ABSTRACT Background Cutaneous melanoma is a potentially lethal cancer for which incidence rates have risen dramatically in white-skinned populations worldwide over the past decades. While some risk factors for melanoma have been clearly established, such as pigmentary characteristics, sun exposure, and familial history of the disease, emerging evidence suggests that other factors, such as hormonal and genetic factors, may play a role in the aetiology of this cancer. The present work aimed at 1) examining the relationships between hormonal factors, benign gynaecological conditions, and the risk of melanoma, and 2) to explore shared risk factors for endometriosis and melanoma in a large French prospective cohort; and 3) to study the potential associations between novel naevus-associated gene variants and the risk of melanoma in a large Australian population-based study. Methods The E3N prospective cohort includes 98,995 French women insured by a national scheme mostly covering teachers, and aged 40-65 years at inclusion. Women were followed-up approximately every two years starting in 1990 through self-administered questionnaires. A first investigation focused on the potential association between a personal history of endometriosis or of other benign gynaecological conditions and the risk of melanoma, which was examined in the E3N cohort using Cox proportional hazards regression models. A second study explored the potential relationships between cutaneous phenotypic factors associated with melanoma and the risk of endometriosis in the E3N cohort, using unconditional logistic regression models. A third investigation used data from the Q-MEGA (an Australian study that followed-up four population-based samples of melanoma patients in Queensland, diagnosed between 1987 and 1995), as well as from the BTNS (a study including adolescent twins and their parents), from which the parents of the twins served as healthy controls in the present investigation. The association between novel naevus-associated gene variants and the site- and subtype-specific risk of melanoma was assessed using unconditional multinomial logistic regression models. Results A significantly positive association was observed between a personal history of endometriosis and the risk of melanoma in the E3N cohort, as well as a significantly positive association between a personal history of uterine fibroma and melanoma risk. The association between endometriosis and melanoma was even stronger when restricting to endometriosis reported as treated or diagnosed by laparoscopic surgery. However, a history of ovarian cyst, uterine polyp, breast adenoma/fibro-adenoma or breast fibrocystic disease was not significantly associated with the risk of melanoma. Also, significantly positive dose-effect relationships were found in the E3N cohort between the risk of endometriosis and skin sensitivity to sun exposure, number of naevi, and number of freckles, while no significant associations were found with hair or skin colour. Finally, variants of MTAP, PLA2G6 and IRF4 were significantly associated with the propensity to develop naevi in the Q-MEGA study. There was also a statistically significant association between MTAP rs10757257 and the risk of melanoma. Although there was no evidence that this association varied according to anatomical site of the tumour, the risk alleles of this polymorphism were more common in patients with superficial spreading melanoma or nodular melanoma than in controls, while patients with melanoma of the lentigo maligna type were no more likely than controls to carry these alleles. In contrast, no association was found between PLA2G6 and IRF4 variants and the risk of melanoma, globally or by site or type of melanoma. Conclusion The present findings suggest a positive association between endometriosis and melanoma, for which they constitute the strongest evidence to date. This finding may reflect the existence of shared risk factors between endometriosis and melanoma, which is supported by the finding of significant associations between endometriosis and some cutaneous phenotypic traits that are established risk factors for melanoma. Because these traits are mostly genetically determined, it can be speculated that endometriosis and melanoma share similar genetic characteristics. More research will be needed in order to clarify common pathways between endometriosis and melanoma. The finding of a positive association between uterine fibroma and melanoma risk had not been previously reported and warrants further investigation. The presented results also confirm an association between MTAP, PLA2G6 and IRF4 variants and naevus propensity, as well as an association between MTAP and melanoma. The findings suggest that the relationship is subtype-specific, which confirms and further refines the overarching “divergent pathways” model. Since MTAP is located at the same locus as CDKN2A, which has also been associated with naevus counts, further research will be necessary to determine whether these results can be attributed to MTAP independently of CDKN2A.
| Identifer | oai:union.ndltd.org:ADTP/279293 |
| Creators | Marina Kvaskoff |
| Source Sets | Australiasian Digital Theses Program |
| Detected Language | English |
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