, Italy.
INNOVALAB, Centro Direzionale Isola A2, Naples, Italy.
Front Oncol. 2021 Mar 29;11:632962. doi: 10.3389/fonc.2021.632962. eCollection 2021.
We previously reported that loss of mutations ("regressive" mutational trajectories) from primary tumors to metastases associated with the oligo-metastatic status in colorectal cancer (CRC). The present study was undertaken in order to analyze the mutational trajectories of in a well-characterized cohort of CRC patients who developed poly- or oligo-metastatic disease.
Patients were treated and followed-up according to European Society of Medical Oncology guidelines. Primary CRC FFPE tissue and metastatic circulating-free DNA were extracted using the QIAamp DNA specific kits (Qiagen, Hilden, Germany). Samples were sequenced with the Oncomine Solid Tumour DNA kit (Thermo Fisher Scientific, Waltham, MA, USA). Plasma collection for liquid biopsy was done from 1 to 14 days before starting first-line chemotherapy. Analysis of the prognostic power of evolutionary trajectories was done with uni- and multivariate analyses.
One-hundred-fourteen patients were enrolled. Sixty-three patients presented with mutated (mut) and 51 with wild-type (wt). mutational concordance was high (70.1%).Two divergent subsets were identified: mut in primary tumors and wt in metastatic ones (regressive: mut → wt in 8.8% of patients), and (progressive: wtK → mut in 21.1% of patients). An association between regressive trajectory and the oligo-metastatic status (P <0.0001) was found. At multivariate analysis, regressive and progressive mutational trajectories emerged as independent prognostic factors for survival, with Hazard Ratios of 0.22 (CI 95%: 0.08-0.61; median survival: not reached) and 2.70 (CI 95%: 1.11-6.56, median survival: 12.1 months), respectively.
Our data provide evidence that the evolutionary trajectories of can have a strong clinical prognostic role and that they can be involved in discriminating between poly-metastatic aggressive oligo-metastatic indolent CRC.
我们之前报道过，在结直肠癌（CRC）中，原发性肿瘤至转移灶的基因突变缺失（“退行性”突变轨迹）与寡转移状态相关。本研究旨在分析一组特征明确的发生多转移或寡转移疾病的CRC患者中KRAS的突变轨迹。
患者按照欧洲医学肿瘤学会指南进行治疗和随访。使用QIAamp DNA专用试剂盒（德国希尔德市Qiagen公司）提取原发性CRC福尔马林固定石蜡包埋（FFPE）组织和转移性游离循环DNA。样本采用Oncomine实体瘤DNA试剂盒（美国马萨诸塞州沃尔瑟姆市赛默飞世尔科技公司）进行测序。在开始一线化疗前1至14天采集血浆用于液体活检。采用单因素和多因素分析评估KRAS进化轨迹的预后能力。
共纳入114例患者。63例患者KRAS发生突变（mut），51例患者KRAS为野生型（wt）。KRAS突变一致性较高（70.1%）。鉴定出两个不同的亚组：原发性肿瘤中KRAS突变而转移灶中KRAS野生型（退行性：8.8%的患者中mut→wt），以及原发性肿瘤中KRAS野生型而转移灶中KRAS突变（进展性：21.1%的患者中wt→mut）。发现KRAS退行性轨迹与寡转移状态之间存在关联（P<0.0001）。多因素分析显示，退行性和进展性突变轨迹是生存的独立预后因素，风险比分别为0.22（95%CI：0.08 - 0.61；中位生存期：未达到）和2.70（95%CI：1.11 - 6.56，中位生存期：12.1个月）。
我们的数据表明，KRAS的进化轨迹具有重要的临床预后作用，并且可用于区分多转移侵袭性与寡转移惰性CRC。
