PO.MD01.02 · 分子诊断与数据
结直肠癌、胰腺癌、小肠癌和肛门癌中不同的年龄相关基因组全景：对来自 AACR Project GENIE v18.0 的 34,000 例肿瘤的泛胃肠道分析
Distinct age associated genomic landscapes in colorectal, pancreatic, small bowel, and anal cancers: A pan gastrointestinal analysis of 34,000 tumors from AACR Project GENIE v18.0
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：早发性胃肠道（GI）癌症在全球范围内不断增加，但跨多种肿瘤类型的年龄相关差异的基因组基础仍未得到充分界定。我们利用 AACR Project GENIE v18.0（N≈34,000 例 GI 肿瘤）来表征结直肠癌、胰腺癌、小肠癌和肛门癌中具有足够早发性代表性的按年龄划分的分子差异。
方法：提取临床和基因组数据，并将肿瘤分类为早发性（<50 岁）和晚发性（≥50 岁）。按癌症类型和年龄组比较突变频率，重点关注复发性驱动基因、DNA 修复、Wnt 信号、RAS/MAPK、染色质重塑基因和可靶向改变。
结果：早发性结直肠癌（N=5,724）显示 Wnt/beta-catenin 通路改变增加：APC（+4.9%）、TCF7L2（+4.1%）和 TP53（+5.0%），而晚发性肿瘤（N=15,807）则富集 BRAF（−5.4%）、RNF43（−1.9%）和 GNAS（−1.1%），提示不同的肿瘤发生通路。早发性胰腺癌（N=890）表现出经典驱动基因显著较低的频率——KRAS（−24.7%）、TP53（−15.6%）、CDKN2A（−6.9%）、SMAD4（−6.0%）——并富集 MEN1（+3.5%）、TSC2（+3.0%）、ATRX（+2.0%）、DAXX（+1.9%）和 CTNNB1（+2.4%），与融合驱动、遗传性和染色质重塑生物学一致。早发性患者的小肠癌（N=99）表现出 DNA 损伤反应和 MAPK/RAS 基因的富集，包括 BRCA2（+7.2%）、NF1（+7.4%）、FBXW7（+8.8%）、FLT4（+6.5%）、ARAF（+6.4%）和 ALK（+5.1%），而晚发性肿瘤（N=538）则富集 KDR（−5.1%）和 MGA（−5.2%）。早发性肛门癌（N=62）显示 MGA（+7.8%）、WHSC1/NSD2（+6.9%）、PBRM1（+6.2%）、FANCA（+5.2%）、ERCC5（+6.2%）和 MSH6（+5.9%）升高，突出了可能与 HPV 生物学相关的染色质重塑和 DNA 修复通路；晚发性肿瘤（N=464）则富集 ATM（−5.6%）、PTEN（−5.5%）、STK11（−5.2%）、APC（−5.2%）和 KMT2C（−5.0%），反映了年龄相关的基因组不稳定性。
结论：这一泛 GI 的年龄分层分析揭示了早发性 GI 癌症中独特的致癌程序，其特征为 Wnt/TP53 驱动的结直肠癌、融合和染色质重塑驱动的胰腺癌、DNA 损伤反应/MAPK 驱动的小肠癌，以及肛门癌中的染色质-免疫 DDR 特征。这些发现强调了对年龄量身定制的精准肿瘤学的需求，并支持在早发性 GI 恶性肿瘤中常规进行基因组谱分析，以识别在年轻患者中富集的可靶向改变。
引用：AACR Project GENIE Consortium. AACR Project GENIE: Powering Precision Medicine Through an International Consortium. Cancer Discov. 2017;7(8):818-831.（数据：GENIE Release 18.0-public）致谢：AACR 和 Project GENIE registry
查看英文原文 English abstract
Background: Early-onset gastrointestinal (GI) cancers are increasing globally, yet the genomic basis for age-related differences across multiple tumor types remains poorly defined. We leveraged AACR Project GENIE v18.0 (N≈34,000 GI tumors) to characterize molecular distinctions by age in colorectal, pancreatic, small bowel, and anal cancers with sufficient early-onset representation.
Methods: Clinical and genomic data were extracted and tumors classified into early-onset (<50 years) and late-onset (≥50 years). Mutation frequencies were compared by cancer type and age group, focusing on recurrent drivers, DNA repair, Wnt signaling, RAS/MAPK, chromatin remodeling genes, and targetable alterations.
Results: Early-onset colorectal cancer (N=5,724) showed increased Wnt/beta-catenin pathway alterations: APC (+4.9%), TCF7L2 (+4.1%), and TP53 (+5.0%), while late-onset tumors (N=15,807) were enriched for BRAF (−5.4%), RNF43 (−1.9%), and GNAS (−1.1%), indicating divergent tumorigenic pathways. Early-onset pancreatic cancer (N=890) exhibited significantly lower frequencies of canonical drivers-KRAS (−24.7%), TP53 (−15.6%), CDKN2A (−6.9%), SMAD4 (−6.0%)-with enrichment of MEN1 (+3.5%), TSC2 (+3.0%), ATRX (+2.0%), DAXX (+1.9%), and CTNNB1 (+2.4%), consistent with fusion-driven, hereditary, and chromatin remodeling biology. Small bowel cancer (N=99) in early-onset patients demonstrated enrichment in DNA damage response and MAPK/RAS genes including BRCA2 (+7.2%), NF1 (+7.4%), FBXW7 (+8.8%), FLT4 (+6.5%), ARAF (+6.4%), and ALK (+5.1%), whereas late-onset tumors (N=538) were enriched for KDR (−5.1%) and MGA (−5.2%). Early-onset anal cancer (N=62) showed elevated MGA (+7.8%), WHSC1/NSD2 (+6.9%), PBRM1 (+6.2%), FANCA (+5.2%), ERCC5 (+6.2%), and MSH6 (+5.9%), highlighting chromatin remodeling and DNA repair pathways potentially related to HPV biology; late-onset tumors (N=464) had enrichment in ATM (−5.6%), PTEN (−5.5%), STK11 (−5.2%), APC (−5.2%), and KMT2C (−5.0%), reflecting age-associated genomic instability.
Conclusions: This pan-GI age-stratified analysis reveals distinctive oncogenic programs in early-onset GI cancers characterized by Wnt/TP53-driven colorectal, fusion- and chromatin remodeling-driven pancreatic, DNA damage response/MAPK-driven small bowel, and chromatin-immune DDR signatures in anal cancers. These findings underscore the need for age-tailored precision oncology and support routine genomic profiling in early-onset GI malignancies to identify targetable alterations enriched in younger patients.
Citation: AACR Project GENIE Consortium. AACR Project GENIE: Powering Precision Medicine Through an International Consortium. Cancer Discov. 2017;7(8):818-831. (Data: GENIE Release 18.0-public)Acknowledgement: AACR and Project GENIE registry
利益披露 Disclosure
A. Abdelhakeem, None..
N. Ganatra, None..
D. Elantably, None..
T. Adeoye, None..
N. H. Abdel-Razeq, None..
M. M. Osama, None.