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Cited by 20Genetic factors in colorectal cancerColorectal Cancer Treatments and StudiesPharmacogenetics and Drug Metabolism

Genetic variants in DNA repair genes as potential predictive markers for oxaliplatin chemotherapy in colorectal cancer

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Kap, E J, Seibold, P, Richter, S, Scherer, D, Habermann, N, Balavarca, Y, Jansen, L, Becker, N +9 more·2015·The Pharmacogenomics Journal
DOI 10.1038/tpj.2015.8PMC PMC4573779
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Abstract

Oxaliplatin-based chemotherapy exerts its effects through generating DNA damage. Hence, genetic variants in DNA repair pathways could modulate treatment response. We used a prospective cohort of 623 colorectal cancer patients with stage II-IV disease treated with adjuvant/palliative chemotherapy to comprehensively investigate 1727 genetic variants in the DNA repair pathways as potential predictive markers for oxaliplatin treatment. Single nucleotide polymorphisms (SNP) associations with overall survival and recurrence-free survival were assessed using a Cox regression model. Pathway analysis was performed using the gamma method. Patients carrying variant alleles of rs3783819 (MNAT1) and rs1043953 (XPC) experienced a longer overall survival after treatment with oxaliplatin than patients who did not carry the variant allele, while the opposite association was found in patients who were not treated with oxaliplatin (false discovery rate-adjusted P-values for heterogeneity 0.0047 and 0.0237, respectively). The nucleotide excision repair (NER) pathway was found to be most likely associated with overall survival in patients who received oxaliplatin (P-value=0.002). Our data show that genetic variants in the NER pathway are potentially predictive of treatment response to oxaliplatin.

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  • Carriers of MNAT1 gene were linked to better treatment outcome of FOLFOX.

    “Moreover, carriers of MNAT1 gene, which is one of the leading genes in the G2/M checkpoint pathway58, were linked to better treatment outcome of FOLFOX54.”

    From Self-supervised learning reveals clinically relevant histomorphological patterns for therapeutic strategies in colon cancer (2025) · cites this paper as [54]

    The Results report that carriers of specific MNAT1 variant alleles had better overall survival after oxaliplatin treatment. The study assessed oxaliplatin-treated colorectal cancer patients, not a FOLFOX-only group, and the association concerns MNAT1 variants rather than simply carrying the gene. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Patients with altered DNA repair capacity showed greater benefits from treatment with oxaliplatin.

    “Interestingly, patients with altered DNA repair capacity showed greater benefits from treatment with oxaliplatin54,57.”

    From Self-supervised learning reveals clinically relevant histomorphological patterns for therapeutic strategies in colon cancer (2025) · cites this paper as [54]

    The Discussion (page unavailable) reports improved overall survival after oxaliplatin treatment among colorectal cancer patients carrying particular MNAT1 or XPC variants and says this suggests greater benefit in patients with altered DNA repair capacity. The citing sentence presents that inference as an established finding, although the paper treats the variants as potential predictive markers and does not report a direct measure of repair capacity. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Treatment response to oxaliplatin plus 5-FU-based regimens is modest with an estimate rate of approximately 50%.

    “Nonetheless, the treatment response is still modest with an estimate rate of approximately 50%1,54”

    From Self-supervised learning reveals clinically relevant histomorphological patterns for therapeutic strategies in colon cancer (2025) · cites this paper as [54]

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Research works printed but not linked: 44

  1. [2]Majek O Gondos A Jansen L Emrich K Holleczek B Katalinic A Survival from colorectal cancer in Germany in the early 21st century Br. J. Cancer 2012 106 1875 1880 22555397 PMC3364110
  2. [3]Schmiegel W Pox C Adler G Fleig W Folsch UR Fruhmorgen P S3-Guidelines Conference "Colorectal Carcinoma" 2004 Z. Gastroenterol 2004 42 1129 1177 15508058
  3. [5]Rothenberg ML Oza AM Bigelow RH Berlin JD Marshall JL Ramanathan RK Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: interim results of a phase III trial J. Clin. Oncol 2003 21 2059 2069 12775730
  4. [6]Goldberg RM Sargent DJ Morton RF Fuchs CS Ramanathan RK Williamson SK A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer J. Clin. Oncol 2004 22 23 30 14665611
  5. [7]Andre T Boni C Mounedji-Boudiaf L Navarro M Tabernero J Hickish T Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer N. Engl. J. Med 2004 350 2343 2351 15175436
  6. [8]Raymond E Faivre S Chaney S Woynarowski J Cvitkovic E Cellular and molecular pharmacology of oxaliplatin Mol. Cancer Ther 2002 1 227 235 12467217
  7. [9]Arnould S Hennebelle I Canal P Bugat R Guichard S Cellular determinants of oxaliplatin sensitivity in colon cancer cell lines Eur. J. Cancer 2003 39 112 119 12504667
  8. [10]Huang MY Huang ML Chen MJ Lu CY Chen CF Tsai PC Multiple genetic polymorphisms in the prediction of clinical outcome of metastatic colorectal cancer patients treated with first-line FOLFOX-4 chemotherapy Pharmacogenet. Genomics 2011 21 18 25 21057378
  9. [11]Theile D Grebhardt S Haefeli WE Weiss J Involvement of drug transporters in the synergistic action of FOLFOX combination chemotherapy Biochem. Pharmacol 2009 78 1366 1373 19622348
  10. [12]Wood RD Mitchell M Sgouros J Lindahl T Human DNA repair genes Science 2001 291 1284 1289 11181991
  11. [13]Sancar A Lindsey-Boltz LA Unsal-Kacmaz K Linn S Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints Annu. Rev. Biochem 2004 73 39 85 39–85. 15189136
  12. [15]Reardon JT Vaisman A Chaney SG Sancar A Efficient nucleotide excision repair of cisplatin, oxaliplatin, and Bis-aceto-ammine-dichloro-cyclohexylamine-platinum(IV) (JM216) platinum intrastrand DNA diadducts Cancer Res 1999 59 3968 3971 10463593
  13. [16]McLeod HL Sargent DJ Marsh S Green EM King CR Fuchs CS Pharmacogenetic predictors of adverse events and response to chemotherapy in metastatic colorectal cancer: results from North American Gastrointestinal Intergroup Trial N9741 J. Clin. Oncol 2010 28 3227 3233 20530282 PMC2903324
  14. [17]Ruzzo A Graziano F Loupakis F Rulli E Canestrari E Santini D Pharmacogenetic profiling in patients with advanced colorectal cancer treated with first-line FOLFOX-4 chemotherapy J Clin. Oncol 2007 25 1247 1254 17401013
  15. [18]Stoehlmacher J Ghaderi V Iobal S Groshen S Tsao-Wei D Park D A polymorphism of the XRCC1 gene predicts for response to platinum based treatment in advanced colorectal cancer Anticancer Res 2001 21 3075 3079 11712813
  16. [19]Lilla C Verla-Tebit E Risch A Jager B Hoffmeister M Brenner H Effect of NAT1 and NAT2 genetic polymorphisms on colorectal cancer risk associated with exposure to tobacco smoke and meat consumption Cancer Epidemiol. Biomarkers Prev 2006 15 99 107 16434594
  17. [20]Jansen L Hoffmeister M Chang-Claude J Koch M Brenner H Arndt V Age-specific administration of chemotherapy and long-term quality of life in stage II and III colorectal cancer patients: a population-based prospective cohort Oncologist 2011 16 1741 1751 22101506 PMC3248773
  18. [21]Fan JB Oliphant A Shen R Kermani BG Garcia F Gunderson KL Highly parallel SNP genotyping Cold Spring Harbor symposia on quantitative biology 2003 68 69 78 15338605
  19. [22]Gabriel S Ziaugra L Tabbaa D SNP genotyping using the Sequenom MassARRAY iPLEX platform Curr. Protoc. Hum. Genet 2009 Chapter 2: Unit. 19170031
  20. [23]Peters U Hutter CM Hsu L Schumacher FR Conti DV Carlson CS Meta-analysis of new genome-wide association studies of colorectal cancer risk Hum. Genet 2012 131 217 234 21761138 PMC3257356
  21. [24]Howie BN Donnelly P Marchini J A flexible and accurate genotype imputation method for the next generation of genome-wide association studies PLoS. Genet 2009 5 e1000529 19543373 PMC2689936
  22. [25]Li Y Willer CJ Ding J Scheet P Abecasis GR MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes Genet. Epidemiol 2010 34 816 834 21058334 PMC3175618
  23. [26]Schemper M Smith TL A note on quantifying follow-up in studies of failure time Control Clin. Trials 1996 17 343 346 8889347
  24. [28]Benjamini Y Hochberg Y Controlling the false discovery rate: a practical and powerful approach to multiple testing Journal of the Royal Statistical Society. Series B (Methodological) 1995 289 300
  25. [31]Biernacka JM Jenkins GD Wang L Moyer AM Fridley BL Use of the gamma method for self-contained gene-set analysis of SNP data Eur. J. Hum. Genet 2012 20 565 571 22166939 PMC3330217
  26. [32]Marchini J Howie B Genotype imputation for genome-wide association studies Nat. Rev. Genet 2010 11 499 511 20517342
  27. [33]Marinoni JC Roy R Vermeulen W Miniou P Lutz Y Weeda G Cloning and characterization of p52, the fifth subunit of the core of the transcription/DNA repair factor TFIIH EMBO J 1997 16 1093 1102 9118947 PMC1169708
  28. [35]Hoogstraten D Nigg AL Heath H Mullenders LH van DR Hoeijmakers JH Rapid switching of TFIIH between RNA polymerase I and II transcription and DNA repair in vivo Mol. Cell 2002 10 1163 1174 12453423
  29. [36]Matsuno M Kose H Okabe M Hiromi Y TFIIH controls developmentally-regulated cell cycle progression as a holocomplex Genes Cells 2007 12 1289 1300 17986012
  30. [37]Chen D Riedl T Washbrook E Pace PE Coombes RC Egly JM Activation of estrogen receptor alpha by S118 phosphorylation involves a ligand-dependent interaction with TFIIH and participation of CDK7 Mol. Cell 2000 6 127 137 10949034
  31. [38]Wu X Spitz MR Lee JJ Lippman SM Ye Y Yang H Novel susceptibility loci for second primary tumors/recurrence in head and neck cancer patients: large-scale evaluation of genetic variants Cancer Prev. Res. (Phila) 2009 2 617 624 19584075 PMC2964280
  32. [39]Qin HD Shugart YY Bei JX Pan QH Chen L Feng QS Comprehensive pathway-based association study of DNA repair gene variants and the risk of nasopharyngeal carcinoma Cancer Res 2011 71 3000 3008 21368091 PMC3383064
  33. [40]Barry KH Koutros S Andreotti G Sandler DP Burdette LA Yeager M Genetic variation in nucleotide excision repair pathway genes, pesticide exposure and prostate cancer risk Carcinogenesis 2012 33 331 337 22102698 PMC3271261
  34. [41]Wang SS Gonzalez P Yu K Porras C Li Q Safaeian M Common genetic variants and risk for HPV persistence and progression to cervical cancer PLoS. One 2010 5 e8667 20084279 PMC2801608
  35. [42]Gao Y Hayes RB Huang WY Caporaso NE Burdette L Yeager M DNA repair gene polymorphisms and tobacco smoking in the risk for colorectal adenomas Carcinogenesis 2011 32 882 887 21504893 PMC3106441
  36. [43]McWilliams RR Bamlet WR de AM Rider DN Cunningham JM Petersen GM Nucleotide excision repair pathway polymorphisms and pancreatic cancer risk: evidence for role of MMS19L Cancer Epidemiol. Biomarkers Prev 2009 18 1295 1302 19318433 PMC2710767
  37. [44]Buch SC Diergaarde B Nukui T Day RS Siegfried JM Romkes M Genetic variability in DNA repair and cell cycle control pathway genes and risk of smoking-related lung cancer Mol. Carcinog 2012 51 Suppl 1 E11 E20 21976407 PMC3289753
  38. [45]Li Y Jin G Wang H Liu H Qian J Gu S Polymorphisms of CAK genes and risk for lung cancer: a case-control study in Chinese population Lung Cancer 2007 58 171 183 17707548
  39. [46]The Genotype-Tissue Expression (GTEx) project Nat. Genet 2013 45 580 585 23715323 PMC4010069
  40. [47]Lewis BP Burge CB Bartel DP Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets Cell 2005 120 15 20 15652477
  41. [49]Volker M Mone MJ Karmakar P van HA Schul W Vermeulen W Sequential assembly of the nucleotide excision repair factors in vivo Mol. Cell 2001 8 213 224 11511374
  42. [50]Yue AM Xie ZB Zhao HF Guo SP Shen YH Wang HP Associations of ABCB1 and XPC genetic polymorphisms with susceptibility to colorectal cancer and therapeutic prognosis in a Chinese population Asian Pac. J. Cancer Prev 2013 14 3085 3091 23803084
  43. [51]Liu D Wu HZ Zhang YN Kang H Sun MJ Wang EH DNA repair genes XPC, XPG polymorphisms: relation to the risk of colorectal carcinoma and therapeutic outcome with Oxaliplatin-based adjuvant chemotherapy Mol. Carcinog 2012 51 Suppl 1 E83 E93 22213216
  44. [52]Yin M Yan J Martinez-Balibrea E Graziano F Lenz HJ Kim HJ ERCC1 and ERCC2 polymorphisms predict clinical outcomes of oxaliplatin-based chemotherapies in gastric and colorectal cancer: a systemic review and meta-analysis Clin. Cancer Res 2011 17 1632 1640 21278243 PMC3060288

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Authors
Kap, E. J., Seibold, P., Richter, S., Scherer, D., Habermann, N., Balavarca, Y., Jansen, L., Becker, N., Pfütze, K., Popanda, O., Hoffmeister, M., Ulrich, A., Benner, A., Ulrich, C. M., Burwinkel, B., Brenner, H., & Chang-Claude, J.
Affiliations
German Cancer Research Center (DE)
Corresponding author
Chang-Claude, J
ORCID
Venue
The Pharmacogenomics Journal
Publisher
Springer Science and Business Media LLC
Published
2015-03-17
Volume
15
Issue
6
Pages
505-512
ISSN
  • 1470-269X (ISSN-L)
  • 1473-1150
DOI
10.1038/tpj.2015.8
PMC
PMC4573779
OpenAlex
W2002753352
Cited by
20
References
4
Citations by year
2025: 1 · 2024: 2 · 2021: 2 · 2020: 2 · 2019: 2 · 2018: 3 · 2017: 3 · 2016: 5
FWCI
2.91
Type
journal article
Language
en
Open access
Licence
Locations
  • The Pharmacogenomics Journal (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • U.S. Department of Health and Human Services
  • Deutsches Krebsforschungszentrum
  • Bundesministerium für Bildung und Forschung
  • National Institutes of Health
  • National Cancer Institute (R01CA059045, U01CA137088)
Topics
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
  • Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Keywords
oxaliplatin, colorectal cancer, DNA repair genes, predictive biomarkers, nucleotide excision repair, single nucleotide polymorphisms, XPC, overall survival, treatment response, adjuvant chemotherapy, pharmacogenomics
MeSH terms
Oxaliplatin, Aged, Alleles, DNA Repair, DNA-Binding Proteins, Female, Genotype, Humans, Male, Middle Aged, Organoplatinum Compounds, Prospective Studies, Biomarkers, Tumor, Colorectal Neoplasms, Case-Control Studies, Polymorphism, Single Nucleotide

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