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。","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":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Findings: </strong>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.</p><p><strong>Interpretation: </strong>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.</p><p><strong>Funding: </strong>None of the authors received funding related to the writing of this manuscript.</p>","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":"{\"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\":\"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Findings: </strong>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.</p><p><strong>Interpretation: </strong>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. 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PNPLA3 polymorphism worsens chemotherapy associated liver injury and affects overall survival in colorectal cancer patients with liver metastasis undergoing hepatic resection.
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.
EBioMedicineBiochemistry, 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.
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