Cancer Res Treat.  2021 Jul;53(3):724-732. 10.4143/crt.2020.457.

Polymorphisms in TYMS for Prediction of Capecitabine-Induced Hand-Foot Syndrome in Chinese Patients with Colorectal Cancer

• Dong SQ
• Wang TM
• Zhang JB
• He YQ
• Xue WQ
• Wu ZY
• Yang DW
• Cao LJ
• Huang JW
• Li XZ
• Zhang PF
• Zheng XH
• Jia WH

• KMID: 2518396
• DOI: http://doi.org/10.4143/crt.2020.457

Abstract

Purpose
Capecitabine is an extensively used oral prodrug of 5-fluorouracil in treatment of colon cancer and is known to cause hand-foot syndrome (HFS). As the target enzyme for capecitabine, thymidylate synthase (TYMS) plays a key role for 5-fluorouracil metabolism and has been associated with some side effects caused by capecitabine. The aim of our study is to identify the possible genetic predictors of capecitabine-induced HFS (CAP-HFS) in Chinese colorectal cancer patients.
Materials and Methods
Whole exons of TYMS were sequenced for 288 extreme phenotype HFS patients, including 144 severe or early-onset (first 2 cycles) moderate HFS extreme cases and 144 extreme controls with no reported HFS. The associations between polymorphisms and CAP-HFS were analyzed using logistic regression under an additive model.
Results
We identified a novel risk mutation (c.1A>G, chr18:657743), was associated with severe HFS in an extreme case who was affected during the first cycle of treatment. Moreover, we identified three new variants, rs3786362, rs699517, rs2790, and two previously reported variants, 5’VNTR 2R/3R and 3′-untranslated region 6-bp ins-del, which were significantly associated with CAP-HFS (p < 0.05). In silico analysis revealed that the effect of these polymorphisms in the TYMS region on the development of HFS might not be restricted solely to the regulation of TYMS expression, but also the TYMS catalytic activity through the indirect effect on ENOSF1 expression.
Conclusion
This study identified new polymorphisms in TYMS gene significantly associated with CAP-HFS, which may serve as useful genetic predictors for CAP-HFS and help to elucidate the underlying mechanism of HFS.

Keyword

Pharmacogenetics; Capecitabine; Hand-foot syndrome; Genetic susceptibility

Figure

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  Fig. 1 Diagram of the location and linkage disequilibrium (LD) of variants in the TYMS region associated with capecitabine-induced hand-foot syndrome (CAP-HFS). It shows the location of the seven exons (blue boxes), the 5’-untranslated region (UTR) and 3’-UTR (white boxes) and six polymorphisms associated with CAP-HFS, in our study. The novel mutation detected in a HFS extreme cases is represented by a red diamond. The LD plot was performed by Haploview v. 4.1.

Reference

References

1. Benson AB, Venook AP, Al-Hawary MM, Cederquist L, Chen YJ, Ciombor KK, et al. NCCN guidelines insights: colon cancer, version 2.2018. J Natl Compr Canc Netw. 2018; 16:359–69.

2. Luo HY, Li YH, Wang W, Wang ZQ, Yuan X, Ma D, et al. Single-agent capecitabine as maintenance therapy after induction of XELOX (or FOLFOX) in first-line treatment of metastatic colorectal cancer: randomized clinical trial of efficacy and safety. Ann Oncol. 2016; 27:1074–81.

3. Goey KK, Elias SG, van Tinteren H, Lacle MM, Willems SM, Offerhaus GJ, et al. Maintenance treatment with capecitabine and bevacizumab versus observation in metastatic colorectal cancer: updated results and molecular subgroup analyses of the phase 3 CAIRO3 study. Ann Oncol. 2017; 28:2128–34.

4. Lee S 2nd, Park SH, Lim DH, Park KW, Lee J, Park JO, et al. A retrospective study of first-line combination chemotherapy in advanced colorectal cancer: a Korean single-center experience. Cancer Res Treat. 2011; 43:96–101.

5. Walko CM, Lindley C. Capecitabine: a review. Clin Ther. 2005; 27:23–44.

6. Reichardt P, Von Minckwitz G, Thuss-Patience PC, Jonat W, Kolbl H, Janicke F, et al. Multicenter phase II study of oral capecitabine (Xeloda(“)) in patients with metastatic breast cancer relapsing after treatment with a taxane-containing therapy. Ann Oncol. 2003; 14:1227–33.

7. Masuda N, Lee SJ, Ohtani S, Im YH, Lee ES, Yokota I, et al. Adjuvant capecitabine for breast cancer after preoperative chemotherapy. N Engl J Med. 2017; 376:2147–59.

8. Danenberg PV. Thymidylate synthetase: a target enzyme in cancer chemotherapy. Biochim Biophys Acta. 1977; 473:73–92.

9. Houghton JA, Tillman DM, Harwood FG. Ratio of 2’-deoxyadenosine-5’-triphosphate/thymidine-5’-triphosphate influences the commitment of human colon carcinoma cells to thymineless death. Clin Cancer Res. 1995; 1:723–30.

10. Yap YS, Kwok LL, Syn N, Chay WY, Chia JW, Tham CK, et al. Predictors of hand-foot syndrome and pyridoxine for prevention of capecitabine-induced hand-foot syndrome: a randomized clinical trial. JAMA Oncol. 2017; 3:1538–45.

11. Horie N, Aiba H, Oguro K, Hojo H, Takeishi K. Functional analysis and DNA polymorphism of the tandemly repeated sequences in the 5’-terminal regulatory region of the human gene for thymidylate synthase. Cell Struct Funct. 1995; 20:191–7.

12. Mandola MV, Stoehlmacher J, Zhang W, Groshen S, Yu MC, Iqbal S, et al. A 6 bp polymorphism in the thymidylate synthase gene causes message instability and is associated with decreased intratumoral TS mRNA levels. Pharmacogenetics. 2004; 14:319–27.

13. Rosmarin D, Palles C, Pagnamenta A, Kaur K, Pita G, Martin M, et al. A candidate gene study of capecitabine-related toxicity in colorectal cancer identifies new toxicity variants at DPYD and a putative role for ENOSF1 rather than TYMS. Gut. 2015; 64:111–20.

14. Meulendijks D, Jacobs BA, Aliev A, Pluim D, van Werkhoven E, Deenen MJ, et al. Increased risk of severe fluoropyrimidine-associated toxicity in patients carrying a G to C substitution in the first 28-bp tandem repeat of the thymidylate synthase 2R allele. Int J Cancer. 2016; 138:245–53.

15. Lin S, Yue J, Guan X, Yuan P, Wang J, Luo Y, et al. Polymorphisms of MTHFR and TYMS predict capecitabine-induced hand-foot syndrome in patients with metastatic breast cancer. Cancer Commun (Lond). 2019; 39:57.

16. Untergasser A, Cutcutache I, Koressaar T, Ye J, Faircloth BC, Remm M, et al. Primer3: new capabilities and interfaces. Nucleic Acids Res. 2012; 40:e115.

17. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007; 81:559–75.

18. Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005; 21:263–5.

19. Boyle AP, Hong EL, Hariharan M, Cheng Y, Schaub MA, Kasowski M, et al. Annotation of functional variation in personal genomes using RegulomeDB. Genome Res. 2012; 22:1790–7.

20. Ward LD, Kellis M. HaploReg v4: systematic mining of putative causal variants, cell types, regulators and target genes for human complex traits and disease. Nucleic Acids Res. 2016; 44:D877–81.

21. Rosmarin D, Palles C, Church D, Domingo E, Jones A, Johnstone E, et al. Genetic markers of toxicity from capecitabine and other fluorouracil-based regimens: investigation in the QUASAR2 study, systematic review, and meta-analysis. J Clin Oncol. 2014; 32:1031–9.

22. Garcia-Gonzalez X, Cortejoso L, Garcia MI, Garcia-Alfonso P, Robles L, Gravalos C, et al. Variants in CDA and ABCB1 are predictors of capecitabine-related adverse reactions in colorectal cancer. Oncotarget. 2015; 6:6422–30.

23. Roberto M, Romiti A, Botticelli A, Mazzuca F, Lionetto L, Gentile G, et al. Evaluation of 5-fluorouracil degradation rate and Pharmacogenetic profiling to predict toxicity following adjuvant Capecitabine. Eur J Clin Pharmacol. 2017; 73:157–64.

24. Joerger M, Huitema AD, Boot H, Cats A, Doodeman VD, Smits PH, et al. Germline TYMS genotype is highly predictive in patients with metastatic gastrointestinal malignancies receiving capecitabine-based chemotherapy. Cancer Chemother Pharmacol. 2015; 75:763–72.

25. Hamzic S, Kummer D, Froehlich TK, Joerger M, Aebi S, Palles C, et al. Evaluating the role of ENOSF1 and TYMS variants as predictors in fluoropyrimidine-related toxicities: an IPD meta-analysis. Pharmacol Res. 2020; 152:104594.

26. Senapati S, Singh S, Das M, Kumar A, Gupta R, Kumar U, et al. Genome-wide analysis of methotrexate pharmacogenomics in rheumatoid arthritis shows multiple novel risk variants and leads for TYMS regulation. Pharmacogenet Genomics. 2014; 24:211–9.

27. Pellicer M, Garcia-Gonzalez X, Garcia MI, Robles L, Gravalos C, Garcia-Alfonso P, et al. Identification of new SNPs associated with severe toxicity to capecitabine. Pharmacol Res. 2017; 120:133–7.

28. Dolnick BJ. Cloning and characterization of a naturally occurring antisense RNA to human thymidylate synthase mRNA. Nucleic Acids Res. 1993; 21:1747–52.

29. Chu J, Dolnick BJ. Natural antisense (rTSalpha) RNA induces site-specific cleavage of thymidylate synthase mRNA. Biochim Biophys Acta. 2002; 1587:183–93.

30. Martin M, Campone M, Bondarenko I, Sakaeva D, Krishnamurthy S, Roman L, et al. Randomised phase III trial of vinflunine plus capecitabine versus capecitabine alone in patients with advanced breast cancer previously treated with an anthracycline and resistant to taxane. Ann Oncol. 2018; 29:1195–202.