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Melanoma risk in association with serum leptin levels and lifestyle parameters: a case–control study
original article
Annals of Oncology 19: 384–389, 2008 doi:10.1093/annonc/mdm464 Published online 8 October 2007
Melanoma risk in association with serum leptin levels and lifestyle parameters: a case–control study H. Gogas1, M. Trakatelli2, N. Dessypris3, A. Terzidis3, A. Katsambas4, G. P. Chrousos5 & E. T. Petridou3,6*
Received 17 May 2007; revised 2 August 2007; accepted 25 August 2007
original article
Background: Solar radiation has been identified as a principal factor for the causation of melanoma, whereas changing lifestyle patterns associated with obesity and diabetes might also contribute to the increasing incidence of the malignancy. No study has investigated the role of leptin, a hormone whose levels increase in obesity and which has also been related to cancer. Patients and methods: Fifty-five patients with incident melanomas and 165 age- and gender-matched healthy controls were interviewed on the basis of a questionnaire that covers phenotypic features, sociodemographic and medical history variables, lifestyle habits and frequency of consumption of major food groups. Anthropometrical measures were also recorded and blood samples were obtained for determination of serum leptin levels. Adjusted odds ratios (ORs) for melanoma risk were derived through multiple logistic regression analyses. Results: An excess melanoma risk was observed for sun sensitive individuals and those with high circulating levels of leptin (OR: 1.56, 95% confidence interval 1.07–2.28, P = 0.02), after controlling for obesity indices, diabetes mellitus and education. Increased physical exercise, lower alcohol consumption and plant food consumption seem to play a protective role against melanoma development. Conclusions: Melanoma risk was found to be positively associated with serum leptin levels and inversely with healthy lifestyle factors. The findings need to be confirmed in prospective studies. Key words: alcohol, diet, exercise, leptin, melanoma
introduction The incidence of malignant melanoma in Caucasian individuals has been increasing worldwide making melanoma the most rapidly increasing cancer in white populations except for lung cancer among women [1]. Only in Europe, the annual death toll is about 15 000, citizens, whereas the newly diagnosed melanoma cases reach a total of 60 000 [2]. The ‘sensitive’ skin phototype (fair skin, tendency to burn and an inability to tan), a prominent mole pattern, the presence of dysplastic nevi, a family history of melanoma and immunosuppression are established risk factors [2–5]. The role of diet has also been explored in several studies but the findings have been inconsistent. Specifically, high intake of specific agents, such as antioxidants and retinoid-rich food has been linked to a protective effect against melanoma *Correspondence to: Prof. E. T. Petridou, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens, School of Medicine, 75 Mikras Asias Str, Goudi, Athens 115 27, Greece. Tel: +30-210-746-2187; Fax: +30-210-746-2105; E-mail: [email protected]
development. Similar associations have been found with higher blood levels of a-tocopherol, b-carotene and retinol, as well as with greater dietary intakes of vitamin E and b-carotene in several case–control studies [6–8], but have not been confirmed in others [9, 10]. In two prospective studies on diet and melanoma, no association was found for carotenoids, or vitamins [11, 12], although in one of the two, an increased risk of melanoma was demonstrated with increasing intake of food derived vitamin C. As with other types of human cancer, increased consumption of alcohol increases the risk of melanoma although the exact pathophysiologic mechanisms remain unclear [6–10, 13]. Anthropometrical measures, such as height, weight and body mass index (BMI), have been associated with an increased risk of several malignancies, including melanoma [14–16], while, in at least once case–control study, exercise appeared to have a protective effect against melanoma development [17]. Leptin, a hormone secreted by adipose tissue, controls food intake and energy balance by providing signals to the
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1 First Department of Internal Medicine, Laiko Hospital, Athens University Medical School, Athens; 2Department of Dermatology, Aristotle School of Medicine, Thessaloniki; 3Department of Hygiene, Epidemiology and Medical Statistics, Athens University Medical School, Athens; 4Department of Dermatology, University of Athens Medical School, Athens; 5First Department of Pediatrics, Athens University Medical School , Athens, Greece; 6Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA
original article
Annals of Oncology
patients and methods The 60 newly diagnosed cases of histologically confirmed malignant melanoma recruited in the study were referred for treatment (adjuvant therapy or chemotherapy) from the Greater Metropolitan area at the Oncology Department of Laikon General Hospital, University of Athens, Greece, as previously described [25]. Refusal rates were minimal (8%). None of the cases reported suffering from any other type of cancer and the staging according to the American Joint Committee on Cancer system was: stage II (eight cases); stage IIa (five cases); stage IIb (six cases); stage III (27 cases); stage IV (nine cases). The distribution of Breslow thickness was as follows: £1.00 mm two cases, 1.01–2.00 mm (seven cases), 2.01–4.00 mm (19 cases), >4.00 mm (11 cases) and nonavailable (16 cases). Twenty-five cases had superficial spreading melanoma, 13 cases nodular melanoma, one case acral lentiginous melanoma and 16 cases histological type was not available. For each melanoma patient, three presumably healthy, eligible controls (a total of 165), matched for gender, age (65 years) and place of residence were recruited among residents of the Athens metropolitan area among those participating in routine health screening examination [26]. Four potential controls refused or were unable to collaborate and were properly substituted for a total of 165 matched control subjects. According to the study protocol, approved by the University of Athens Medical School Ethics Committee, all participants provided informed consent. All study subjects were interviewed for 30 min by one of four trained interviewers and information pertaining to sociodemographic, anthropometrical, lifestyle and medical history variables was recorded along with skin type, hair and eye color characteristics. Skin sensitivity was grouped into two categories, the first comprising Fitzpatrick’s I and II phototypes (very fair skin, always burns, never tans and fair skin easily burns and difficultly tans) and the second corresponding to Fitzpatrick’s phototypes III and IV (moderately sun sensitive and barely sun sensitive, respectively) [27]. Eventually, a sun sensitivity score was computed, comprising the sum of values for: (i) skin type, (0 = burns some times and finally tans or rarely burns and easily tans, 1 = always/easily burns and never/difficult tans); (ii) hair color (0 = black/brown, 1 = blond/red) and (iii) eye color (0 = brown/black, 1 = blue/green). Thus, the score ranged from zero (very resistant) to three (very sensitive). Anthropometrical variables were measured by the trained interviewers (height, with subjects wearing no shoes; weight, waist and hip circumference, with subjects
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wearing no clothes), whereas, the reported two month before diagnosis weight was also recorded. The physical exercise has been derived from the sum of the total reported time spent in walking, gymnastics, jogging, swimming and ‘other sports’ participation. A condensed version of an extended questionnaire comprising items related to the consumption of the basic food groups in a variation of the scheme recommended by Davidson and Passmore [28], validated and regularly used in nutritional epidemiological studies in Greece [29, 30] provided information on dietary patterns. For the purposes of this study, cereals and starchy roots; sugars and syrups; pulses, nuts and seeds; vegetables and fruits comprised the plant foods category, whereas meat and meat products, fish and seafood, milk and dairy products comprised the animal foods category. Morning blood samples were taken from all cases and controls for hormonal measurements and for the determination of blood glucose concentrations. All coded samples were centrifuged and stored at 270C with a similar average preservation time for cases and controls, although leptin levels are not usually altered by storage time [31]. The samples, blinded as to case–control status, were air shipped with dry ice in one batch to the Beth Israel Deaconess Medical Center, in Boston USA. Serum leptin determinations were carried out by trained technicians using a commercially available radioimmunoassay with a sensitivity of 0.5 ng/ml and intra-assay coefficient of variation of 8.3% [31]. For the statistical analyses, representative values [mean, standard deviation (SD) and percentiles] of serum leptin levels and of anthropometrical variables were calculated among cases and controls. Pearson correlation coefficients were then calculated in order to examine the associations of serum leptin with age as well as the somatometric variables among healthy controls. To study the association of leptin with melanoma, we modeled the data through multiple conditional logistic regression analysis using case–control as the outcome variable and leptin (in increments of one SD of the hormone among controls), controlling for a series of covariates and lifestyle factors, namely: BMI 2 months before onset of symptoms (in 2 kg/m2 increments), waist to hip ratio (in 20% increment), the sun sensitivity score (in four categories ordered), education (in three categories, ordered), physical exercise (in 30 min increments), alcohol consumption (up to one glass per day or more), smoking habit (yes or ex-smoker/never ) and the self-reported diabetes mellitus or result of glucose analysis in fasting morning blood sample over 124 mg/dl (yes/no). For the analysis of the dietary data, representative values (mean, SD and percentiles) of the two principal food groups were calculated among cases and controls and the t-test was used to assess the direction and the statistical significance of the association between the consumption of the food groups and melanoma risk. Adjustment for the previously described core variables was accomplished by modeling the data through conditional logistic regression, whereas additionally introduced variables in the model were intakes of the two principal food groups added in quintiles, ordered. The SAS statistical package was used in all analyses [32].
results The age range among cases was 23–88 years with a mean value of 52.7 years whereas among controls the respective figures were 23–87 years with a mean value of 53.2 years. Females comprised 42% of the matched study sample. In Table 1, data for the cohort of 55 melanoma patients and their 165 matched controls distributed by sun sensitivity score, lifestyle variables and medical history are presented. These data serve mostly descriptive purposes and are not
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hypothalamus [18]. Serum levels of leptin are positively related with body composition and insulin levels, female sex and alcohol consumption and inversely related to cigarette smoking [19–21]. Increased plasma levels of leptin have been associated with obesity and some types of cancer, including breast and endometrial cancer [22–24]. No previous study, however, has explored whether serum leptin is associated with melanoma. Greece provides a unique opportunity to study the role of lifestyle factors in developing melanoma, given that the country experiences relatively low incidence of this malignancy, despite high annual sunshine levels and a relatively high adherence to the Mediterranean lifestyle. In particular, we sought to investigate the relations between melanoma and a series of potentially modifiable risk factors, such as groups of nutrient intakes, alcohol consumption, and physical exercise and leptin, thought of as a biochemical expression of disturbed metabolism.
original article
Annals of Oncology
Table 1. Distribution of 55 cases of melanoma and 165 age- and gender-matched controls by personal characteristics, demographic, lifestyle and medical history variables Variable
%
24 24 7
43.7 43.7 12.6
70 72 23
42.4 43.7 13.9
23 14 9 9
41.8 25.4 16.4 16.4
105 37 14 9
63.6 22.4 8.5 5.5
3 22 30
5.5 40.0 54.5
14 70 81
8.5 42.4 49.1
16 11 15 9 4
29.1 20.0 27.2 16.4 7.3
18 50 35 26 36
10.9 30.3 21.2 15.8 21.8
16 39
29.1 70.9
30 135
18.2 81.8
36 19
65.5 34.5
103 62
62.4 37.6
8 47
14.5 85.5
13 152
7.9 92.1
% matched variable
0.001*
0.39*
0.009*
0.08**
0.69**
0.14**
a
Sum of values for: a. skin type, (0 = burns some times and finally tans or rarely burns and easily tans, 1 = always/easily burns and never/difficult tans); b. hair color (0 = black/brown, 1 = blond/red) and c. eye color (0 = brown/black, 1 = blue/green).
directly interpretable because of mutual confounding. However, they reveal an established host risk profile for the malignancy under investigation with melanoma patients having statistically significantly higher sun sensitivity scores and reporting less frequent exercise patterns compared with their controls. There is also a suggestion of marginal statistical significance that those with a history of increased alcohol consumption are at higher risk for melanoma, whereas the positive association with diabetes is far from being statistically significant. Table 2 shows representative values of serum leptin levels, somatometrics and food groups variables by case–control status. Interestingly, mean serum levels of leptin were found to be positively and statistically significantly associated with melanoma risk, whereas practically no crude measurements of obesity or central obesity showed such an association in this study sample, apart from hip circumference. The mean serum leptin levels varied among melanoma stages but there was no statistical significant difference when comparing across different stages. With regards to the studied food groups, overall plant food consumption was inversely and statistically significantly
386 | Gogas et al.
associated with the disease, whereas overall animal food consumption showed a statistically significant positive association with melanoma risk. Again, these results may not be directly interpretable because of the possibility of mutual confounding. Pearson correlation coefficients were then calculated in order to examine the associations of serum leptin with somatometric variables as well as age among healthy controls. Leptin was positively correlated with obesity, especially central obesity, as expected [22]. In Table 3, the variables indicated in Tables 1 and 2 are mutually adjusted for by modeling data through conditional logistic regression. As expected, intrinsic factors, namely sun sensitivity related variables are positively associated with melanoma risk and so is the robust association of the disease with leptin [odds ratio (OR) = 1.56, P = 0.02]. No association with crude measures of obesity was evident; subjects suffering from diabetes, a mostly obesity related disease, appear however to be at substantially higher risk (OR: 3.33), although the association does not reach nominally statistical significance (P = 0.06). On the contrary, modifiable risk factors, namely increased physical exercise, lower alcohol consumption and a food intake pattern overall
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Age <50 years 50–69 70+ Sun sensitivity scorea 0 (very resistant) 1 (resistant) 2 (sensitive) 3 (very sensitive) Education <6 years 6–11 12+ Physical exercise 0 min/day 1–29 30–59 60–89 90+ Alcohol consumption 32+ 0–31 (glasses/month) Smoking Yes/ex-smoker No Diabetes Yes No
Controls N
P value v2 for trend*/contrast**
Cases N
original article
Annals of Oncology
Table 2. Representative values of serum leptin levels, anthropometrical measurements and food groups consumption by case–control status Variable
N
Minimum value
Media n
75%
Maximum value
Standard deviation
Mean
P value t-test 0.003
5.4
8.9
17.1
45.6
9.35
12.2
6.0 10.1 5.2 5.8 3.7 3.4
8.4 13.2 6.2 11.4 5.3 5.5
14.6 17.4 23.9 16.1 6.2 9.9
24.7 20.3 45.6 34.9 19.2 60.8
7.34 5.00 16.78 9.25 6.19 7.42
11.0 13.8 15.0 13.1 7.4 7.9 0.92
25.2 24.6
26.8 26.5
29.4 29.7
91 88
96 94
102 103
102 98
109 103
112 110
37.1 45.0
3.60 4.41
27.2 27.1
117 148
10.36 13.71
96.3 94.8
133 140
8.00 11.05
107.4 104.0
108.9 138.2
8.94 10.62
89.8 91.4
288 408.5
51.37 69.22
118.2 163.3
0.0001
190 211
34.37 32.18
77.0 62.3
0.004
0.42
0.01
0.32 85.0 84.3
82 116
92.1 92.9
95.8 97.6
114 146
139 204
73 57
98 79
54.5 40
Table 3. Conditional logistic regression derived, mutually adjusted ORs and 95% CIs for melanoma by serum leptin and study covariates Variable
Category or increment
OR
95% CI
Leptin BMI before illness Waist to hip ratio Sun sensitivity score Education Physical exercise Alcohol consumption
One SD among controls 2 kg/m2 more 20% more One level more One level more 30 min more per day Up to one glass per day More No Yes/ex-smoker No Yes
1.56 0.97 0.79 1.60 1.47 0.70 Baseline 2.45 Baseline 0.99 Baseline 3.33
1.07 0.65 0.55 1.11 0.79 0.51
2.28 1.45 1.14 2.32 2.74 0.94
0.02 0.89 0.20 0.01 0.22 0.02
1.00
6.13
0.05
0.44
2.21
0.98
0.96
11.64
0.06
One quintile more One quintile more
0.49 2.28
0.34 1.52
0.71 3.43
Smoking Diabetes Additionally introduced variables Plant food monthly consumption Animal food monthly consumption
P value
0.0002 0.0001
OR, odds ratio; CI, confidence interval; BMI, body mass index; SD, standard deviation.
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Leptin (ng/ml) Cases 55 1.4 Stage II 8 5.1 IIa 5 8.3 IIb 6 3.2 III 27 1.4 IV 9 2.9 Controls 165 1.4 Anthropometrical measurements BMI two months before diagnosis (kg/m2) Cases 55 20.8 Controls 165 18.0 Waist circumference (cm) Cases 55 71 Controls 165 64 Hip circumference (cm) Cases 55 87 Controls 165 68 Waist/Hip ratio (%) Cases 55 64.6 Controls 165 64.8 Monthly food groups consumption (portions) Plant foods Cases 55 16 Controls 165 45 Animal foods Cases 55 12 Controls 165 11
25%
original article adhering to the healthy Mediterranean diet seem to play a protective role against melanoma development.
discussion
388 | Gogas et al.
the catecholamines and prostagladins [43]. Importantly, some of these factors have been associated with neoplastic processes. Increased levels of circulating leptin have been reported in several cancers associated with obesity [22–24, 44], in particular, breast, endometrial and colorectal cancer. In this study, mean serum levels of leptin were associated with melanoma risk but not with obesity. The apparent discrepancy may be due to the fact that BMI and adipose tissue may not be one and the same. In the context of cancer, leptin has some interesting relations with neoplasms and may have direct oncogenic properties. Thus, leptin expression can be induced under hypoxic conditions, which often occur in solid tumors [45]. Also, leptin regulates neoangiogenesis by itself and in concert with vascular endothelial growth factor and fibroblast growth factor-2 [46]. In addition, this hormone enhances endothelial cell growth [46] and suppresses apoptosis through a bcl-2-dependent mechanism [47]. Leptin also acts as a mitogen or as a migration-inducing factor for many different cell types, including smooth muscle cells [48], normal and neoplastic colon cells [49] and normal and malignant mammary epithelial cells [50]. This is the first study to explore the role of leptin in melanoma development. Even though it is relatively small, this study confirmed the well-established strong association with sun exposure—also found with principal proxies of exposure—and the lifestyle factor-related associations. This indicates that the positive association of melanomas with leptin levels observed might not be a random finding. Additionally, our earlier results of melanoma association with serum adiponectin concentrations in the same patient population are in concert and reinforce the current observation [25], whereas after controlling also for serum adiponectin in the present analyses, the statistical models remained robust with regards to the positive association of melanoma with leptin. However, as it has been previously published [51] limitations and biases cannot be thoroughly ruled out. In conclusion, melanoma was found to be positively associated with leptin and inversely with healthy lifestyle factors, such as physical exercise, low alcohol consumption and a food intake pattern overall adhering to the Mediterranean diet. Prospective studies are warranted, however, to fully elucidate the underlying pathophysiologic mechanisms and the role of the above factors in predicting future risk of melanoma in humans.
funding University of Athens.
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This case–control study confirms the previously reported positive association of sensitive skin type and fair eye color with melanoma risk in a population exposed rather constantly to high annual sunshine levels. The association of sun exposure with melanoma has been well established in epidemiological studies with the risk being higher in individuals with a ‘sensitive’ skin phototype, especially among those who had sustained intermittent sun exposure [2–5]. The relatively low proportion of individuals with sensitive skin types among those residing in countries of the Mediterranean basin, such as Greece, along with climatic conditions offering constant daily sunshine may provide some explanation regarding the rather low incidence of melanoma in this part of the world [33]. Sun exposure, however, is not the sole risk factor for developing melanoma and several recent studies have explored the association of the disease with diet, alcohol intake and somatometric variables. Indeed, an excess melanoma risk was observed with high alcohol intake, which is consistent with findings reported in most [6–8, 10, 14], but not all [11, 34] previous case–control studies. A dietary pattern high in cereal, starchy roots, pulses, nuts, seeds and vegetables was inversely associated with melanoma risk. In a recently published study from Italy, however, no appreciable association of melanoma risk with selected food items, including fish, meat, vegetables, fruit, dairy products, whole meal bread, coffee and tea drinking was found [9]. Lastly, earlier studies showed a strong inverse relation between high intakes of polyunsaturated fatty acids [7, 35], but this was not confirmed by others [12]. No association in somatometrics was found in a large occupational cohort, comprising 68 588 subjects [14] and practically no difference was noted between cases and controls in the current study. That was not the case, however, both in studies from the USA and Norway and in another Mediterranean country (Italy), where BMI was significantly related to melanoma risk [11, 15–17]. On the contrary, routine exercise seems to be a protective factor against melanoma development and this result is consistent with previous findings reporting that exercising 5–7 days per week decreased the risk of melanoma [17]. Following several reports for other types of malignancies related with obesity [22], we principally aimed to study the possible role of leptin, a cytokine that is elevated in obese individuals. Leptin is an important regulator of energy balance, and in adult animals, leptin messenger RNA was primarily detected in white and brown adipose tissue [36]. Subsequent studies documented that in addition to its primary function as a regulator of food intake, leptin can affect fetal development, sex maturation, lactation, hematopoiesis and the immune response [18, 37, 38]. In humans, the major factor influencing plasma leptin concentrations is adipose tissue mass [22]. The synthesis of leptin in adipocytes is influenced by several humoral factors, most notably insulin [39], tumor necrosis factor alpha [40], glucocorticoids [41], gonadal hormones [42],
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original article
Annals of Oncology 19: 384–389, 2008 doi:10.1093/annonc/mdm464 Published online 8 October 2007
Melanoma risk in association with serum leptin levels and lifestyle parameters: a case–control study H. Gogas1, M. Trakatelli2, N. Dessypris3, A. Terzidis3, A. Katsambas4, G. P. Chrousos5 & E. T. Petridou3,6*
Received 17 May 2007; revised 2 August 2007; accepted 25 August 2007
original article
Background: Solar radiation has been identified as a principal factor for the causation of melanoma, whereas changing lifestyle patterns associated with obesity and diabetes might also contribute to the increasing incidence of the malignancy. No study has investigated the role of leptin, a hormone whose levels increase in obesity and which has also been related to cancer. Patients and methods: Fifty-five patients with incident melanomas and 165 age- and gender-matched healthy controls were interviewed on the basis of a questionnaire that covers phenotypic features, sociodemographic and medical history variables, lifestyle habits and frequency of consumption of major food groups. Anthropometrical measures were also recorded and blood samples were obtained for determination of serum leptin levels. Adjusted odds ratios (ORs) for melanoma risk were derived through multiple logistic regression analyses. Results: An excess melanoma risk was observed for sun sensitive individuals and those with high circulating levels of leptin (OR: 1.56, 95% confidence interval 1.07–2.28, P = 0.02), after controlling for obesity indices, diabetes mellitus and education. Increased physical exercise, lower alcohol consumption and plant food consumption seem to play a protective role against melanoma development. Conclusions: Melanoma risk was found to be positively associated with serum leptin levels and inversely with healthy lifestyle factors. The findings need to be confirmed in prospective studies. Key words: alcohol, diet, exercise, leptin, melanoma
introduction The incidence of malignant melanoma in Caucasian individuals has been increasing worldwide making melanoma the most rapidly increasing cancer in white populations except for lung cancer among women [1]. Only in Europe, the annual death toll is about 15 000, citizens, whereas the newly diagnosed melanoma cases reach a total of 60 000 [2]. The ‘sensitive’ skin phototype (fair skin, tendency to burn and an inability to tan), a prominent mole pattern, the presence of dysplastic nevi, a family history of melanoma and immunosuppression are established risk factors [2–5]. The role of diet has also been explored in several studies but the findings have been inconsistent. Specifically, high intake of specific agents, such as antioxidants and retinoid-rich food has been linked to a protective effect against melanoma *Correspondence to: Prof. E. T. Petridou, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens, School of Medicine, 75 Mikras Asias Str, Goudi, Athens 115 27, Greece. Tel: +30-210-746-2187; Fax: +30-210-746-2105; E-mail: [email protected]
development. Similar associations have been found with higher blood levels of a-tocopherol, b-carotene and retinol, as well as with greater dietary intakes of vitamin E and b-carotene in several case–control studies [6–8], but have not been confirmed in others [9, 10]. In two prospective studies on diet and melanoma, no association was found for carotenoids, or vitamins [11, 12], although in one of the two, an increased risk of melanoma was demonstrated with increasing intake of food derived vitamin C. As with other types of human cancer, increased consumption of alcohol increases the risk of melanoma although the exact pathophysiologic mechanisms remain unclear [6–10, 13]. Anthropometrical measures, such as height, weight and body mass index (BMI), have been associated with an increased risk of several malignancies, including melanoma [14–16], while, in at least once case–control study, exercise appeared to have a protective effect against melanoma development [17]. Leptin, a hormone secreted by adipose tissue, controls food intake and energy balance by providing signals to the
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1 First Department of Internal Medicine, Laiko Hospital, Athens University Medical School, Athens; 2Department of Dermatology, Aristotle School of Medicine, Thessaloniki; 3Department of Hygiene, Epidemiology and Medical Statistics, Athens University Medical School, Athens; 4Department of Dermatology, University of Athens Medical School, Athens; 5First Department of Pediatrics, Athens University Medical School , Athens, Greece; 6Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA
original article
Annals of Oncology
patients and methods The 60 newly diagnosed cases of histologically confirmed malignant melanoma recruited in the study were referred for treatment (adjuvant therapy or chemotherapy) from the Greater Metropolitan area at the Oncology Department of Laikon General Hospital, University of Athens, Greece, as previously described [25]. Refusal rates were minimal (8%). None of the cases reported suffering from any other type of cancer and the staging according to the American Joint Committee on Cancer system was: stage II (eight cases); stage IIa (five cases); stage IIb (six cases); stage III (27 cases); stage IV (nine cases). The distribution of Breslow thickness was as follows: £1.00 mm two cases, 1.01–2.00 mm (seven cases), 2.01–4.00 mm (19 cases), >4.00 mm (11 cases) and nonavailable (16 cases). Twenty-five cases had superficial spreading melanoma, 13 cases nodular melanoma, one case acral lentiginous melanoma and 16 cases histological type was not available. For each melanoma patient, three presumably healthy, eligible controls (a total of 165), matched for gender, age (65 years) and place of residence were recruited among residents of the Athens metropolitan area among those participating in routine health screening examination [26]. Four potential controls refused or were unable to collaborate and were properly substituted for a total of 165 matched control subjects. According to the study protocol, approved by the University of Athens Medical School Ethics Committee, all participants provided informed consent. All study subjects were interviewed for 30 min by one of four trained interviewers and information pertaining to sociodemographic, anthropometrical, lifestyle and medical history variables was recorded along with skin type, hair and eye color characteristics. Skin sensitivity was grouped into two categories, the first comprising Fitzpatrick’s I and II phototypes (very fair skin, always burns, never tans and fair skin easily burns and difficultly tans) and the second corresponding to Fitzpatrick’s phototypes III and IV (moderately sun sensitive and barely sun sensitive, respectively) [27]. Eventually, a sun sensitivity score was computed, comprising the sum of values for: (i) skin type, (0 = burns some times and finally tans or rarely burns and easily tans, 1 = always/easily burns and never/difficult tans); (ii) hair color (0 = black/brown, 1 = blond/red) and (iii) eye color (0 = brown/black, 1 = blue/green). Thus, the score ranged from zero (very resistant) to three (very sensitive). Anthropometrical variables were measured by the trained interviewers (height, with subjects wearing no shoes; weight, waist and hip circumference, with subjects
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wearing no clothes), whereas, the reported two month before diagnosis weight was also recorded. The physical exercise has been derived from the sum of the total reported time spent in walking, gymnastics, jogging, swimming and ‘other sports’ participation. A condensed version of an extended questionnaire comprising items related to the consumption of the basic food groups in a variation of the scheme recommended by Davidson and Passmore [28], validated and regularly used in nutritional epidemiological studies in Greece [29, 30] provided information on dietary patterns. For the purposes of this study, cereals and starchy roots; sugars and syrups; pulses, nuts and seeds; vegetables and fruits comprised the plant foods category, whereas meat and meat products, fish and seafood, milk and dairy products comprised the animal foods category. Morning blood samples were taken from all cases and controls for hormonal measurements and for the determination of blood glucose concentrations. All coded samples were centrifuged and stored at 270C with a similar average preservation time for cases and controls, although leptin levels are not usually altered by storage time [31]. The samples, blinded as to case–control status, were air shipped with dry ice in one batch to the Beth Israel Deaconess Medical Center, in Boston USA. Serum leptin determinations were carried out by trained technicians using a commercially available radioimmunoassay with a sensitivity of 0.5 ng/ml and intra-assay coefficient of variation of 8.3% [31]. For the statistical analyses, representative values [mean, standard deviation (SD) and percentiles] of serum leptin levels and of anthropometrical variables were calculated among cases and controls. Pearson correlation coefficients were then calculated in order to examine the associations of serum leptin with age as well as the somatometric variables among healthy controls. To study the association of leptin with melanoma, we modeled the data through multiple conditional logistic regression analysis using case–control as the outcome variable and leptin (in increments of one SD of the hormone among controls), controlling for a series of covariates and lifestyle factors, namely: BMI 2 months before onset of symptoms (in 2 kg/m2 increments), waist to hip ratio (in 20% increment), the sun sensitivity score (in four categories ordered), education (in three categories, ordered), physical exercise (in 30 min increments), alcohol consumption (up to one glass per day or more), smoking habit (yes or ex-smoker/never ) and the self-reported diabetes mellitus or result of glucose analysis in fasting morning blood sample over 124 mg/dl (yes/no). For the analysis of the dietary data, representative values (mean, SD and percentiles) of the two principal food groups were calculated among cases and controls and the t-test was used to assess the direction and the statistical significance of the association between the consumption of the food groups and melanoma risk. Adjustment for the previously described core variables was accomplished by modeling the data through conditional logistic regression, whereas additionally introduced variables in the model were intakes of the two principal food groups added in quintiles, ordered. The SAS statistical package was used in all analyses [32].
results The age range among cases was 23–88 years with a mean value of 52.7 years whereas among controls the respective figures were 23–87 years with a mean value of 53.2 years. Females comprised 42% of the matched study sample. In Table 1, data for the cohort of 55 melanoma patients and their 165 matched controls distributed by sun sensitivity score, lifestyle variables and medical history are presented. These data serve mostly descriptive purposes and are not
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hypothalamus [18]. Serum levels of leptin are positively related with body composition and insulin levels, female sex and alcohol consumption and inversely related to cigarette smoking [19–21]. Increased plasma levels of leptin have been associated with obesity and some types of cancer, including breast and endometrial cancer [22–24]. No previous study, however, has explored whether serum leptin is associated with melanoma. Greece provides a unique opportunity to study the role of lifestyle factors in developing melanoma, given that the country experiences relatively low incidence of this malignancy, despite high annual sunshine levels and a relatively high adherence to the Mediterranean lifestyle. In particular, we sought to investigate the relations between melanoma and a series of potentially modifiable risk factors, such as groups of nutrient intakes, alcohol consumption, and physical exercise and leptin, thought of as a biochemical expression of disturbed metabolism.
original article
Annals of Oncology
Table 1. Distribution of 55 cases of melanoma and 165 age- and gender-matched controls by personal characteristics, demographic, lifestyle and medical history variables Variable
%
24 24 7
43.7 43.7 12.6
70 72 23
42.4 43.7 13.9
23 14 9 9
41.8 25.4 16.4 16.4
105 37 14 9
63.6 22.4 8.5 5.5
3 22 30
5.5 40.0 54.5
14 70 81
8.5 42.4 49.1
16 11 15 9 4
29.1 20.0 27.2 16.4 7.3
18 50 35 26 36
10.9 30.3 21.2 15.8 21.8
16 39
29.1 70.9
30 135
18.2 81.8
36 19
65.5 34.5
103 62
62.4 37.6
8 47
14.5 85.5
13 152
7.9 92.1
% matched variable
0.001*
0.39*
0.009*
0.08**
0.69**
0.14**
a
Sum of values for: a. skin type, (0 = burns some times and finally tans or rarely burns and easily tans, 1 = always/easily burns and never/difficult tans); b. hair color (0 = black/brown, 1 = blond/red) and c. eye color (0 = brown/black, 1 = blue/green).
directly interpretable because of mutual confounding. However, they reveal an established host risk profile for the malignancy under investigation with melanoma patients having statistically significantly higher sun sensitivity scores and reporting less frequent exercise patterns compared with their controls. There is also a suggestion of marginal statistical significance that those with a history of increased alcohol consumption are at higher risk for melanoma, whereas the positive association with diabetes is far from being statistically significant. Table 2 shows representative values of serum leptin levels, somatometrics and food groups variables by case–control status. Interestingly, mean serum levels of leptin were found to be positively and statistically significantly associated with melanoma risk, whereas practically no crude measurements of obesity or central obesity showed such an association in this study sample, apart from hip circumference. The mean serum leptin levels varied among melanoma stages but there was no statistical significant difference when comparing across different stages. With regards to the studied food groups, overall plant food consumption was inversely and statistically significantly
386 | Gogas et al.
associated with the disease, whereas overall animal food consumption showed a statistically significant positive association with melanoma risk. Again, these results may not be directly interpretable because of the possibility of mutual confounding. Pearson correlation coefficients were then calculated in order to examine the associations of serum leptin with somatometric variables as well as age among healthy controls. Leptin was positively correlated with obesity, especially central obesity, as expected [22]. In Table 3, the variables indicated in Tables 1 and 2 are mutually adjusted for by modeling data through conditional logistic regression. As expected, intrinsic factors, namely sun sensitivity related variables are positively associated with melanoma risk and so is the robust association of the disease with leptin [odds ratio (OR) = 1.56, P = 0.02]. No association with crude measures of obesity was evident; subjects suffering from diabetes, a mostly obesity related disease, appear however to be at substantially higher risk (OR: 3.33), although the association does not reach nominally statistical significance (P = 0.06). On the contrary, modifiable risk factors, namely increased physical exercise, lower alcohol consumption and a food intake pattern overall
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Age <50 years 50–69 70+ Sun sensitivity scorea 0 (very resistant) 1 (resistant) 2 (sensitive) 3 (very sensitive) Education <6 years 6–11 12+ Physical exercise 0 min/day 1–29 30–59 60–89 90+ Alcohol consumption 32+ 0–31 (glasses/month) Smoking Yes/ex-smoker No Diabetes Yes No
Controls N
P value v2 for trend*/contrast**
Cases N
original article
Annals of Oncology
Table 2. Representative values of serum leptin levels, anthropometrical measurements and food groups consumption by case–control status Variable
N
Minimum value
Media n
75%
Maximum value
Standard deviation
Mean
P value t-test 0.003
5.4
8.9
17.1
45.6
9.35
12.2
6.0 10.1 5.2 5.8 3.7 3.4
8.4 13.2 6.2 11.4 5.3 5.5
14.6 17.4 23.9 16.1 6.2 9.9
24.7 20.3 45.6 34.9 19.2 60.8
7.34 5.00 16.78 9.25 6.19 7.42
11.0 13.8 15.0 13.1 7.4 7.9 0.92
25.2 24.6
26.8 26.5
29.4 29.7
91 88
96 94
102 103
102 98
109 103
112 110
37.1 45.0
3.60 4.41
27.2 27.1
117 148
10.36 13.71
96.3 94.8
133 140
8.00 11.05
107.4 104.0
108.9 138.2
8.94 10.62
89.8 91.4
288 408.5
51.37 69.22
118.2 163.3
0.0001
190 211
34.37 32.18
77.0 62.3
0.004
0.42
0.01
0.32 85.0 84.3
82 116
92.1 92.9
95.8 97.6
114 146
139 204
73 57
98 79
54.5 40
Table 3. Conditional logistic regression derived, mutually adjusted ORs and 95% CIs for melanoma by serum leptin and study covariates Variable
Category or increment
OR
95% CI
Leptin BMI before illness Waist to hip ratio Sun sensitivity score Education Physical exercise Alcohol consumption
One SD among controls 2 kg/m2 more 20% more One level more One level more 30 min more per day Up to one glass per day More No Yes/ex-smoker No Yes
1.56 0.97 0.79 1.60 1.47 0.70 Baseline 2.45 Baseline 0.99 Baseline 3.33
1.07 0.65 0.55 1.11 0.79 0.51
2.28 1.45 1.14 2.32 2.74 0.94
0.02 0.89 0.20 0.01 0.22 0.02
1.00
6.13
0.05
0.44
2.21
0.98
0.96
11.64
0.06
One quintile more One quintile more
0.49 2.28
0.34 1.52
0.71 3.43
Smoking Diabetes Additionally introduced variables Plant food monthly consumption Animal food monthly consumption
P value
0.0002 0.0001
OR, odds ratio; CI, confidence interval; BMI, body mass index; SD, standard deviation.
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Leptin (ng/ml) Cases 55 1.4 Stage II 8 5.1 IIa 5 8.3 IIb 6 3.2 III 27 1.4 IV 9 2.9 Controls 165 1.4 Anthropometrical measurements BMI two months before diagnosis (kg/m2) Cases 55 20.8 Controls 165 18.0 Waist circumference (cm) Cases 55 71 Controls 165 64 Hip circumference (cm) Cases 55 87 Controls 165 68 Waist/Hip ratio (%) Cases 55 64.6 Controls 165 64.8 Monthly food groups consumption (portions) Plant foods Cases 55 16 Controls 165 45 Animal foods Cases 55 12 Controls 165 11
25%
original article adhering to the healthy Mediterranean diet seem to play a protective role against melanoma development.
discussion
388 | Gogas et al.
the catecholamines and prostagladins [43]. Importantly, some of these factors have been associated with neoplastic processes. Increased levels of circulating leptin have been reported in several cancers associated with obesity [22–24, 44], in particular, breast, endometrial and colorectal cancer. In this study, mean serum levels of leptin were associated with melanoma risk but not with obesity. The apparent discrepancy may be due to the fact that BMI and adipose tissue may not be one and the same. In the context of cancer, leptin has some interesting relations with neoplasms and may have direct oncogenic properties. Thus, leptin expression can be induced under hypoxic conditions, which often occur in solid tumors [45]. Also, leptin regulates neoangiogenesis by itself and in concert with vascular endothelial growth factor and fibroblast growth factor-2 [46]. In addition, this hormone enhances endothelial cell growth [46] and suppresses apoptosis through a bcl-2-dependent mechanism [47]. Leptin also acts as a mitogen or as a migration-inducing factor for many different cell types, including smooth muscle cells [48], normal and neoplastic colon cells [49] and normal and malignant mammary epithelial cells [50]. This is the first study to explore the role of leptin in melanoma development. Even though it is relatively small, this study confirmed the well-established strong association with sun exposure—also found with principal proxies of exposure—and the lifestyle factor-related associations. This indicates that the positive association of melanomas with leptin levels observed might not be a random finding. Additionally, our earlier results of melanoma association with serum adiponectin concentrations in the same patient population are in concert and reinforce the current observation [25], whereas after controlling also for serum adiponectin in the present analyses, the statistical models remained robust with regards to the positive association of melanoma with leptin. However, as it has been previously published [51] limitations and biases cannot be thoroughly ruled out. In conclusion, melanoma was found to be positively associated with leptin and inversely with healthy lifestyle factors, such as physical exercise, low alcohol consumption and a food intake pattern overall adhering to the Mediterranean diet. Prospective studies are warranted, however, to fully elucidate the underlying pathophysiologic mechanisms and the role of the above factors in predicting future risk of melanoma in humans.
funding University of Athens.
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This case–control study confirms the previously reported positive association of sensitive skin type and fair eye color with melanoma risk in a population exposed rather constantly to high annual sunshine levels. The association of sun exposure with melanoma has been well established in epidemiological studies with the risk being higher in individuals with a ‘sensitive’ skin phototype, especially among those who had sustained intermittent sun exposure [2–5]. The relatively low proportion of individuals with sensitive skin types among those residing in countries of the Mediterranean basin, such as Greece, along with climatic conditions offering constant daily sunshine may provide some explanation regarding the rather low incidence of melanoma in this part of the world [33]. Sun exposure, however, is not the sole risk factor for developing melanoma and several recent studies have explored the association of the disease with diet, alcohol intake and somatometric variables. Indeed, an excess melanoma risk was observed with high alcohol intake, which is consistent with findings reported in most [6–8, 10, 14], but not all [11, 34] previous case–control studies. A dietary pattern high in cereal, starchy roots, pulses, nuts, seeds and vegetables was inversely associated with melanoma risk. In a recently published study from Italy, however, no appreciable association of melanoma risk with selected food items, including fish, meat, vegetables, fruit, dairy products, whole meal bread, coffee and tea drinking was found [9]. Lastly, earlier studies showed a strong inverse relation between high intakes of polyunsaturated fatty acids [7, 35], but this was not confirmed by others [12]. No association in somatometrics was found in a large occupational cohort, comprising 68 588 subjects [14] and practically no difference was noted between cases and controls in the current study. That was not the case, however, both in studies from the USA and Norway and in another Mediterranean country (Italy), where BMI was significantly related to melanoma risk [11, 15–17]. On the contrary, routine exercise seems to be a protective factor against melanoma development and this result is consistent with previous findings reporting that exercising 5–7 days per week decreased the risk of melanoma [17]. Following several reports for other types of malignancies related with obesity [22], we principally aimed to study the possible role of leptin, a cytokine that is elevated in obese individuals. Leptin is an important regulator of energy balance, and in adult animals, leptin messenger RNA was primarily detected in white and brown adipose tissue [36]. Subsequent studies documented that in addition to its primary function as a regulator of food intake, leptin can affect fetal development, sex maturation, lactation, hematopoiesis and the immune response [18, 37, 38]. In humans, the major factor influencing plasma leptin concentrations is adipose tissue mass [22]. The synthesis of leptin in adipocytes is influenced by several humoral factors, most notably insulin [39], tumor necrosis factor alpha [40], glucocorticoids [41], gonadal hormones [42],
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