■早发性结直肠癌(EOCRC)是一种异质性结直肠癌亚型,具有明显的遗传倾向,发病率不断增加。我们试图确定EOCRC的易感基因和分子特征。
■330例EO转移性CRC(mCRC)(≤55年)和110例平均起病(AO)mCRC患者(>55年)。使用520个基因的测序组对肿瘤组织和配对的白细胞进行基于捕获的靶向测序。分析了分子改变与总生存期(OS)之间的关联。
■在330例EOmCRC患者中,31携带致病性或可能致病性种系突变,其中16人被诊断患有林奇综合征。15例患者存在非错配修复基因的种系突变,包括四个在穆西,三个在RAD50中,一个在TP53中,八个在其他基因中。EOmCRC中有29个基因反复突变,包括TP53,APC,KRAS,SMAD4和BRCA2。EO和A0mCRC之间的大多数基因组改变是相当的。EOmCRC患者更可能具有高肿瘤突变负荷(p<0.05)。RNF43,RBM10,TSC,BRAFV600E突变在EOmCRC中更常见,而APC,ASXL1、DNMT3B、和MET基因在AO患者中更常见的改变。在途径层面,WNT通路是EO和AOmCRC之间唯一的差异突变通路(p<0.0001)。野生型WNT途径(p=0.0017)和突变的TGF-β途径(p=0.023)与EOmCRC中的不良OS相关。
■大约十分之一的EOmCRC与遗传性肿瘤相关。EO和AOmCRC之间的体细胞改变谱在很大程度上具有可比性,但有几个显着差异。
UNASSIGNED: Early onset colorectal cancer (EO CRC) is a heterogeneous colorectal cancer subtype with obvious hereditary tendencies and increasing incidence. We sought to determine the susceptibility genes and molecular characteristics of EO CRC.
UNASSIGNED: 330 EO metastatic CRC (mCRC) (≤55 years) and 110 average-onset (AO) mCRC patients (>55 years) were enrolled. Capture-based targeted sequencing was performed on tumor tissue and paired white blood cells using a sequencing panel of 520 genes. The association between molecular alterations and overall survival (OS) was analyzed.
UNASSIGNED: Of the 330 EO mCRC patients, 31 carried pathogenic or likely pathogenic germline mutations, with 16 of them diagnosed with lynch syndrome. Fifteen patients had germline mutations in non-mismatch repair genes, including four in MUTHY, three in RAD50, one in TP53, and eight in other genes. Twenty-nine genes were recurrently mutated in EO mCRC, including TP53, APC, KRAS, SMAD4, and BRCA2. The majority of genomic alterations were comparable between EO and AO mCRC. EO mCRC patients were more likely to have a high tumor mutation burden (p < 0.05). RNF43, RBM10, TSC, and BRAF V600E mutations were more commonly observed in EO mCRC, while APC, ASXL1, DNMT3B, and MET genes were more commonly altered in AO patients. At the pathway level, the WNT pathway was the only differentially mutated pathway between EO and AO mCRC (p < 0.0001). The wild-type WNT pathway (p = 0.0017) and mutated TGF-β pathway (p = 0.023) were associated with unfavorable OS in EO mCRC.
UNASSIGNED: Approximately one in 10 EO mCRC was associated with hereditary tumors. The spectrum of somatic alterations was largely comparable between EO and AO mCRC with several notable differences.