PNPLA3 polymorphism worsens chemotherapy associated liver injury and affects overall survival in colorectal cancer patients with liver metastasis undergoing hepatic resection.

IF 10.8 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

EBioMedicine Pub Date : 2025-09-16 DOI:10.1016/j.ebiom.2025.105928

Benedikt Rumpf, Jonas Santol, Anna E Kern, Markus Ammann, Joel Probst, Ruth Baumgartner, Anna S Jankoschek, Vanja Podrascanin, Florian Lehner, Felix X Huber, David Pereyra, Gregor Ortmayr, Yawen Dong, Sophia Petschnak, Brigitte Wolf, Alice Assinger, Hubert Hackl, Stefan Gilg, Thomas Gruenberger, Patrick Starlinger

{"title":"PNPLA3 polymorphism worsens chemotherapy associated liver injury and affects overall survival in colorectal cancer patients with liver metastasis undergoing hepatic resection.","authors":"Benedikt Rumpf, Jonas Santol, Anna E Kern, Markus Ammann, Joel Probst, Ruth Baumgartner, Anna S Jankoschek, Vanja Podrascanin, Florian Lehner, Felix X Huber, David Pereyra, Gregor Ortmayr, Yawen Dong, Sophia Petschnak, Brigitte Wolf, Alice Assinger, Hubert Hackl, Stefan Gilg, Thomas Gruenberger, Patrick Starlinger","doi":"10.1016/j.ebiom.2025.105928","DOIUrl":null,"url":null,"abstract":"Background: Neoadjuvant chemotherapy (NAC) has been controversial for patients with colorecal cancer liver metastasis (CRLM) with resectable disease. Chemotherapy associated liver injury (CALI) may explain the lack of overall survival (OS) benefit in some studies. It remains unclear why CALI severity varies between patients despite receiving the same duration and type of NAC. Single nucleotide polymorphisms (SNPs) have been associated with liver disease and could account for these interindividual differences. Within this study we used the APRI + ALBI score, a non-invasive liver function marker that increases in response to CALI development during NAC, to assess whether preoperative liver function affects OS in CRLM patients undergoing hepatectomy and explore the impact of SNPs on CALI development.Methods: 551 patients with CRLM undergoing liver surgery after NAC were included. In 149 patients, DNA from histological specimens was genotyped and the presence of SNPs associated with liver disease was assessed.Findings: Patients with APRI + ALBI scores (≥-2.46), associated with the development of CALI, showed decreased OS after hepatectomy (median OS APRI + ALBI < -2.46 = 46.1 months; median OS APRI + ALBI ≥ -2.46 = 34.3, p = 0.027). The mutated rs738409 variant on the patatin-like phospholipase domain-containing protein 3 (PNPLA3) displayed a close association with chemotherapy-associated steatohepatitis (p = 0.007) as well as intrahepatic fat (p = 0.004). Additionally, all PNPLA3 homozygotes shifted into the high-risk APRI + ALBI group during NAC.Interpretation: CALI and its effects on liver function not only impact immediate postoperative outcomes but also significantly affect OS in CRLM patients undergoing liver resection. PNPLA3 polymorphism was associated with CALI development. Considering that PNPLA3 polymorphisms are significantly higher in Asian populations, these results could partly explain the heterogeneity in reported effects of NAC in CRLM patients and might improve patient selection.Funding: None of the authors received funding related to the writing of this manuscript.","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"120 ","pages":"105928"},"PeriodicalIF":10.8000,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12466148/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"EBioMedicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.ebiom.2025.105928","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}

引用次数: 0

Abstract

Background: Neoadjuvant chemotherapy (NAC) has been controversial for patients with colorecal cancer liver metastasis (CRLM) with resectable disease. Chemotherapy associated liver injury (CALI) may explain the lack of overall survival (OS) benefit in some studies. It remains unclear why CALI severity varies between patients despite receiving the same duration and type of NAC. Single nucleotide polymorphisms (SNPs) have been associated with liver disease and could account for these interindividual differences. Within this study we used the APRI + ALBI score, a non-invasive liver function marker that increases in response to CALI development during NAC, to assess whether preoperative liver function affects OS in CRLM patients undergoing hepatectomy and explore the impact of SNPs on CALI development.

Methods: 551 patients with CRLM undergoing liver surgery after NAC were included. In 149 patients, DNA from histological specimens was genotyped and the presence of SNPs associated with liver disease was assessed.

Findings: Patients with APRI + ALBI scores (≥-2.46), associated with the development of CALI, showed decreased OS after hepatectomy (median OS APRI + ALBI < -2.46 = 46.1 months; median OS APRI + ALBI ≥ -2.46 = 34.3, p = 0.027). The mutated rs738409 variant on the patatin-like phospholipase domain-containing protein 3 (PNPLA3) displayed a close association with chemotherapy-associated steatohepatitis (p = 0.007) as well as intrahepatic fat (p = 0.004). Additionally, all PNPLA3 homozygotes shifted into the high-risk APRI + ALBI group during NAC.

Interpretation: CALI and its effects on liver function not only impact immediate postoperative outcomes but also significantly affect OS in CRLM patients undergoing liver resection. PNPLA3 polymorphism was associated with CALI development. Considering that PNPLA3 polymorphisms are significantly higher in Asian populations, these results could partly explain the heterogeneity in reported effects of NAC in CRLM patients and might improve patient selection.

Funding: None of the authors received funding related to the writing of this manuscript.

查看原文本刊更多论文

PNPLA3多态性加重化疗相关肝损伤，影响行肝切除术的结直肠癌肝转移患者的总生存。

背景：对于可切除的结直肠癌肝转移（CRLM）患者，新辅助化疗（NAC）一直存在争议。在一些研究中，化疗相关肝损伤（CALI）可能解释了总生存期（OS）获益的缺乏。目前尚不清楚为什么尽管接受相同的NAC持续时间和类型，但不同患者的CALI严重程度不同。单核苷酸多态性（SNPs）与肝脏疾病有关，可以解释这些个体间差异。在本研究中，我们使用APRI + ALBI评分（一种非侵入性肝功能指标，在NAC期间随着CALI的发展而增加）来评估术前肝功能是否影响行肝切除术的CRLM患者的OS，并探讨snp对CALI发展的影响。方法：551例CRLM患者行NAC术后肝脏手术。在149例患者中，来自组织学标本的DNA进行了基因分型，并评估了与肝脏疾病相关的snp的存在。结果：与CALI发生相关的APRI + ALBI评分（≥-2.46）的患者，肝切除术后OS降低（中位OS APRI + ALBI < -2.46 = 46.1个月；中位OS APRI + ALBI≥-2.46 = 34.3个月，p = 0.027）。PNPLA3上的突变rs738409变异与化疗相关的脂肪性肝炎（p = 0.007）以及肝内脂肪（p = 0.004）密切相关。此外，所有PNPLA3纯合子在NAC期间转移到高危APRI + ALBI组。解释：CALI及其对肝功能的影响不仅影响CRLM肝切除术患者的术后即时预后，而且显著影响OS。PNPLA3多态性与CALI的发生有关。考虑到PNPLA3多态性在亚洲人群中明显更高，这些结果可以部分解释NAC在CRLM患者中报道的影响的异质性，并可能改善患者选择。经费：所有作者均未获得与撰写本文相关的经费。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

EBioMedicine Biochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology

CiteScore

17.70

自引率

0.90%

发文量

579

审稿时长

5 weeks

期刊介绍： eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.