Association of Single-Nucleotide Polymorphisms of Gene XPC with Susceptibility to Basal Cell Carcinoma in Brazilian Population

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Mayara dos Santos Maia
Otávio Sérgio Lopes
Poliane da Silva Calixto
Sylvia Satomi Takeno Herrero
Augusto Monteiro de Souza
Carlos Alberto Longui
Ivan Rodrigues de Carvalho Filho
Leonardo Ferreira Soares
Plínio Delatorre
Renally Barbosa da Silva
Danielle Calcagno
Rommel Rodriguez Burbano
Eleonidas Moura Lima


Basal cell carcinoma, Nucleotide excision repair, Single nucleotide polymorphism, DSASP, Genotyping, Molecular Modeling.


Background: Basal cell carcinoma (BCC) is the common neoplasm in humans and its main etiological factor is exposure to solar radiation. Mutations in repair genes can lead to tumor progression and loss of cell integrity leading to the onset of cancer. Nucleotide excision repair (NER) is an important mechanism primarily used to repair injuries caused by UV.

Objective: To evaluate and describe for the first time the single nucleotide polymorphisms rs745769173, rs761106780 and rs535425175 and risk of developing BCC.

Methods: The present study analyzed 100 samples of paraffin-embedded tissue from patients with histopathological diagnosis of BCC and 100 control samples. The results were obtained by genotyping method, Dideoxy Unique Allele Specific – PCR (DSASP) and molecular modeling.

Results: The SNP rs535425175 of the XPC gene showed a significant association with the BCC in the analyzed samples (P <0.005) and molecular docking showed different binding energy of the complex between the XPC region 99-156 and the PH domain of TFIIH p62, being more negative, -710.53 kcal/mol, with the Asn residue at position 108 and less negative, -611.10 kcal/mol, with Lys residue related to the polymorphism.

Conclusion: The results suggest that the SNP rs535425175 of the XPC gene, which causes mutation at codon 108 of the XPC protein, which consists of replacing the Ans residue with the Lys, may be considered a risk factor associated with the development of BCC.


1. Otsuka A, Levesque MP, Dummer R, et al (2015) Hedgehog signaling in Basal Cell Carcinoma. Japanese Society for Investigative Dermatology. doi:10.1016/j.jdermsci.2015.02.007.

2. Jorgensen T. J, et al (2012) A population-based study of hedgehog pathway gene variants in relation to the dual risk of basal cell carcinoma plus another câncer. Cancer Epidemiol. doi:10.1016/j.canep.2012.05.001.

3. Dourmishev LA; rusinova D, Botev I (2013) Clinical variants, stages, and management of basal cell carcinoma. Indian Dermatology Online Journal. doi: 10.4103/2229-5178.105456.

4. Scott GA, Laughlin TS, Rothberg PG (2014) Mutations of the TERT promoter are common in basal cell carcinoma and squamous cell carcinoma. Modern Pathology. doi:10.1038/modpathol.2013.167.

5. Kosiniak-Kamysz A, Pośpiech E, Wojas-Pelc A, et al (2012) Potential association of single nucleotide polymorphisms in pigmentation genes with the development of Basal Cell Carcinoma. Journal of Dermatology. doi: 10.1111/j.1346-8138.2012.01559.x.

6. Decordier I, Loock KV, Lirsch-Volders M (2010). Phenotyping for DNA repair capacity. Mutation Research. doi: 10.1016/j.mrrev.2010.05.002.

7. Nemzow1 L, Lubin A, Zhang L, Gong F. XPC: Going where no DNA damage sensor has gone before. DNA Repair (Amst). 2015. doi:10.1016/j.dnarep.2015.09.004.

8. Tanaka K, Miura N, Satokata I, et al (1990) Analysis of human DNA excision repair gene involved in group A xeroderma pigmentosum and containing a zinc-finger domain. Nature. doi:10.1038 / 348073a0.

9. Ding D, Zhang Y, Yu H, et al (2012) Genetic variation of XPA gene and risk of cancer: a systematic review and pooled analysis. International Journal of Cancer. doi:10.1002/ijc.26391.

10. Scharer OD (2013) Nucleotide Excision Repair in Eukaryotes. Cold Spring Harbor Perspectives in Biology. doi:10.1101/cshperspect.a012609.

11. Nishi R, Okuda Y, Watanabe E, et al (2005) Centrin 2 Stimulates Nucleotide Excision Repair by Interacting with Xeroderma Pigmentosum Group C Protein. Molecular and Cellular Biology. doi:10.1128/MCB.25.13.5664-5674.2005.

12. Kamionka M, Feigon J (2004) Structure of the XPC binding domain of hHR23A reveals hydrophobic patches for protein interaction. Protein Sci. doi:10.1110/ps.04824304.

13. Sugasawa, K (2016) Molecular mechanisms of DNA damage recognition for mammalian nucleotide excision repair. DNA Repair. doi:10.1016/j.dnarep.2016.05.015.

14. Francisco G, Menezes PR, Chammas R (2008) XPC polymorphisms play a role in tissue-specific carcinogenesis: a meta-analysis. European Journal of Human Genetics. doi:10.1038/ejhg.2008.6.

15. Brambullo T, Colonna MR, Vindigni V,1 Piaserico S, et al (2022). Xeroderma Pigmentosum: A Genetic Condition Skin Cancer Correlated—A Systematic Review. BioMed Research International. doi:10.1155/2022/8549532.

16. Miller KL, Karagas MR, Kraft P, et al (2006) XPA, haplotypes, and risk of Basal and Squamous Cell Carcinoma. Carcinogenesis. doi:10.1093/carcin/bgi376.

17. Mei C, Hou M, Guo S, et al (2013) Polymorphisms in DNA repair genes of XRCC1, XPA, XPC, XPD and associations with lung cancer risk in Chinese people. Thoracic Cancer. doi:10.1111/1759-7714.12073.

18. Sakoda LC, Loomis MM, Doherty JA, et al (2012) Germ line variation in nucleotide excision repair genes and lung cancer risk in smokers. Int J Mol Epidemiol Genet 3:1-17.

19. He L, Deng T, Hesheng L (2015) XPA A23G polymorphism and risk of digestive system cancers: a meta-analysis. Onco Targets and Therapy 8:385–94.

20. Lin Y, Chahal HS, Wu1 W, Cho HG, et al (2017). Association study of genetic variation in DNA repair pathway genes and risk of basal cell carcinoma Int J Cancer. doi:10.1002/ijc.30786.

21 - Shang-Rong S, Cotel, RJ, Wu L, et al (2002) DNA extraction from archival formalin-fixed, paraffin-embedded tissue section based on the antigen retrieval principle: heating under the influence of pH. The Journal of Histochemestry e Cytochemestry. Thousand Oaks CA 50:1005-11.

22 - Lima EM, Lopes OS, Soares LF; et al (2015) Dideoxy single allele-specific PCR - DSASP new method to discrimination allelic. Braz arch biol Technol 58:414-20.

23. Okuda M, Kinoshita M, Kakumu E, et al (2015) Structural insight into the mechanism of TFIIH recognition by the acidic string of the nucleotide excision repair factor XPC. Structure 23:1827-37.

24. Guex N, Peitsch MC (1997) Swiss‐Model and the Swiss‐Pdb Viewer: an environment for comparative protein modeling. Electrophoresis. doi: 10.1002 / elps.1150181505.

25. Emsley P, Cowtan K (2004) Coot: model-building tools for molecular graphics. Acta Crystallographica Section D: Biological Crystallography. doi: 10.1107/S0907444904019158.

26. Ko J, Park H, Heo L, et al (2012) GalaxyWEB server for protein structure prediction and refinement. Nucleic acids research. doi:10.1093/nar/gks493.

27. Wiederstein M, Sippl MJ (2007) ProSA-web: interactive web service for the recognition of errors in three-dimensional structures of proteins. Nucleic acids research. doi:10.1093/nar/gkm290.

28. Benkert P, Biasini M, Schwede T (2011) Toward the estimation of the absolute quality of individual protein structure models. Bioinformatics. doi:10.1093/bioinformatics/btq662.

29. Benkert P, Tosatto SCE.; Schomburg D (2008) QMEAN: A comprehensive scoring function for model quality assessment. Proteins: Structure, Function and Bioinformatics. doi:10.1002/prot.21715.

30. Ritchie DW, Kemp GJL (2000) Protein Docking Using Spherical Polar Fourier Correlations. Proteins: Struct. Funct. Genet. doi:10.1002/(SICI)1097-0134(20000501)39:2<178:AID-PROT8>3.0.CO.

31. Delano WL (2002) Pymol: An open-source molecular graphics tool. CCP4 Newsletter On Protein Crystallography 40:82-92.

32. Ding D, Zhang Y, Yu H, et al (2012) Genetic variation of XPA gene and risk of cancer: a systematic review and pooled analysis. International Journal of Cancer. doi: 10.1002/ijc.26391.

33. Jin B, Dong Y, Zhang X, et al (2014) Association of XPC Polymorphisms and Lung Cancer Risk: A Meta-Analysis. Plos One. doi: 10.1371/journal.pone.0093937.

34. Farnebo L, Stjernström A, Fredrikson M, et al (2015) DNA repair genes XPC, XPD, XRCC1, and XRCC3 are associated with risk and survival of squamous cell carcinoma of the head and neck. DNA Repair. doi:10.1016/j.dnarep.2015.05.003.

35. Zhou L, Lu Y, Yang G, et al (2014) Quantitative assessment of the association between XPC Lys939Gln polymorphism and Cutaneous Melanoma risk. Tumor Biol. doi:10.1007/s13277-013-1196-y