Background: Cutaneous squamous cell carcinoma (cSCC) is the second most common cancer in United States, and its incidence is substantially higher in men than women, but the reasons for the difference are unknown. We explored whether common mitochondrial DNA (mtDNA) haplogroups, which have been associated with cancer risk, and in particular squamous cell carcinoma risk arising in other organs, could explain this biological sex difference in cSCC susceptibility.

Methods: We performed a retrospective cohort study using data from the Genetic Epidemiology Research in Adult Health and Aging cohort composed of 67,868 non-Hispanic white subjects (7,701 cSCC cases and 60,167 controls). Genotype information on >665,000 SNPs was generated using Affymetrix Axiom arrays designed to maximize genome-wide coverage, and 102 high-quality mtDNA SNPs were used to determine mtDNA haplogroups. Associations between each mtDNA haplogroup and cSCC risk were evaluated by logistic regression analysis adjusting for age, sex, and population stratification using ancestry principal components.

Results: cSCC was more common in men (15.4% vs. 8.4% for women). Nine common mtDNA haplogroups (frequency ≥1%) were identified in addition to the most common haplogroup, H, used as the reference group. No association with cSCC risk was detected for any of the mtDNA haplogroups or overall or sex-stratified analyses.

Conclusions: Common mitochondrial variation is not associated with cSCC risk.

Impact: This well-powered study refutes the hypothesis that common mitochondrial haplogroups play a role in the differential sex predilection of cSCCs. Cancer Epidemiol Biomarkers Prev; 27(7); 838–41. ©2018 AACR.

Cutaneous squamous cell carcinoma (cSCC) is one of the most common malignancies among non-Hispanic whites and arises more frequently in men, with recent incidence estimates of 207.5 cases per 100,000 person-years in men versus 128.8 in women (1). The reasons underlying this sex predilection are largely unknown. Human mitochondrial DNA (mtDNA) haplogroups, which are maternally inherited, are defined by unique sets of mitochondrial variants and reflect specific ancestral populations and geographic origins (2). Changes in mitochondrial genotype play a significant role in the initiation, progression, and treatment of cancer. Mitochondrial haplogroups have been linked to cancer risk, and to squamous cell carcinoma arising in other organs, such as the esophagus. Yet the relationship between mtDNA haplogroups and cSCC risk has not been previously reported. Mitochondrial apoptosis pathways may be involved in the pathogenic and molecular mechanisms of cSCC, with mitochondrial dysfunction promoting cell proliferation in cSCC through the accumulation of the dynaminrelated protein 1 (Drp1), a mediator of mitochondrial fission (3). Here, we report an association study of mtDNA haplogroups and the risk of cSCC in a large, well-characterized cohort.

The study sample of non-Hispanic white members of the Genetic Epidemiology Research in Adult Health and Aging (GERA) cohort included 7,701 cSCC cases (4,421 men and 3,280 women) and 60,167 controls (24,330 men and 35,837 women), as described previously (4). DNA samples were genotyped at over 665,000 SNPs on Affymetrix Axiom arrays optimized for coverage of known common variants across the genome, including 116 mitochondrial DNA polymorphisms (mtSNP) that were identified from publicly available databases (Affymetrix, HapMap; ref. 5). A total of 102 mtSNPs passed post-genotype quality filtering and were used to determine mitochondrial haplogroups (Table 1).

Table 1.

102 mtSNPs on the EUR Affymetrix Axiom array that passed post-genotype quality filtering

SNPPosition in mtDNA (bp)Minor allele frequencySNPPosition in mtDNA (bp)Minor allele frequency
rs2853519 G769A 0.00401 rs28357682 G14905A 0.1021 
rs28358572 T1243C 0.01822 rs28357684 G15043A 0.04452 
rs2001030 G1438A 0.02976 rs28357372 A15607G 0.1011 
rs28358574 A1736G 0.003195 rs28357373 T15629C 0.000394 
rs41349444 T2158C 0.01041 rs41337244 A15758G 0.01396 
rs28358578 C2332T 0.000339 rs41504845 C15833T 0.01655 
rs28358580 T2416C 0.002437 rs28617642 G15884A 0.01157 
rs2854128 G2706A 0.4199 rs2853513 C16223T 0.08716 
rs28619217 A2755G 0.000637 rs35452858 T16325C 0.008543 
rs2854130 T2885C 0.001746 rs28357675 T14318C 0.001533 
rs3928306 G3010A 0.2279 rs28358270 G9123A 0.01536 
rs28358582 T3308C 0.001968 rs28358273 G9554A 0.001434 
rs28358584 A3480G 0.09449 rs28358278 C10400T 0.009301 
rs28358586 A3547G 0.003748 rs28358282 T10810C 0.006361 
rs41355750 A3720G 0.01279 rs28358884 C8414T 0.001246 
rs28647453 A3927G 0.000163 rs28359175 A13263G 0.005202 
rs28357981 T4977C 0.001504 rs28379170 T13401C 0.002227 
rs2015062 T7028C 0.4173 rs28397767 G12501A 0.03492 
rs2298011 A9180G 0.001815 rs28456039 A5319G 0.003079 
rs28575684 T9647C 0.000352 rs28502681 G8572A 0.001884 
rs41502750 T9716C 0.01966 rs2853512 G16153A 0.005829 
rs28411821 T9824C 0.000217 rs2853515 G263A 0.0105 
rs3902407 T9833C 0.000462 rs56489998 A663G 0.003148 
rs3134801 T9950C 0.002839 rs1029294 C6473T 0.002075 
rs41347846 T10034C 0.02583 rs1116904 G8027A 0.004107 
rs28358275 T10238C 0.03533 rs2298009 A9120G 0.001955 
rs28358277 G10373A 0.000448 rs28357672 T14212C 0.004481 
rs28358281 G10586A 0.001663 rs28357676 G14560A 1.36E-05 
rs2853490 G11176A 0.002336 rs28357683 C14911T 0.000149 
rs3915952 A11251G 0.1959 rs28358581 C2789T 0.001259 
rs28358285 T11299C 0.0911 rs28358887 G8994A 0.02233 
rs2853493 A11467G 0.2327 rs28359183 C13914A 0.000354 
rs2853494 A11641G 0.000895 rs28445709 T7084C 2.71E-05 
rs2853495 A11719G 0.4705 rs28462217 A9389G 0.000325 
rs2853497 G12007A 0.01651 rs2853505 G14861A 0.002787 
rs28359170 G12236A 0.000988 rs2854134 C3594T 0.00339 
rs2853499 G12372A 0.2361 rs28558945 C2415T 1.35E-05 
rs28359172 A12612G 0.09561 rs2857287 C13506T 0.001449 
rs3926883 C12633A 0.02391 rs28591518 A12768G 0.00019 
rs28359173 A12693G 0.001477 rs28690056 T9909C 9.49E-05 
rs2854122 C12705T 0.08524 rs28709356 C10733A 0.002226 
rs3899498 G13368A 0.1024 rs28718242 T11899C 0.002501 
rs28359177 G13590A 0.006178 rs3902406 A6461G 0.000801 
rs2853503 T13617C 0.07729 rs3928312 A2833G 0.000231 
rs28359178 G13708A 0.1108 rs41369547 C12669T 9.49E-05 
rs41421644 T13734C 0.01235 rs41427749 G8616T 0.006364 
rs41509754 T13965C 0.01926 rs41534744 G16129A 0.08603 
rs41535848 A13966G 0.0194 rs28357682 G14905A 0.1021 
rs28357673 C14284T 0.000339 rs28357684 G15043A 0.04452 
rs28357681 T14798C 0.1602 rs28357372 A15607G 0.1011 
SNPPosition in mtDNA (bp)Minor allele frequencySNPPosition in mtDNA (bp)Minor allele frequency
rs2853519 G769A 0.00401 rs28357682 G14905A 0.1021 
rs28358572 T1243C 0.01822 rs28357684 G15043A 0.04452 
rs2001030 G1438A 0.02976 rs28357372 A15607G 0.1011 
rs28358574 A1736G 0.003195 rs28357373 T15629C 0.000394 
rs41349444 T2158C 0.01041 rs41337244 A15758G 0.01396 
rs28358578 C2332T 0.000339 rs41504845 C15833T 0.01655 
rs28358580 T2416C 0.002437 rs28617642 G15884A 0.01157 
rs2854128 G2706A 0.4199 rs2853513 C16223T 0.08716 
rs28619217 A2755G 0.000637 rs35452858 T16325C 0.008543 
rs2854130 T2885C 0.001746 rs28357675 T14318C 0.001533 
rs3928306 G3010A 0.2279 rs28358270 G9123A 0.01536 
rs28358582 T3308C 0.001968 rs28358273 G9554A 0.001434 
rs28358584 A3480G 0.09449 rs28358278 C10400T 0.009301 
rs28358586 A3547G 0.003748 rs28358282 T10810C 0.006361 
rs41355750 A3720G 0.01279 rs28358884 C8414T 0.001246 
rs28647453 A3927G 0.000163 rs28359175 A13263G 0.005202 
rs28357981 T4977C 0.001504 rs28379170 T13401C 0.002227 
rs2015062 T7028C 0.4173 rs28397767 G12501A 0.03492 
rs2298011 A9180G 0.001815 rs28456039 A5319G 0.003079 
rs28575684 T9647C 0.000352 rs28502681 G8572A 0.001884 
rs41502750 T9716C 0.01966 rs2853512 G16153A 0.005829 
rs28411821 T9824C 0.000217 rs2853515 G263A 0.0105 
rs3902407 T9833C 0.000462 rs56489998 A663G 0.003148 
rs3134801 T9950C 0.002839 rs1029294 C6473T 0.002075 
rs41347846 T10034C 0.02583 rs1116904 G8027A 0.004107 
rs28358275 T10238C 0.03533 rs2298009 A9120G 0.001955 
rs28358277 G10373A 0.000448 rs28357672 T14212C 0.004481 
rs28358281 G10586A 0.001663 rs28357676 G14560A 1.36E-05 
rs2853490 G11176A 0.002336 rs28357683 C14911T 0.000149 
rs3915952 A11251G 0.1959 rs28358581 C2789T 0.001259 
rs28358285 T11299C 0.0911 rs28358887 G8994A 0.02233 
rs2853493 A11467G 0.2327 rs28359183 C13914A 0.000354 
rs2853494 A11641G 0.000895 rs28445709 T7084C 2.71E-05 
rs2853495 A11719G 0.4705 rs28462217 A9389G 0.000325 
rs2853497 G12007A 0.01651 rs2853505 G14861A 0.002787 
rs28359170 G12236A 0.000988 rs2854134 C3594T 0.00339 
rs2853499 G12372A 0.2361 rs28558945 C2415T 1.35E-05 
rs28359172 A12612G 0.09561 rs2857287 C13506T 0.001449 
rs3926883 C12633A 0.02391 rs28591518 A12768G 0.00019 
rs28359173 A12693G 0.001477 rs28690056 T9909C 9.49E-05 
rs2854122 C12705T 0.08524 rs28709356 C10733A 0.002226 
rs3899498 G13368A 0.1024 rs28718242 T11899C 0.002501 
rs28359177 G13590A 0.006178 rs3902406 A6461G 0.000801 
rs2853503 T13617C 0.07729 rs3928312 A2833G 0.000231 
rs28359178 G13708A 0.1108 rs41369547 C12669T 9.49E-05 
rs41421644 T13734C 0.01235 rs41427749 G8616T 0.006364 
rs41509754 T13965C 0.01926 rs41534744 G16129A 0.08603 
rs41535848 A13966G 0.0194 rs28357682 G14905A 0.1021 
rs28357673 C14284T 0.000339 rs28357684 G15043A 0.04452 
rs28357681 T14798C 0.1602 rs28357372 A15607G 0.1011 
View Large

For each subject, a mitochondrial group variant list was defined on the basis of the differences from the Cambridge Reference Sequence (6). Each subject's set of mtSNPs was imported into MITOMASTER, an online analytic system that permits the automatic evaluation of mtDNA variants for assignment into haplogroups, assigning a single haplogroup to each subject. Haplogroup H, the most common, was used as the reference group.

Logistic regression analysis was performed to assess association between cSCC susceptibility risk and mitochondrial haplogroups. We used Eigenstrat (7) to calculate ancestry principal components (PC), which are essential to incorporate into any analysis of mitochondrial variation, because mitochondrial variation is, by definition, an ancestry informative marker, and failing to account for ancestry can lead to false positive associations (8). We included the top 10 ancestry PCs, a covariate for Ashkenazi Jewish ancestry, age, and sex as covariates in models. Analyses were performed using SAS version 9.3.

Women were more highly represented in the cohort, (n = 39,117; 57.6%), but the prevalence of cSCC cases was higher in men (15.4% in men vs. 8.4% in women). Nine common mtDNA haplogroups (frequency ≥1%) were identified in addition to the most common haplogroup, H (reference group). No associations with cSCC risk were observed overall. Stratified analysis by sex did not reveal a significant association in women or men (Table 2).

Table 2.

Association of cSCC risk and mtDNA haplogroups in GERA non-Hispanic white subjects overall and stratified by sex

AllMenWomen
HaplogroupCase/control %OR (95% CI)PCase/control %OR (95% CI)PCase/control %ORP
A <1% 0.58 (0.31–1.07) 0.08 <1% 0.73 (0.35–1.52) 0.40 <1% 0.36 (0.11–1.17) 0.09 
B <1% 0.58 (0.26–1.28) 0.18 <1% 0.80 (0.31–2.09) 0.65 <1% 0.17 (0.02–1.25) 0.08 
C <1% 0.78 (0.39–1.58) 0.49 <1% 0.57 (0.20–1.64) 0.30 <1% 1.10 (0.42–2.87) 0.84 
D <1% 1.27 (0.61–2.62) 0.53 <1% 1.82 (0.76–4.35) 0.18 <1% 0.64 (0.15–2.74) 0.55 
HV <1% 0.88 (0.63–1.23) 0.44 <1% 0.87 (0.55–1.38) 0.55 <1% 0.88 (0.54–1.43) 0.59 
I 2.81/2.61 1.03 (0.87–1.22) 0.71 2.88/2.56 1.15 (0.91–1.45) 0.24 2.66/2.64 0.91 (0.71–1.17) 0.46 
J 10.57/9.61 1.10 (1.00–1.21) 0.051 10.70/9.57 1.12 (0.98–1.28) 0.10 10.43/9.62 1.08 (0.94–1.25) 0.28 
JT <1% 2.10 (0.49–8.99) 0.32 <1% 4.41 (0.22–88.79) 0.33 <1% 1.64 (0.30–9.07) 0.57 
K 9.50/9.59 1.01 (0.91–1.11) 0.92 9.34/9.93 1.01 (0.87–1.16) 0.95 9.66/9.36 1.00 (0.86–1.16) 0.99 
L <1% 0.81 (0.49–1.35) 0.42 <1% 0.72 (0.35–1.47) 0.36 <1% 0.92 (0.45–1.86) 0.81 
M <1% 0.69 (0.40–1.20) 0.19 <1% 0.80 (0.38–1.66) 0.54 <1% 0.59 (0.25–1.36) 0.21 
N 18.55/18.17 1.02 (0.94–1.11) 0.56 18.42/18.11 1.05 (0.94–1.18) 0.37 18.72/18.22 1.00 (0.89–1.12) 0.93 
P <1% 1.74 (0.46–6.61) 0.42 <1% 3.39 (0.52–22.15) 0.20 <1% 0.91 (0.11–7.59) 0.93 
R 4.57/5.01 0.95 (0.83–1.08) 0.42 4.68/4.97 0.98 (0.82–1.18) 0.82 4.43/5.03 0.91 (0.751.10) 0.33 
T 10.09/10.35 0.96 (0.87–1.06) 0.44 10.07/10.32 0.97 (0.84–1.11) 0.63 10.11/10.38 0.96 (0.83–1.10) 0.53 
U 14.18/14.64 0.95 (0.87–1.03) 0.20 14.40/14.80 0.96 (0.85–1.08) 0.47 13.93/14.53 0.94 (0.82–1.06) 0.31 
V <1% 0.90 (0.47–1.72) 0.74 <1% 0.96 (0.39–2.34) 0.92 <1% 0.85 (0.33–2.19) 0.74 
W 1.78/1.79 1.00 (0.81–1.22) 0.96 1.90/1.86 1.14 (0.87–1.50) 0.35 1.61/1.74 0.89 (0.65–1.21) 0.46 
X 1.44/1.53 1.00 (0.80–1.25) 0.99 1.49/1.52 1.09 (0.80–1.48) 0.59 1.38/1.54 0.93 (0.66–1.29) 0.64 
AllMenWomen
HaplogroupCase/control %OR (95% CI)PCase/control %OR (95% CI)PCase/control %ORP
A <1% 0.58 (0.31–1.07) 0.08 <1% 0.73 (0.35–1.52) 0.40 <1% 0.36 (0.11–1.17) 0.09 
B <1% 0.58 (0.26–1.28) 0.18 <1% 0.80 (0.31–2.09) 0.65 <1% 0.17 (0.02–1.25) 0.08 
C <1% 0.78 (0.39–1.58) 0.49 <1% 0.57 (0.20–1.64) 0.30 <1% 1.10 (0.42–2.87) 0.84 
D <1% 1.27 (0.61–2.62) 0.53 <1% 1.82 (0.76–4.35) 0.18 <1% 0.64 (0.15–2.74) 0.55 
HV <1% 0.88 (0.63–1.23) 0.44 <1% 0.87 (0.55–1.38) 0.55 <1% 0.88 (0.54–1.43) 0.59 
I 2.81/2.61 1.03 (0.87–1.22) 0.71 2.88/2.56 1.15 (0.91–1.45) 0.24 2.66/2.64 0.91 (0.71–1.17) 0.46 
J 10.57/9.61 1.10 (1.00–1.21) 0.051 10.70/9.57 1.12 (0.98–1.28) 0.10 10.43/9.62 1.08 (0.94–1.25) 0.28 
JT <1% 2.10 (0.49–8.99) 0.32 <1% 4.41 (0.22–88.79) 0.33 <1% 1.64 (0.30–9.07) 0.57 
K 9.50/9.59 1.01 (0.91–1.11) 0.92 9.34/9.93 1.01 (0.87–1.16) 0.95 9.66/9.36 1.00 (0.86–1.16) 0.99 
L <1% 0.81 (0.49–1.35) 0.42 <1% 0.72 (0.35–1.47) 0.36 <1% 0.92 (0.45–1.86) 0.81 
M <1% 0.69 (0.40–1.20) 0.19 <1% 0.80 (0.38–1.66) 0.54 <1% 0.59 (0.25–1.36) 0.21 
N 18.55/18.17 1.02 (0.94–1.11) 0.56 18.42/18.11 1.05 (0.94–1.18) 0.37 18.72/18.22 1.00 (0.89–1.12) 0.93 
P <1% 1.74 (0.46–6.61) 0.42 <1% 3.39 (0.52–22.15) 0.20 <1% 0.91 (0.11–7.59) 0.93 
R 4.57/5.01 0.95 (0.83–1.08) 0.42 4.68/4.97 0.98 (0.82–1.18) 0.82 4.43/5.03 0.91 (0.751.10) 0.33 
T 10.09/10.35 0.96 (0.87–1.06) 0.44 10.07/10.32 0.97 (0.84–1.11) 0.63 10.11/10.38 0.96 (0.83–1.10) 0.53 
U 14.18/14.64 0.95 (0.87–1.03) 0.20 14.40/14.80 0.96 (0.85–1.08) 0.47 13.93/14.53 0.94 (0.82–1.06) 0.31 
V <1% 0.90 (0.47–1.72) 0.74 <1% 0.96 (0.39–2.34) 0.92 <1% 0.85 (0.33–2.19) 0.74 
W 1.78/1.79 1.00 (0.81–1.22) 0.96 1.90/1.86 1.14 (0.87–1.50) 0.35 1.61/1.74 0.89 (0.65–1.21) 0.46 
X 1.44/1.53 1.00 (0.80–1.25) 0.99 1.49/1.52 1.09 (0.80–1.48) 0.59 1.38/1.54 0.93 (0.66–1.29) 0.64 
View Large

We observed a higher proportion of cSCC cases in men compared with women, consistent with previous reports. We found no evidence of association between mtDNA haplogroups and cSCC overall or when stratifying by sex, and previous genetic association studies did not find sex differences in genetic effects of associated loci. Our study was well powered to detect effects of common mitochondrial haplogroups on cSCC susceptibility with statistical significance.

Some of the sex-specific variation in cSCC incidence could be due to differential exposure to environmental factors, such as sun exposure or behavioral factors such as smoking. Epidemiologic studies have highlighted that men have more frequent sun exposure compared with women, and often with less sun protection and also higher men's tobacco smoking prevalence rates. There may also be differences in intrinsic susceptibility of keratinocytes, as more recent studies using in vivo animal models have demonstrated a sex-specific biological response in UVB-induced skin carcinogenesis, and in particular cSCC. Some of the innate susceptibility may be estrogen mediated. Exploring the contribution of innate versus environmental risk factors to sex-specific variation in cSCC risk would be particularly informative.

We did not observe a significant association of any mitochondrial haplogroups with cSCC susceptibility and conclude that common mitochondrial variation in non-Hispanic whites is not predictive of cSCC risk. Further investigations will be needed to identify the risk factors contributing to the sex-specific variability in cSCC susceptibility. Moreover, it is known that men have more clinically aggressive cSCC than women, so future studies investigating environmental and genetic modifiers in cSCC aggressiveness might be of particular interest. Such future studies could shed light on the significant phenotypic heterogeneity (e.g., tumor multiplicity, burden, grade, and localization) of this common skin cancer and provide insight into the natural history and pathophysiology of cSCC. Better understanding the specific genetic mechanisms underlying cSCC susceptibility will be important for targeted prevention and treatment efforts.

M.M. Asgari reports receiving commercial research grants from Pfizer and Valeant. No potential conflicts of interest were disclosed by the other authors.

The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Conception and design: H. Choquet, M.M. Asgari

Development of methodology: M.M. Asgari

Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): M.M. Asgari

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): E. Jorgenson, H. Choquet, J. Yin

Writing, review, and/or revision of the manuscript: E. Jorgenson, H. Choquet, M.M. Asgari

Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): E. Jorgenson, J. Yin

Study supervision: M.M. Asgari

This study was supported by a grant from the NCI at the NIH (R01CA166672 to M.M. Asgari) and the National Eye Institute (R01 EY027004 to E. Jorgenson).

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.

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©2018 American Association for Cancer Research.
2018
American Association for Cancer Research.