for the Investigators of the Melan-Cohort
Affiliations of authors: Laboratoire de Biochimie Hormonale et Génétique, Hôpital Bichat-Claude Bernard, AP-HP, Faculté de Médecine Paris VII, Paris, France (NS, RM, GB, AB, BG); Inserm U 410 Faculté de Médecine Paris VII Bichat-Claude Bernard, Paris, France (J-JL); EA 3516, Université Paris 7, Faculté de Médecine Paris VII Bichat-Claude Bernard, Paris, France (FF); Service de Dermatologie, Hôpital Bichat-Claude Bernard, Paris, AP-HP, Faculté de Médecine ParisVII, Paris, France (VD, BC); Service de Dermatologie, Hôpital Saint-Louis, AP-HP, Faculté de Médecine Paris VII, Paris, France (LO, AA, CL, NB-S); Service de Dermatologie, Hôpital Ambroise Paré, AP-HP, Faculté de Médecine Paris-Ile de France Ouest, Boulogne Billancourt, France (PS)
Correspondence to: Nadem Soufir, MD, PhD, Laboratoire de Biochimie Hormonale et Génétique, IFR02; Hopital Bichat-Claude Bernard, 46 rue Henri Huchard, 75018 Paris, France (e-mail: nadem.soufir{at}bch.ap-hop-paris.fr).
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ABSTRACT |
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The endothelin receptor B (EDNRB) is a G-protein-coupled, seven-transmembrane receptor that interacts with endothelins (EDN1, EDN2, and EDN3), multifunctional peptides involved in many cellular and physiologic processes (12). EDNRB signaling is required during embryogenesis for the migration of melanoblasts from the neural crest to the interfollicular epidermidis, retinal epithelium, and follicular hair (13) and plays a crucial role in regulating the number of progenitor melanocytes and melanocyte differentiation (14). Loss of EDNRB function is associated with several genetic diseases: Hirschsprung disease (HSCR, 600155) (15,16), Waardenburg syndrome 4 (WS4; OMIM 277580) (17), and Waardenburg-Shah syndrome (18). These diseases are characterized by major defects in the neural crest cell lineages. In addition to its role in melanocyte development, activation of the endothelin system also plays a crucial role in the skin's response to ultraviolet irradiation. EDN1, a paracrine peptide that is secreted by keratinocytes in response to UVB radiation (1921), is a ligand for EDNRB and induces proliferation of mature melanocytes and stimulates melanogenesis, producing a photoprotective effect (22).
We therefore tested the hypothesis that a germline defect of the EDNRB pathway could be associated with a genetic predisposition to melanoma. The coding sequence and intronic flanking regions of the EDNRB gene were entirely sequenced in this case control study.
Melanoma patients (n = 137) and control subjects (n = 130) were prospectively recruited between 1999 and 2004 by the Dermatology Departments of the Bichat Claude-Bernard, the Percy, the Ambroise Paré, and the Saint-Louis Hospitals in Paris. The study population consisted of patients aged 2080 years with histologically confirmed MM. Twenty-nine of the patients had at least one relative with melanoma, but none harbored a CDKN2A or a CDK4 germline mutation. The control group was extended from the one previously described (23) and was composed of individuals who had no personal or family history of skin cancer, were in the same age range, and were referred by the same departments and hospitals as the MM patients. The birthplaces of the parents and grandparents were recorded to ensure that all patients and control subjects were of Caucasian origin. The Hospital Medical Ethics Committee (CCPPRB) approved the study protocol. Informed consent was obtained from all patients and control subjects enrolled in the study.
The clinical characteristics of the MM patients and control subjects are summarized in Table 1. The strongest risk factors identified for MM were a mole count of >50 (P<.001), the presence of an atypical mole syndrome (P<.001), fair skin color (P<.001), and having dorsal lentigines (P<.001). Other pigmentation characteristics (light-colored eyes and hair, as well as skin type I or II) were not associated with MM risk. In addition, the presence of MC1R functional variants was strongly associated with MM risk (for the presence of one variant, odds ratio [OR] = 2.94, 95% confidence interval [CI] = 1.73 to 5.02, and for two variants, OR = 8.88, 95% CI = 3.19 to 24.67).
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None of the patients or control subjects carrying EDNRB variants displayed any symptoms of HSCR or gross hypopigmentation disorders. However, the presence of nonsynonymous EDNRB variants was statistically associated with skin type I/II in melanoma patients (P = .007), although no effect on any other pigmentation characteristics could be detected. Multiple logistic regression analysis was performed on each skin type group separately. In the skin type I/II group, the association between EDNRB variants and melanoma risk remained statistically significant (OR = 19.9, 95% CI = 1.34 to 296.21; P = .030) (Table 4), suggesting that EDNRB variants may modulate MM risk independently of pigmentation characteristics and MC1R variants.
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One possible hypothesis for the association between loss of EDNRB function and risk of MM is that a defect in EDNRB signaling could prevent melanoblasts from achieving differentiation, thus increasing the risk of their transformation into a malignant melanoma. Second, individuals with EDNRB mutations may have had fewer melanocyteseven though this was not clinically apparentwhich may make them constitutively less well protected against UV radiation. Similarly, mutant EDNRB may be less effective than the wild-type receptor in inducing an efficient response by mature melanocytes to UV radiation (via EDN1). However, the association of EDNRB variants with MM risk persisted after stratification for skin type, suggesting that the role of EDNRB variants may, at least in part, involve a pigmentation-independent mechanism.
Finally, EDNRB itself may have an important role in the pathogenesis of MM. EDNRB is widely expressed in melanocytes but downregulated in melanoma cells, possibly being related to malignancy or apoptosis (3234), suggesting that inactivating mutations of EDNRB could contribute to tumor progression.
The overall EDNRB mutational rate is reported to be 4.15% in familial and sporadic cases of HSCR disease (16,3548). However, the presence of the predisposing variant is neither necessary nor sufficient for the disease to be expressed, and genetic interactions between several loci have been demonstrated (4952).
A similar model may also apply to the genetic predisposition for melanoma, a disease with both familial and sporadic forms. Various combinations of hypomorphic alleles at different loci, including CDKN2A, EDNRB, and MC1R, may contribute to susceptibility to the disease. It will be interesting to find out whether interactions between EDNRB and other loci contribute to melanoma predisposition.
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NOTES |
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VD, BC, LO, AA, CL, NB-S, and PS contributed equally to this work.
This work was supported by grants from contract grant sponsor L'Assistance Publique des Hôpitaux de Paris (AP-HP, number CRC00128) and from La Société Française de Dermatologie (SFD).
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Manuscript received January 25, 2005; revised May 24, 2005; accepted July 6, 2005.
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