Exploratory Investigation of Genetic Associations with Basal Cell Carcinoma Risk: Genome-Wide Association Study in Jeju Island, Korea

  • Yun, Byung Min (Departments of Plastic and Reconstructive Surgery, School of Medicine, Jeju National University) ;
  • Song, Jung-Kook (Department of Preventive Medicine, School of Medicine, Jeju National University) ;
  • Lee, Ji-Young (Cardiovascular Genome Center, Yonsei University College of Medicine, Yonsei University)
  • Published : 2014.09.15


Aim: Little is known about the genetic associations with Basal cell carcinoma (BCC) risk in non-Caucasian populations, in which BCC is rare, as in Korea. We here conducted a pilot genome-wide association study (GWAS) in 12 patients and 48 standard controls. Method: A total of 263,511 SNPs were analyzed with the Illumina HumanOmni1 Quad v1.0 DNA Analysis BeadChip for cases and Korean HapMap 570K for controls. Results: SNP-based analyses, based on the allele genetic model with adjustment for sex and age showed suggestive associations with BCC risk for 6 SNPs with a P-value (P < 0.0005). However, these associations were not statistically significant after Bonferroni correction: rs1040503, rs2216491, rs13407683, rs4751072, rs9891263, and rs1368474. In addition, results from gene-based analyses showed suggestive associations with BCC risk for 33 candidate genes with a P-value (P <0.0005). Consistent with previous GWAS and replication studies in Caucasian populations, PADI6, RHOU and SLC45A2 were identified as having null associations with BCC (P > 0.05), likely due to the smaller sample size. Conclusions: Although this was a small-scale negative study, to our knowledge, we have conducted the first GWAS for BCC risk in an Asian population. Further large studies in non-Caucasian populations are required to achieve statistical significance and confirm these findings.


Supported by : Jeju National University Hospital Research


  1. Betti R, Menni S, Radaelli G, Bombonato C, Crosti C (2010). Micronodular basal cell carcinoma: A distinct subtype? Relationship with nodular and infiltrative basal cell carcinomas. J Dermatol, 37, 611-6.
  2. Brown KM, MacGregor S, Montgomery GW, et al (2008). Common sequence variants on 20q11.22 confer melanoma susceptibility. Nat Genet, 40, 838-40.
  3. Cho S, Hahm JH, Hong YS (2001). Analysis of p53 and BAX mutations, loss of heterozygosity, p53 and BLC2 expression and apoptosis in basal cell carcinoma in Korean patients. Br J Dermatol, 144, 841-8.
  4. Diepgen TL, Mahler V (2002). The epidemiology of skin cancer. Br J Dermatol, 146, 1-6.
  5. Duffy DL, Zhao ZZ, Sturm RA, et al (2010). Multiple pigmentation gene polymorphisms account for a substantial proportion of risk of cutaneous malignant melanoma. J Invest Dermatol, 130, 520-8.
  6. Elghissassi I, Mikou A, Inrhaoun H, et al (2009). Metastatic basal cell carcinoma to the bone and bone marrow. Int J Dermatol, 48, 481-3
  7. Falchi M, Bataille V, Hayward NK, et al (2009). Genome-wide association study identifies variants at 9p21 and 22q13 associated with development of cutaneous nevi. Nat Genet, 41, 915-8.
  8. Fernandez LP, Milne RL, Pita G, et al (2008). SLC45A2: a novel malignant melanoma- associated gene. Hum Mutat, 29, 1161-7.
  9. Gerstenblith MR, Shi J, Landi MT (2010). Genome-wide association studies of pigmentation and skin cancer: a review and meta-analysis. Pigment Cell Melanoma Res, 23, 587-606.
  10. Graf J, Hodgson R, van Daal A (2005). Single nucleotide polymorphisms in the MATP gene are associated with normal human pigmentation variation. Hum Mutat, 25, 278-84.
  11. Gudbjartsson DF, Sulem P, Stacey SN, et al (2009). ASIP and TYR pigmentation variants associate with cutaneous melanoma and basal cell carcinoma. Nat Genet, 40, 886-91.
  12. Guedj M, Bourillon A, Combadieres C, et al (2008). Variants of the MATP/SLC45A2 gene are protective for melanoma in the French population. Hum Mutat, 29, 1154-60.
  13. Han J, Kraft P, Nan H, et al (2008). A genome-wide association study identifies novel alleles associated with hair color and skin pigmentation. PLoS Genet, 4, e1000074.
  14. Hirschhorn JN, Lohmueller K, Byrne E, Hirschhorn K (2002). A comprehensive review of genetic association studies. Genet Med, 4, 45-61.
  15. Kang SY, Lee KG, Lee W, et al (2007). Polymorphisms in the DNA repair gene XRCC1 associated with basal cell carcinoma and squamous cell carcinoma of the skin in a Korean population. Cancer Sci, 98, 716-20.
  16. Kim MY, Park HJ, Baek SC, Byun DG, Houh D (2002). Mutations of the p53 and PTCH gene in basal cell carcinomas: UV mutation signature and strand bias. J Dematol Sci, 29, 1-9.
  17. Korea Central Cancer Registry, the Korean Ministry of Health and Welfare. Unpublished data, 2014
  18. Macha MA, Batra SK, Ganti AK (2013). Profile of vismodegib and its potential in the treatment of advanced basal cell carcinoma. Cancer Manag Res, 5, 197-203.
  19. Madan V, Lear JT, Szeimies RM (2010). Non-melanoma skin cancer. The Lancet, 375, 673-85.
  20. Malik MA, Umar M, Gupta U, Zargar SA, Mittal B (2014). Phospholipase C epsilon 1 (PLCE1 rs2274223A>G, rs3765524C>T and rs7922612C>T) polymorphisms and esophageal cancer risk in the Kashmir Valley. Asian Pac J Cancer Prev, 15, 4319-23.
  21. Nan H, Kraft P, Hunter DJ, Han J (2009a). Genetic variants in pigmentation genes, pigmentary phentoypes and risk of skin cancer in Caucasians. Int J Cancer, 125, 909-17.
  22. Nan H, Kraft P, Qureshi AA, et al (2009b). Genome-wide association study of tanning phenotype in a population of European ancestry. J Invest Dermatol, 129, 2250-7.
  23. Pelucchi C, Di Landro A, Naldi L, La Vecchia C (2007). Risk factors for histological types and anatomic sites of cutaneous basal-cell carcinoma: An Italian case-control study. J Invest Dermatol, 127, 935-44.
  24. Rafnar T, Sulem P, Stacey SN, et al (2009). Sequence variants at the TER-CLPTM1L locus associate with many cancer types. Nat Genet, 41, 221-7.
  25. Ramos J, Villa J, Ruiz A, Armstrong R, Matta J (2004). UV dose determines key characteristics of nonmelanoma skin cancer. Cancer Epidemiol Biomarkers Prev, 13, 2006-11.
  26. Sekulic A, Migden MR, Oro AE, et al (2012). Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med, 366, 2171-9.
  27. Sorin D (2003). Data Analysis Tools For DNA Microarrays. U.S., CHAPMAN&HALL/CRC.
  28. Stacey, SN, Gudbjartsson DF, Sulem P, et al (2008). Common variants on 1p36 and 1q42 are associated with cutaneous basal cell carcinoma but not with melanoma or pigmentation traits. Nat Genet, 40, 1313-8.
  29. Stacey, SN, Sulem P, Masson G, et al (2009). New common variants affecting susceptibility to basal cell carcinoma. Nat Genet, 41, 909-14.
  30. Stokowski RP, Pant PVK, Dadd T, et al (2007). A genomewide association study of skin pigmentation in a South Asian population. Am J Hum Genet, 81, 1119-32.
  31. Sulem P, Gudbjartsson DF, Stacey SN, et al (2007). Genetic determinants of hair, eye and skin pigmentation in Europeans. Nat Genet, 39, 1443-52.
  32. Sulem P, Gudbjartsson DF, Stacey SN, et al (2008). Two newly identified genetic determinants of pigmentation in Europeans. Nat Genet, 40, 835-7.
  33. Tang JY, Mackay-Wiggan JM, Aszterbaum M, et al (2012). Inhibiting the hedgehog pathway in patients with the basalcell nevus syndrome. N Engl J Med, 366, 2180-8.
  34. Tilli C, von Steensel M, Krekels G, Neumann H, Ramaekers FCS (2005). Molecular aetiology and pathogenesis of basal cell carcinoma. Br J Dermatol, 152, 1108-24.
  35. von Domarus H, Stevens PJ (1984). Metastatic basal cell carcinoma: report of five cases and review of 170 cases in the literature. J Am Acad Dermatol, 10, 1043-60.
  36. Wei Q, Matanoski GM, Farmer ER, Hedayati MA, Grossman L (1993). DNA repair and aging in basal cell carcinoma: a molecular epidemiology study. Proc Natl Acad Sci USA, 90, 1614-8.
  37. Weir BS (1996). Genetic Data Analysis II: Methods for discrete population genetic data. Sunderland, MA, Sinauer Associates.
  38. Yakubu A, Mabogunje OA (1993). Skin cancer in African albinos. Acta Oncol, 32, 621-2.
  39. Zhang YR, Xu Y, Yang K, et al (2012). Association of six susceptibility loci with prostate cancer in northern Chinese men. Asian Pac J Cancer Prev, 13, 6273-6.