Association between a single nucleotide polymorphism in the R3HCC1 gene and irinotecan toxicity.
Humans
Irinotecan
Polymorphism, Single Nucleotide
Camptothecin
/ adverse effects
Antineoplastic Combined Chemotherapy Protocols
/ adverse effects
Pancreatic Neoplasms
/ drug therapy
Colorectal Neoplasms
/ drug therapy
Fluorouracil
Colonic Neoplasms
/ drug therapy
Neutropenia
/ chemically induced
Rectal Neoplasms
/ drug therapy
Leucovorin
/ adverse effects
Pancreatic Neoplasms
R3HCC1
colorectal cancer
irinotecan
neutropenia
pancreatic cancer
Journal
Cancer medicine
ISSN: 2045-7634
Titre abrégé: Cancer Med
Pays: United States
ID NLM: 101595310
Informations de publication
Date de publication:
02 2023
02 2023
Historique:
revised:
05
09
2022
received:
20
07
2022
accepted:
15
09
2022
pubmed:
30
10
2022
medline:
3
3
2023
entrez:
29
10
2022
Statut:
ppublish
Résumé
Irinotecan is a useful anticancer drug for colorectal cancer treatment. UGT1A1*28 and *6 gene polymorphisms are known risk factors for irinotecan-associated toxicity. However, severe adverse effects due to irinotecan have been observed even in patients who do not harbor UGT1A1*28 or *6. We investigated gene polymorphisms in the whole exome to identify useful biomarkers for irinotecan toxicity other than UGT1A. A total of 178 patients with metastatic colorectal cancer (mCRC) and 87 patients with pancreatic cancer were treated with FOLFIRI, FOLFOX, FOLFOXIRI, modified FOLFIRINOX, or gemcitabine plus nab-paclitaxel. Genome-wide screening was performed using whole-exome sequencing (WES), and validation analysis was performed using qPCR with a hydrolysis probe. Using WES after a doublet chemotherapy regimen comprising irinotecan and 5-fluorouracil (n = 15), seven single nucleotide polymorphisms (SNPs) were identified as candidate biomarkers for irinotecan-associated toxicity of neutropenia. Among the seven SNPs, an SNP in R3H domain and coiled-coil containing 1 (R3HCC1; c.919G > A, rs2272761) showed a significant association with neutropenia (>grade 3) after doublet chemotherapy. Patients receiving irinotecan including triplet chemotherapy, FOLFOXIRI for mCRC (n = 23) or modified FOLFIRINOX for pancreatic cancer (n = 40), also showed significant linear trends between R3HCC1 polymorphism and neutropenia (p = 0.017 and 0.046, respectively). No significant association was observed in patients treated with irinotecan-free regimens, FOLFOX for mCRC (n = 66), and gemcitabine plus nab-paclitaxel for pancreatic cancer (n = 47). Thus, an SNP in the R3HCC1 gene may be a useful biomarker for the toxicity of irinotecan-containing chemotherapy for mCRC and pancreatic cancer.
Identifiants
pubmed: 36308049
doi: 10.1002/cam4.5299
pmc: PMC9972014
doi:
Substances chimiques
Irinotecan
7673326042
Camptothecin
XT3Z54Z28A
Fluorouracil
U3P01618RT
Leucovorin
Q573I9DVLP
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4294-4305Informations de copyright
© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
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