Germline polymorphisms in genes maintaining the replication fork predict the efficacy of oxaliplatin and irinotecan in patients with metastatic colorectal cancer.

Aged Antineoplastic Combined Chemotherapy Protocols / administration & dosage Bevacizumab / administration & dosage Biomarkers, Tumor / genetics Camptothecin / administration & dosage Cell Cycle Proteins / genetics Colonic Neoplasms / drug therapy DNA Replication DNA-Binding Proteins / genetics Female Fluorouracil / administration & dosage Germ-Line Mutation Humans Intracellular Signaling Peptides and Proteins / genetics Leucovorin / administration & dosage Male Neoplasm Metastasis Organoplatinum Compounds / administration & dosage Polymorphism, Single Nucleotide Survival Rate

Journal

British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635

Informations de publication

Date de publication:
01 2022
Historique:
received: 28 07 2021
accepted: 06 10 2021
revised: 27 09 2021
pubmed: 25 10 2021
medline: 23 2 2022
entrez: 24 10 2021
Statut: ppublish

Résumé

The TIMELESS-TIPIN complex protects the replication fork from replication stress induced by chemotherapeutic drugs. We hypothesised genetic polymorphisms of the TIMELESS-TIPIN complex may affect the response, progression-free survival (PFS), and overall survival (OS) of cytotoxic drugs in patients with metastatic colorectal cancer (mCRC). We analysed data from the MAVERICC trial, which compared FOLFOX/bevacizumab and FOLFIRI/bevacizumab in untreated patients with mCRC. Genomic DNA extracted from blood samples was genotyped using an OncoArray. Eight functional single nucleotide polymorphisms (SNPs) in TIMELESS and TIPIN were tested for associations with clinical outcomes. In total, 324 patients were included (FOLFOX/bevacizumab arm, n = 161; FOLFIRI/bevacizumab arm, n = 163). In the FOLFOX/bevacizumab arm, no SNPs displayed confirmed associations with survival outcomes. In the FOLFIRI/bevacizumab arm, TIMELESS rs2291739 was significantly associated with OS in multivariate analysis (G/G vs. any A allele, hazard ratio = 3.06, 95% confidence interval = 1.49-6.25, p = 0.004). TIMELESS rs2291739 displayed significant interactions with treatment regarding both PFS and OS. TIMELESS rs2291739 might have different effects on therapeutic efficacy between oxaliplatin- and irinotecan-based chemotherapies. Upon further validation, our findings may be useful for personalised approaches in the first-line treatment of mCRC.

Sections du résumé

BACKGROUND
The TIMELESS-TIPIN complex protects the replication fork from replication stress induced by chemotherapeutic drugs. We hypothesised genetic polymorphisms of the TIMELESS-TIPIN complex may affect the response, progression-free survival (PFS), and overall survival (OS) of cytotoxic drugs in patients with metastatic colorectal cancer (mCRC).
METHODS
We analysed data from the MAVERICC trial, which compared FOLFOX/bevacizumab and FOLFIRI/bevacizumab in untreated patients with mCRC. Genomic DNA extracted from blood samples was genotyped using an OncoArray. Eight functional single nucleotide polymorphisms (SNPs) in TIMELESS and TIPIN were tested for associations with clinical outcomes.
RESULTS
In total, 324 patients were included (FOLFOX/bevacizumab arm, n = 161; FOLFIRI/bevacizumab arm, n = 163). In the FOLFOX/bevacizumab arm, no SNPs displayed confirmed associations with survival outcomes. In the FOLFIRI/bevacizumab arm, TIMELESS rs2291739 was significantly associated with OS in multivariate analysis (G/G vs. any A allele, hazard ratio = 3.06, 95% confidence interval = 1.49-6.25, p = 0.004). TIMELESS rs2291739 displayed significant interactions with treatment regarding both PFS and OS.
CONCLUSIONS
TIMELESS rs2291739 might have different effects on therapeutic efficacy between oxaliplatin- and irinotecan-based chemotherapies. Upon further validation, our findings may be useful for personalised approaches in the first-line treatment of mCRC.

Identifiants

DOI: 10.1038/s41416-021-01592-7 PMID: 34689170 PMC: PMC8727586
pubmed: 34689170
doi: 10.1038/s41416-021-01592-7
pii: 10.1038/s41416-021-01592-7
pmc: PMC8727586
doi:

Substances chimiques

Biomarkers, Tumor 0
Cell Cycle Proteins 0
DNA-Binding Proteins 0
Intracellular Signaling Peptides and Proteins 0
Organoplatinum Compounds 0
TIMELESS protein, human 0
Tipin protein, human 0
Bevacizumab 2S9ZZM9Q9V
Leucovorin Q573I9DVLP
Fluorouracil U3P01618RT
Camptothecin XT3Z54Z28A

Types de publication

Clinical Trial, Phase II Journal Article Multicenter Study Randomized Controlled Trial Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

72-78

Informations de copyright

© 2021. The Author(s), under exclusive licence to Springer Nature Limited.

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Auteurs

Hiroyuki Arai (H)

Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Yi Xiao (Y)

Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Joshua Millstein (J)

Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Jingyuan Wang (J)

Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Francesca Battaglin (F)

Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Natsuko Kawanishi (N)

Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Priya Jayachandran (P)

Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Shivani Soni (S)

Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Wu Zhang (W)

Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Christoph Mancao (C)

Oncology Biomarker Development, Genentech Inc, Basel, Switzerland.

Bodour Salhia (B)

Department of Translational Genomics, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Shannon M Mumenthaler (SM)

Lawrence J. Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA, USA.

Aparna R Parikh (AR)

Division of Hematology and Oncology, Massachusetts General Hospital, Boston, MA, USA.
ORCID: 0000-0002-5245-7841

Heinz-Josef Lenz (HJ)

Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. lenz@usc.edu.
ORCID: 0000-0003-2178-9568

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Classifications MeSH

questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Sujet âgé › Germline polymorphisms in genes maintaining...
questionsmedicales.fr › Thérapeutique › Traitement médicamenteux › Association de médicaments › Protocoles de polychimiothérapie antinéoplasique › Germline polymorphisms in genes maintaining...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Globulines › Sérum-globulines › Immunoglobulines › Anticorps › Anticorps monoclonaux › Anticorps monoclonaux humanisés › Bévacizumab › Germline polymorphisms in genes maintaining...
questionsmedicales.fr › Facteurs biologiques › Marqueurs biologiques › Marqueurs biologiques tumoraux › Germline polymorphisms in genes maintaining...
questionsmedicales.fr › Composés hétérocycliques › Alcaloïdes › Camptothécine › Germline polymorphisms in genes maintaining...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines du cycle cellulaire › Germline polymorphisms in genes maintaining...
questionsmedicales.fr › Maladies de l'appareil digestif › Maladies gastro-intestinales › Maladies intestinales › Tumeurs de l'intestin › Tumeurs du côlon › Germline polymorphisms in genes maintaining...
questionsmedicales.fr › Phénomènes génétiques › Réplication de l'ADN › Germline polymorphisms in genes maintaining...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines de liaison à l'ADN › Germline polymorphisms in genes maintaining...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Pyrimidines › Pyrimidinones › Uracile › Fluorouracil › Germline polymorphisms in genes maintaining...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Mutation germinale › Germline polymorphisms in genes maintaining...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Germline polymorphisms in genes maintaining...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Germline polymorphisms in genes maintaining...
questionsmedicales.fr › Enzymes et coenzymes › Coenzymes › Tétrahydrofolates › Formyltétrahydrofolates › Leucovorine › Germline polymorphisms in genes maintaining...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Processus néoplasiques › Métastase tumorale › Germline polymorphisms in genes maintaining...
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