DataSheet_2_Germline Profiling and Molecular Characterization of Early Onset Metastatic Colorectal Cancer.xlsx

BackgroundEarly 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.
Methods330 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.
ResultsOf 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.
ConclusionsApproximately 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.

背景 早发性结直肠癌（Early onset colorectal cancer, EO CRC）是一类具有明显遗传倾向、发病率持续攀升的异质性结直肠癌亚型。本研究旨在明确早发性结直肠癌的易感基因与分子特征。
方法 本研究共纳入330例≤55岁的早发性转移性结直肠癌（metastatic colorectal cancer, mCRC）患者，以及110例＞55岁的普通发病年龄转移性结直肠癌（average-onset, AO mCRC）患者。采用包含520个基因的测序panel对肿瘤组织及其配对白细胞开展基于捕获的靶向测序，并分析分子突变与总生存期（overall survival, OS）的相关性。
结果 在330例早发性转移性结直肠癌患者中，31例携带致病性或可能致病性种系突变，其中16例被诊断为林奇综合征（Lynch syndrome）。另有15例患者存在错配修复基因以外的种系突变，包括4例MUTHY突变、3例RAD50突变、1例TP53突变，其余8例累及其他基因。早发性转移性结直肠癌中共存在29个复发性突变基因，涵盖TP53、APC、KRAS、SMAD4及BRCA2。两组患者的多数基因组变异特征整体相似，但早发性转移性结直肠癌患者更易出现高肿瘤突变负荷（tumor mutation burden, TMB）（p < 0.05）。RNF43、RBM10、TSC及BRAF V600E突变在早发性组中更为常见，而APC、ASXL1、DNMT3B及MET基因的变异则更多见于普通发病年龄组。在通路层面，WNT通路是两组间唯一存在突变差异的通路（p < 0.0001）。野生型WNT通路（p = 0.0017）与突变型转化生长因子β（transforming growth factor-β, TGF-β）通路均与早发性转移性结直肠癌患者较差的总生存期相关（p = 0.023）。
结论 约10%的早发性转移性结直肠癌与遗传性肿瘤相关。尽管存在若干显著差异，早发性与普通发病年龄转移性结直肠癌的体细胞变异谱整体相似。