Cell cycle regulation and apoptosis are essential defenses against cancer. Functional relevance of some germ line variants in cell cycle and apoptosis genes has been evaluated and inconsistent results have been reported on the associations between these variants and a number of cancer sites. The genotoxic effect of sunlight exposure has been shown in the etiology of both melanoma and nonmelanocytic skin cancer (1). UV radiation is capable of causing a wide range of lesions in DNA. UV-induced DNA damage can cause cell cycle arrest and apoptosis (2). We evaluated selected variants in genes involved in cell cycle and apoptosis (STK15, cyclin D1, p73, and caspase-8) with skin cancer risk in a nested case-control study within the Nurses' Health Study.

We conducted a nested case-control study within the Nurses' Health Study. Eligible cases in this study consisted of women with incident skin cancer from the subcohort who gave a blood specimen in 1989-1990 (n = 32,826), including squamous cell carcinoma and basal cell carcinoma cases with a diagnosis anytime after blood collection up to June 1, 1998 and melanoma cases (including 33 lentigo maligna and 77 in situ cases) up to June 1, 2000 with no previously diagnosed skin cancer. Detailed information about this study (219 melanoma, 286 squamous cell carcinoma, 300 basal cell carcinoma, and 873 controls) has been reported previously (3). Information on skin cancer risk factors was obtained from the prospective biennial questionnaires and the retrospective supplementary questionnaire. A cumulative lifetime sun exposure while wearing a bathing suit for each individual was developed by combining the UV database and the information obtained from the supplementary questionnaires. We constructed a multivariate confounder score to create a constitutional susceptibility score, summarizing natural skin color, natural hair color, child or adolescent tendency to burn, and the number of palpably raised moles on arms. We used this score to define women the constitutional susceptibility.

Genotyping assays were done by the 5′ nuclease assay (TaqMan) using the ABI Prism 7900HT Sequence Detection System (Applied Biosystems, Foster City, CA). Genotyping was done by laboratory personnel blinded to case-control status, and blinded quality control samples were inserted to validate genotyping procedures; concordance for the blinded samples was 100%. We used a common control series in data analysis to increase statistical power. Unconditional logistic regression was employed to calculate odds ratio (OR) and 95% confidence interval (95% CI) to assess the risks of the three types of skin cancer. All statistical tests were two sided.

A detailed description of the characteristics of cases and controls in the skin cancer nested case-control study was reported elsewhere (3). The genotype distributions of the five single-nucleotide polymorphisms were in Hardy-Weinberg equilibrium among controls. No significant associations were observed for the five polymorphisms with the three types of skin cancer (Table 1). We also explored the potential synergistic effects of the five polymorphisms by examining the associations of the number of these variant alleles carried and skin cancer risk. This exploratory analysis suggested a combined effect of these genetic variants in melanoma skin cancer development (OR of melanoma for ≥4 variants, 1.61; 95% CI, 0.96-2.69). No significant interactions were observed between these genetic variants and constitutional susceptibility score, the number of lifetime severe sunburns which blistered, and cumulative lifetime sun exposure while wearing a bathing suit.

Table 1.

Selected variants of genes involved in cell cycle and apoptosis with skin cancer risk

GenotypeControls, n (%)Melanoma
Squamous cell carcinoma
Basal cell carcinoma
Cases, n (%)Multivariate OR*Multivariate ORCases, n (%)Multivariate OR*Multivariate ORCases, n (%)Multivariate OR*Multivariate OR
STK15 F31I           
    FF 534 (62.3) 123 (57.2) 1.00 1.00 175 (61.4) 1.00 1.00 188 (64.6) 1.00 1.00 
    FI 279 (32.6) 76 (35.4) 1.19 (0.86-1.65) 1.20 (0.85-1.69) 97 (34.0) 1.05 (0.79-1.41) 1.03 (0.76-1.40) 85 (29.2) 0.86 (0.64-1.16) 0.84 (0.61-1.16) 
    II 44 (5.1) 16 (7.4) 1.54 (0.84-2.84) 1.48 (0.77-2.86) 13 (4.6) 0.90 (0.47-1.70) 0.93 (0.48-1.83) 18 (6.2) 1.17 (0.66-2.07) 1.25 (0.68-2.30) 
    FI + II 323 (37.7) 92 (42.8) 1.24 (0.91-1.68) 1.24 (0.89-1.72) 110 (38.6) 1.03 (0.78-1.36) 1.03 (0.77-1.37) 103 (35.4) 0.91 (0.69-1.19) 0.91 (0.68-1.22) 
STK15 V57I           
    VV 578 (69.0) 144 (69.6) 1.00 1.00 201 (71.3) 1.00 1.00 190 (66.4) 1.00 1.00 
    VI 237 (28.3) 55 (26.6) 0.90 (0.64-1.28) 0.89 (0.61-1.28) 78 (27.7) 0.95 (0.70-1.29) 0.96 (0.69-1.32) 89 (31.1) 1.14 (0.85-1.53) 1.06 (0.77-1.44) 
    II 23 (2.7) 8 (3.9) 1.40 (0.61-3.22) 1.54 (0.64-3.68) 3 (1.1) 0.38 (0.11-1.26) 0.36 (0.10-1.27) 7 (2.5) 0.95 (0.40-2.26) 0.86 (0.35-2.12) 
    VI + II 260 (31.0) 63 (30.4) 0.95 (0.68-1.32) 0.94 (0.66-1.34) 81 (28.7) 0.90 (0.67-1.21) 0.91 (0.67-1.25) 96 (33.6) 1.13 (0.84-1.50) 1.09 (0.81-1.47) 
cyclin D1 G241A           
    GG 257 (30.1) 58 (26.7) 1.00 1.00 90 (32.4) 1.00 1.00 86 (30.0) 1.00 1.00 
    GA 409 (48.0) 106 (48.9) 1.17 (0.82-1.67) 1.17 (0.80-1.72) 138 (49.6) 0.96 (0.71-1.31) 1.01 (0.73-1.40) 141 (49.1) 1.03 (0.76-1.41) 1.03 (0.75-1.43) 
    AA 187 (21.9) 53 (24.4) 1.28 (0.84-1.94) 1.25 (0.80-1.96) 50 (18.0) 0.76 (0.51-1.12) 0.84 (0.56-1.27) 60 (20.9) 0.95 (0.65-1.39) 1.02 (0.68-1.52) 
    GA + AA 596 (69.9) 159 (73.3) 1.20 (0.86-1.68) 1.20 (0.84-1.72) 188 (67.6) 0.90 (0.67-1.20) 0.94 (0.69-1.27) 201 (70.0) 1.01 (0.75-1.35) 1.02 (0.75-1.38) 
p73 C14T           
    CC 525 (63.1) 119 (56.7) 1.00 1.00 170 (63.2) 1.00 1.00 168 (61.3) 1.00 1.00 
    CT 273 (32.8) 82 (39.1) 1.32 (0.96-1.82) 1.29 (0.92-1.82) 88 (32.7) 0.99 (0.74-1.34) 0.99 (0.72-1.35) 89 (32.5) 1.01 (0.75-1.37) 1.04 (0.76-1.43) 
    TT 34 (4.1) 9 (4.3) 1.21 (0.57-2.61) 1.26 (0.56-2.82) 11 (4.1) 0.98 (0.49-1.98) 0.93 (0.44-1.94) 17 (6.2) 1.55 (0.84-2.85) 1.47 (0.77-2.80) 
    CT + TT 307 (36.9) 91 (43.3) 1.31 (0.96-1.79) 1.29 (0.93-1.79) 99 (36.8) 0.99 (0.75-1.32) 0.99 (0.74-1.34) 106 (38.7) 1.07 (0.81-1.42) 1.10 (0.82-1.47) 
caspase-8 D285H           
    DD 634 (75.4) 164 (79.2) 1.00 1.00 203 (71.2) 1.00 1.00 215 (74.9) 1.00 1.00 
    DH 191 (22.7) 40 (19.3) 0.80 (0.54-1.17) 0.80 (0.53-1.20) 77 (27.0) 1.27 (0.93-1.73) 1.34 (0.96-1.86) 69 (24.0) 1.07 (0.78-1.46) 1.09 (0.78-1.52) 
    HH 16 (1.9) 3 (1.5) 0.67 (0.19-2.35) 0.47 (0.13-1.75) 5 (1.8) 1.00 (0.36-2.76) 0.86 (0.29-2.51) 3 (1.1) 0.57 (0.17-1.99) 0.43 (0.12-1.55) 
    DH + HH 207 (24.6) 43 (20.8) 0.79 (0.54-1.15) 0.76 (0.51-1.14) 82 (28.8) 1.25 (0.92-1.69) 1.28 (0.93-1.77) 72 (25.1) 1.03 (0.75-1.40) 1.02 (0.74-1.42) 
Combined variants           
    0-1 184 (23.8) 37 (19.9) 1.00 1.00 74 (28.9) 1.00 1.00 64 (25.8) 1.00 1.00 
    2-3 456 (58.9) 104 (55.9) 1.11 (0.73-1.68) 1.03 (0.67-1.60) 133 (52.0) 0.73 (0.52-1.01) 0.78 (0.55-1.11) 134 (54.0) 0.84 (0.60-1.19) 0.83 (0.58-1.19) 
    ≥ 4 134 (17.3) 45 (24.2) 1.67 (1.02-2.73) 1.61 (0.96-2.69) 49 (19.1) 0.91 (0.59-1.39) 0.99 (0.63-1.55) 50 (20.2) 1.08 (0.70-1.67) 1.06 (0.67-1.67) 
GenotypeControls, n (%)Melanoma
Squamous cell carcinoma
Basal cell carcinoma
Cases, n (%)Multivariate OR*Multivariate ORCases, n (%)Multivariate OR*Multivariate ORCases, n (%)Multivariate OR*Multivariate OR
STK15 F31I           
    FF 534 (62.3) 123 (57.2) 1.00 1.00 175 (61.4) 1.00 1.00 188 (64.6) 1.00 1.00 
    FI 279 (32.6) 76 (35.4) 1.19 (0.86-1.65) 1.20 (0.85-1.69) 97 (34.0) 1.05 (0.79-1.41) 1.03 (0.76-1.40) 85 (29.2) 0.86 (0.64-1.16) 0.84 (0.61-1.16) 
    II 44 (5.1) 16 (7.4) 1.54 (0.84-2.84) 1.48 (0.77-2.86) 13 (4.6) 0.90 (0.47-1.70) 0.93 (0.48-1.83) 18 (6.2) 1.17 (0.66-2.07) 1.25 (0.68-2.30) 
    FI + II 323 (37.7) 92 (42.8) 1.24 (0.91-1.68) 1.24 (0.89-1.72) 110 (38.6) 1.03 (0.78-1.36) 1.03 (0.77-1.37) 103 (35.4) 0.91 (0.69-1.19) 0.91 (0.68-1.22) 
STK15 V57I           
    VV 578 (69.0) 144 (69.6) 1.00 1.00 201 (71.3) 1.00 1.00 190 (66.4) 1.00 1.00 
    VI 237 (28.3) 55 (26.6) 0.90 (0.64-1.28) 0.89 (0.61-1.28) 78 (27.7) 0.95 (0.70-1.29) 0.96 (0.69-1.32) 89 (31.1) 1.14 (0.85-1.53) 1.06 (0.77-1.44) 
    II 23 (2.7) 8 (3.9) 1.40 (0.61-3.22) 1.54 (0.64-3.68) 3 (1.1) 0.38 (0.11-1.26) 0.36 (0.10-1.27) 7 (2.5) 0.95 (0.40-2.26) 0.86 (0.35-2.12) 
    VI + II 260 (31.0) 63 (30.4) 0.95 (0.68-1.32) 0.94 (0.66-1.34) 81 (28.7) 0.90 (0.67-1.21) 0.91 (0.67-1.25) 96 (33.6) 1.13 (0.84-1.50) 1.09 (0.81-1.47) 
cyclin D1 G241A           
    GG 257 (30.1) 58 (26.7) 1.00 1.00 90 (32.4) 1.00 1.00 86 (30.0) 1.00 1.00 
    GA 409 (48.0) 106 (48.9) 1.17 (0.82-1.67) 1.17 (0.80-1.72) 138 (49.6) 0.96 (0.71-1.31) 1.01 (0.73-1.40) 141 (49.1) 1.03 (0.76-1.41) 1.03 (0.75-1.43) 
    AA 187 (21.9) 53 (24.4) 1.28 (0.84-1.94) 1.25 (0.80-1.96) 50 (18.0) 0.76 (0.51-1.12) 0.84 (0.56-1.27) 60 (20.9) 0.95 (0.65-1.39) 1.02 (0.68-1.52) 
    GA + AA 596 (69.9) 159 (73.3) 1.20 (0.86-1.68) 1.20 (0.84-1.72) 188 (67.6) 0.90 (0.67-1.20) 0.94 (0.69-1.27) 201 (70.0) 1.01 (0.75-1.35) 1.02 (0.75-1.38) 
p73 C14T           
    CC 525 (63.1) 119 (56.7) 1.00 1.00 170 (63.2) 1.00 1.00 168 (61.3) 1.00 1.00 
    CT 273 (32.8) 82 (39.1) 1.32 (0.96-1.82) 1.29 (0.92-1.82) 88 (32.7) 0.99 (0.74-1.34) 0.99 (0.72-1.35) 89 (32.5) 1.01 (0.75-1.37) 1.04 (0.76-1.43) 
    TT 34 (4.1) 9 (4.3) 1.21 (0.57-2.61) 1.26 (0.56-2.82) 11 (4.1) 0.98 (0.49-1.98) 0.93 (0.44-1.94) 17 (6.2) 1.55 (0.84-2.85) 1.47 (0.77-2.80) 
    CT + TT 307 (36.9) 91 (43.3) 1.31 (0.96-1.79) 1.29 (0.93-1.79) 99 (36.8) 0.99 (0.75-1.32) 0.99 (0.74-1.34) 106 (38.7) 1.07 (0.81-1.42) 1.10 (0.82-1.47) 
caspase-8 D285H           
    DD 634 (75.4) 164 (79.2) 1.00 1.00 203 (71.2) 1.00 1.00 215 (74.9) 1.00 1.00 
    DH 191 (22.7) 40 (19.3) 0.80 (0.54-1.17) 0.80 (0.53-1.20) 77 (27.0) 1.27 (0.93-1.73) 1.34 (0.96-1.86) 69 (24.0) 1.07 (0.78-1.46) 1.09 (0.78-1.52) 
    HH 16 (1.9) 3 (1.5) 0.67 (0.19-2.35) 0.47 (0.13-1.75) 5 (1.8) 1.00 (0.36-2.76) 0.86 (0.29-2.51) 3 (1.1) 0.57 (0.17-1.99) 0.43 (0.12-1.55) 
    DH + HH 207 (24.6) 43 (20.8) 0.79 (0.54-1.15) 0.76 (0.51-1.14) 82 (28.8) 1.25 (0.92-1.69) 1.28 (0.93-1.77) 72 (25.1) 1.03 (0.75-1.40) 1.02 (0.74-1.42) 
Combined variants           
    0-1 184 (23.8) 37 (19.9) 1.00 1.00 74 (28.9) 1.00 1.00 64 (25.8) 1.00 1.00 
    2-3 456 (58.9) 104 (55.9) 1.11 (0.73-1.68) 1.03 (0.67-1.60) 133 (52.0) 0.73 (0.52-1.01) 0.78 (0.55-1.11) 134 (54.0) 0.84 (0.60-1.19) 0.83 (0.58-1.19) 
    ≥ 4 134 (17.3) 45 (24.2) 1.67 (1.02-2.73) 1.61 (0.96-2.69) 49 (19.1) 0.91 (0.59-1.39) 0.99 (0.63-1.55) 50 (20.2) 1.08 (0.70-1.67) 1.06 (0.67-1.67) 

NOTE: The number of participants does not sum to total women because of missing data on genotype.

*

Unconditional logistic regression adjusted for the matching variables: age and race (Caucasian, missing).

Unconditional logistic regression adjusted for the matching variables, constitutional susceptibility score (tertiles), family history of skin cancer (yes/no), the number of lifetime severe sunburns which blistered (none, 1-5, 6-11, >11), sunlamp use or tanning salon attendance (yes/no), cumulative sun exposure while wearing a bathing suit (tertiles), and geographic region.

Our data do not support the hypothesis that these variants in cell cycle and apoptosis genes are associated with skin cancer risk. STK15 participates in cell cycle regulation from G2 to M phase. The Ile allele of the F31I polymorphism in STK15 was more effective in transforming rat cells to a more malignant phenotype (4). The results of a meta-analysis for 15 studies of cancer at multiple sites combined were significant for cancer risk in both heterozygotes (OR, 1.10; 95% CI, 1.03-1.18) and homozygotes (OR, 1.40; 95% CI, 1.22-1.59; ref. 5). In a hospital-based case-control study of 236 nonmelanocytic skin cancer cases and 182 controls, heterozygotes had an OR of 0.86 (95% CI, 0.57-1.29) and homozygotes showed an OR of 1.48 (95% CI, 0.49-4.46; ref. 5).

Cyclin D1 is involved in the transition from G1 to S phase. The A allele of the G241A polymorphism generates the truncated protein with a longer half-life (6). In a nested case-control study from Sweden and Finland of 197 basal cell carcinoma cases and 548 controls, the OR for heterozygotes was 1.11 (95% CI, 0.73-1.68) and that for homozygotes was 1.46 (95% CI, 0.90-2.36; ref. 7).

The p73 gene is a member of p53 family and induces G1 cell cycle arrest and apoptosis. Two linked polymorphisms, G4A and C14T, may influence the efficiency of translation initiation (8). The caspase-8 gene is involved in the initiation of apoptosis. No report has been published on the associations between the p73 C14T and the caspase-8 D285H polymorphisms and skin cancer risks.

In summary, we did not find evidence for associations between the selected variants in cell cycle and apoptosis genes and the risks of melanoma and nonmelanocytic skin cancer, nor were the associations modified by constitutional susceptibility, severe sunburns, and cumulative sun exposure while wearing a bathing suit.

Grant support: NIH grants CA113100 and CA87969 and Harvard Specialized Program of Research Excellence in Skin Cancer (J. Han).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

We thank Dr. Hardeep Ranu, Craig Labadie, Pati Soule, and Alicia Whittington for their laboratory assistance, Carolyn Guo for her programming support, and the participants in the Nurses' Health Study for their dedication and commitment.

1
Ravanat JL, Douki T, Cadet J. Direct and indirect effects of UV radiation on DNA and its components.
J Photochem Photobiol B
2001
;
63
:
88
–102.
2
Melnikova VO, Ananthaswamy HN. Cellular and molecular events leading to the development of skin cancer.
Mutat Res
2005
;
571
:
91
–106.
3
Han J, Colditz GA, Liu JS, Hunter DJ. Genetic variation in XPD, sun exposure, and risk of skin cancer.
Cancer Epidemiol Biomarkers Prev
2005
;
14
:
1539
–44.
4
Ewart-Toland A, Briassouli P, de Koning JP, et al. Identification of Stk6/STK15 as a candidate low-penetrance tumor-susceptibility gene in mouse and human.
Nat Genet
2003
;
34
:
403
–12.
5
Ewart-Toland A, Dai Q, Gao YT, et al. Aurora-A/STK15 T+91A is a general low penetrance cancer susceptibility gene: a meta-analysis of multiple cancer types.
Carcinogenesis
2005
;
26
:
1368
–73. Epub 2005 Mar 31.
6
Sawa H, Ohshima TA, Ukita H, et al. Alternatively spliced forms of cyclin D1 modulate entry into the cell cycle in an inverse manner.
Oncogene
1998
;
16
:
1701
–12.
7
Festa F, Kumar R, Sanyal S, et al. Basal cell carcinoma and variants in genes coding for immune response, DNA repair, folate and iron metabolism.
Mutat Res
2005
;
574
:
105
–11. Epub 2005 Mar 26.
8
Kaghad M, Bonnet H, Yang A, et al. Monoallelically expressed gene related to p53 at 1p36, a region frequently deleted in neuroblastoma and other human cancers.
Cell
1997
;
90
:
809
–19.