In this study, the SNP rs1805007 was identified with the strongest associations with both melanoma and non-melanoma skin cancers. MC1R encodes a 317-amino acid seven-pass transmembrane G-protein-coupled receptor, and the SNP rs1805007 encodes an Arg151Cys substitution. A well-known red hair color variant, the SNP rs1805007, along with other genetic variants in the MC1R
gene, was shown to confer susceptibility to both melanoma and non-melanoma (BCC and SCC) skin cancers in our previous study and studies performed by other groups (4
). This supports the validity of our GWAS data and further validates our self-reported BCC data set. Also, we identified two novel alleles, rs12210050 near the EXOC2
gene at 6p25 and rs7335046 near the UBAC2
gene at 13q32, associated with non-melanoma skin cancer. EXOC2 is a component of the exocyst complex involved in the docking of exocystic vesicles with fusion sites on the plasma membrane. Some genetic variants in the EXOC2
gene (including rs12210050) were identified as contributing to human pigmentary traits such as hair color, skin color and tanning ability, in our previous GWAS on hair color and tanning ability (14
). Hence, we performed an additional analysis for the association between rs12210050 at 6p25 and BCC risk after further adjusting for pigmentary phenotypes, tanning tendency and hair color, and the result remained to reach genome-wide significant association in the combined discovery set and replication set (P
= 1.2 × 10−9
). At the same locus 6p25, Sulem et al
) previously identified the SNP rs1540771 conferring susceptibility to pigmentary phenotypes, including freckling and skin sensitivity to sun. However, this SNP was not associated with the risks of BCC and melanoma in the other previous study conducted by Gudbjartsson et al
). The SNP rs1540771 and the SNP rs12210050 are not in LD (r2
= 0.05 in HapMap CEU). The SNP rs1540771 showed nominal association with BCC risk in the discovery set of this study [rs1540771[C]: OR (95% CI), 0.93 (0.86–1.00); P
= 0.047]. This association was eliminated after adjusting for the SNP rs12210050 (P
= 0.42). The UBAC2
gene encoding ubiquitin-associated domain-containing protein 2 is alternatively called phosphoglycerate dehydrogenase-like protein 1 (PHGDHL1). This locus has been identified as a genetic susceptibility locus for Behçet's disease, a chronic systemic inflammatory disease (17
A possible issue raised in this GWAS is the effect heterogeneity. Although five studies were used in the discovery set of this study, they came from only two demographically similar cohorts (NHS and HPFS). It is plausible that differences in the sampling scheme across the five case–control sub-studies could in principle introduce some effect heterogeneity, although this effect is likely to be small (18
). To flag markers that show evidence of effect heterogeneity, we have calculated Cochran's Q statistic (19
) and reported the corresponding P
-values in the tables. Also, given the large number of SNPs (more than 2 million SNPs) analyzed in this study, nominally significant P
-values for heterogeneity are difficult to interpret, and may represent false positives due to sampling variation. For example, although there is some evidence of heterogeneity for the SNP rs7335046 in the discovery set (P
= 0.01), the P
-value for heterogeneity of this SNP in either replication set or combined set was not significant. In addition, as mentioned above, considering the number of SNPs analyzed in this study, the P
-value of 0.01 for heterogeneity in the discovery set is more likely attributable to chance. Still, we have taken a conservative approach and excluded the SNPs with P
-values for heterogeneity test <0.01 from further consideration for replication.
In this study, BCC cases used for data analysis were self-reported. The validity of self-report of BCC in these medically sophisticated populations has been assessed in previous studies (20
). Colditz et al
) evaluated the validity of self-reported illnesses including skin cancer in the NHS. Among 33 random samples of women who had reported non-melanoma skin cancer, medical records indicated that 30 (91%) had correctly reported the skin cancer. The three incorrect self-reports were actinic keratosis, a premalignant skin lesion. Also, Hunter et al
) previously examined the risk factors of BCC in the NHS using the self-reported cases. As expected, they found that lighter pigmentation (blonde or red hair color), less childhood and adolescent tanning tendency and higher tendency to sunburn were associated with an increased risk of BCC. Also, they found that women residing in California and Florida were more likely to develop BCC compared with women living in the Northeast. In addition, using the self-reported BCC cases, we identified the previously well-documented genetic variant in the MC1R
gene (rs1805007) as the strongest locus in this study. These data support the validity of self-report of BCC in our study.
It is possible that the similar biases are present in both the discovery set and replication set because they were from two large cohort studies, the NHS and the HPFS. In the discovery set of this study, 43% of BCC cases were men, whereas 10% of BCC cases were men in the replication set. Also, we note that there are some differences between the two cohorts, such as gender (the NHS is female cohort, and the HPFS is male cohort), geographical background and social economic status.
In summary, in the current GWAS of individuals of European ancestry, we identified two novel loci, the EXOC2 gene on 6p25 and the UBAC2 gene on 13q32, as associated with the risks of non-melanoma skin cancer, BCC and SCC. In addition, we verified the skin cancer susceptibility locus at the MC1R gene on 16q24. Future studies are warranted to evaluate the effect of interactions between these promising SNPs and skin cancer risk factors on the risk of skin cancer. Understanding the role of these novel loci in the development of non-melanoma skin cancer could provide important insight into non-melanoma skin cancer pathogenesis and effectively improve the prevention of non-melanoma skin cancer.