PO.BCS01.15 · 生物信息与计算
基于泛基因组的99例韩国患者早发型和晚发型结直肠癌体细胞突变图谱
Pangenome-based somatic mutation landscape of early- and late-onset colorectal cancer in 99 Korean patients
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
结直肠癌（CRC）是全球第三大常见癌症类型。尽管由于筛查改善使CRC总体发病率有所下降，但50岁以下患者的早发型CRC（EOCRC）在全球（包括韩国）正迅速增加，这与晚发型CRC（LOCRC）的下降趋势形成对比。已有多项研究试图鉴定EOCRC特异性突变；然而，大多数研究局限于全外显子组测序，因而未能全面捕获CRC相关的非编码变异。此外，以往的突变分析研究依赖GRCh38参考基因组，这是一个线性的、很大程度上偏向欧洲人群的组装体，缺乏对人类遗传多样性的代表，从根本上限制了新突变的发现。为解决这些局限，我们对49例EOCRC和50例LOCRC韩国患者的配对肿瘤及匹配血液样本进行了全基因组测序（WGS）。体细胞突变使用基于图谱的人类泛基因组参考（人类泛基因组参考联盟，2023年发布）鉴定，该参考整合了全球49个个体的基因组多样性。每个样本产生14.09亿条读段，平均覆盖度为37.7×。EOCRC和LOCRC在编码区平均携带1,673个和801个体细胞突变，在非编码区携带236,610个和127,616个——分别比基于GRCh38的结果高21%和43%。鉴定出十个EOCRC特异性编码基因，包括LMTK3、GALNT11和NPHP1，其中LMTK3也曾在一项中国研究中报道。在非编码区，检测到32个EOCRC特异性基因组区域，包括PRKAG2-GALNTL5、MRGPRF-TPCN2和ACTRT2-TTC34。其中，GALNT11、MRGPRF-TPCN2和ACTRT2-TTC34含有与EOCRC患者生存显著相关的突变。尽管仍需进一步的表达水平验证，我们提出这三个区域作为EOCRC诊断和治疗的有前景的基因组级候选。此外，所有WGS数据已存入欧洲基因组-表型档案库（EGA；EGAS50000000544），有望为在基因组层面研究CRC或EOCRC的研究人员提供宝贵资源。
查看英文原文 English abstract
Colorectal cancer (CRC) is the third most prevalent cancer type worldwide. Although overall CRC incidence has declined due to improved screening, early-onset CRC (EOCRC) in patients under 50 years old is rapidly increasing globally, including in Korea, unlike the decreasing trend of late-onset CRC (LOCRC). Several studies have attempted to identify EOCRC-specific mutations; however, most were limited to whole-exome sequencing and thus failed to capture CRC-related non-coding variants comprehensively. Moreover, previous mutation-profiling studies relied on the GRCh38 reference genome, a linear and largely European-biased assembly that lacks representation of human genetic diversity, fundamentally limiting the discovery of novel mutations. To address these limitations, we performed whole-genome sequencing (WGS) of paired tumor and matched blood samples from 49 EOCRC and 50 LOCRC Korean patients. Somatic mutations were identified using the graph-based Human Pangenome Reference (Human Pangenome Reference Consortium, released in 2023), which integrates genomic diversity from 49 individuals worldwide. Each sample produced 1.409 billion reads with an average coverage of 37.7×. EOCRC and LOCRC carried an average of 1,673 and 801 somatic mutations in coding regions and 236,610 and 127,616 in non-coding regions-21% and 43% higher than GRCh38-based results. Ten EOCRC-specific coding genes were identified, including LMTK3, GALNT11, and NPHP1, with LMTK3 also reported in a previous Chinese study. In non-coding regions, 32 EOCRC-specific genomic regions were detected, including PRKAG2-GALNTL5, MRGPRF-TPCN2, and ACTRT2-TTC34. Among these, GALNT11, MRGPRF-TPCN2, and ACTRT2-TTC34 contained mutations significantly associated with EOCRC patient survival. Although further expression-level validation is warranted, we propose these three regions as promising genome-level candidates for EOCRC diagnosis and therapy. Additionally, all WGS data have been deposited in the European Genome-phenome Archive (EGA; EGAS50000000544) and are expected to provide a valuable resource for researchers investigating CRC or EOCRC at the genomic level.
利益披露 Disclosure
J. Kim, None..
S. Joe, None..
S. Lee, None..
Y. Yoon, None..
J. Jeon, None..
J. Kim, None..
J. Yang, None..
S. Baek, None..
J. Park, None..
S. Kim, None..
S. Kim, None.