PO.MCB08.05 · 分子与细胞生物学
拉丁裔胃腺癌的分子特征分析确定同源重组缺陷和TGF-beta通路为侵袭性基因组稳定型肿瘤的治疗靶点
Molecular characterization of Latino gastric adenocarcinomas identifies homologous recombination deficiency and TGF-beta pathways as targets for aggressive genomically stable tumors
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摘要 Abstract
中文摘要
背景:胃癌(GC)对拉丁裔人群的影响尤为严重,但来自这些患者的基因组数据仍然稀缺。这种代表性不足限制了对可能指导靶向治疗的祖源特异性分子特征的理解。以基因组稳定(GS)亚型为特征的肿瘤与更差的预后相关,且在亚裔和西班牙裔中比在非拉丁裔白人(NLW)和黑人人群中更为普遍。
方法:我们使用低深度全基因组测序(LP-WGS)或全外显子组测序,分析了来自拉丁裔患者(哥伦比亚、墨西哥和美国)的192例胃腺癌肿瘤。对分子亚型进行分类,并评估体细胞改变,与癌症基因组图谱(TCGA)中以NLW为主的队列进行比较。
结果:与既往研究类似,GS亚型在该拉丁裔队列中占主导地位(57.8%),显著高于以NLW为主的TCGA-STAD(11.5%,p<10⁻²⁹)。GS肿瘤在钙黏蛋白/连环蛋白复合物基因(CDH1、CTNND1)以及DNA损伤修复基因ATM和TGF-beta相关通路成员TGFBR2和ELF3中频繁发生改变。我们在非超突变肿瘤中鉴定出六个新的显著突变基因,以及基于自我认定种族而频率不同的亚型特异性驱动基因。比较分析揭示了与遗传祖源相关的差异,包括弥漫型组织学肿瘤中更高的美洲原住民(IA)祖源成分和更高的CDH1突变频率。对治疗上可操作的生物标志物的分析表明,GS肿瘤中此类标志物有限(65%缺乏靶点),但ATM突变提示可能从PARP抑制剂中获益。
结论:拉丁裔GC肿瘤富集GS亚型,并携带独特的基因组改变,包括新的驱动基因和HRR通路缺陷。这些发现强调了以祖源为依据的治疗策略的必要性,并突显PARP抑制作为GS肿瘤有前景的治疗途径。
查看英文原文 English abstract
Background: Gastric cancer (GC) disproportionately affects Latino populations, yet genomic data from these patients remain scarce. This underrepresentation limits understanding of ancestry-specific molecular features that could inform targeted therapies. Tumors characterized by a genomically stable (GS) subtype are associated with worse outcomes and is more prevalent among Asians and Hispanics than among non-Latino White (NLW) and Black populations.
Methods: We analyzed 192 gastric adenocarcinoma tumors from Latino patients (Colombia, Mexico, and U.S.) using low-pass whole-genome sequencing (LP-WGS), or whole-exome sequencing. Molecular subtypes were classified, and somatic alterations were assessed and compared to the NLW cohort from the cancer genome atlas (TCGA).
Results: Similar to previous studies, the GS subtype was predominant (57.8%) in this Latino cohort, significantly higher than the mostly NLW, TCGA-STAD (11.5%, p < 10⁻²⁹). GS tumors had frequent alterations in cadherin/catenin complex genes (CDH1, CTNND1) as well as the DNA damage repair gene ATM, and TGF-beta related pathway members TGFBR2 and ELF3. We identified six novel significantly mutated genes in non-hypermutated tumors and subtype-specific drivers that differ in frequency based on self-identified race. Comparative analysis revealed genetic ancestry-linked differences, including greater Indigenous American (IA) ancestry in diffuse histology tumors and higher CDH1 mutation frequency. Analysis of the therapeutically actionable biomarkers were limited in GS tumors (65% lacked targets), but ATM mutations suggest potential benefit from PARP inhibitors.
Conclusions: Latino GC tumors are enriched for GS subtype and harbor unique genomic alterations, including novel drivers and HRR pathway defects. These findings underscore the need for ancestry-informed therapeutic strategies and highlight PARP inhibition as a promising avenue for GS tumors.
利益披露 Disclosure
D. J. Montoya, None..
K. Chiu, None..
J. Villalpando, None..
S. Reddy, None..
J. Diaz Sezati, None..
F. Castro, None..
G. Polanco-Echeverry, None..
M. Echeverry de Polanco, None..
J. Torres, None..
M. Bohorquez, None..
L. G. Carvajal-Carmona, None.