| A paragraph describing the group
The dermato-oncology research group at the Sheba Medical Center consists of the Dermato-Oncology Unit and the Oncogenetics Unit. The research program of the group includes:
(1) Elucidating the role of candidate genes in conferring inherited predisposition to melanoma in Jewish families with clustering of malignant melanoma in general, with a special emphasis on a subgroup of families with the melanoma – neural system tumor syndrome.
(2) The role of host and environmental factors in the evolution of acquired melanocytic nevi.
(3) Kaposi Sarcoma.
Malignant Melanoma in Israel – Background
Cumulative epidemiological data from Israel from the last three decades have substantiated the causative role of sun exposure in the pathogenesis of melanoma in the Israeli population, and demonstrated that the disease incidence is modified by environmental factors.
Israel provides a unique natural "laboratory" for studying the role of genetic and environmental factors in the induction of melanoma for several reasons. First, it is a subtropical country, with a sunny weather prevailing almost 9 months a year. Secondly, the Jewish population living in Israel is heterogeneous, composed of waves of immigration from East and West, mainly during the last century, with a following generation of Israeli-born offspring. Thirdly, it comprises a dynamic mixture of cultures, habits and life-styles, reflecting the adjustments of a wide diversity of migrant populations to a modern Mediterranean country.
Melanoma incidence varies considerably between the different migrant populations living in Israel. Incidence is high in those from Europe and America (Ashkenazim) and low in migrants from Asia and Africa (=non-Ashkenazim or Sephardic). These differences in incidence are related to pigmentation, the latter being darker skinned, with a higher degree of sun protection. In addition, the risk of melanoma among European Jews increases with the duration of residence in Israel, approximately doubling after 30 years. Individuals who migrated to Israel before age 10 have an increased risk of melanoma. Finally, incidence in the Israel-born population is much higher than in the migrants: on the world-wide melanoma incidence scale, Israeli-born Jews are the second highest after Australia and New Zealand.
Genetic susceptibility to melanoma – an ongoing research project
The risk of an individual for developing melanoma is the end result of two vectors: environmental and genetic factors. In about 10% of Melanoma patients a familial clustering is noted, raising the possibility of an inherited susceptibility conferred by a germline mutation in one of several genes, notably at the p 16 locus. The phenotype that raises the possibility of inherited predisposition is defined by a minimum of two melanoma cases (first or second degree relatives) in a pedigree, or a single individual harboring multiple melanomas.
We had established a clinical-epidemiological-genetic database of over 80 Jewish familial melanoma kindreds. Preliminary screening of 30 Israeli melanoma kindred revealed two p16 germline mutations (G101w and G122V) with a low estimated mutation frequency of 7% [1]. Extension of the analysis to p14(ARF) and CDK4 loci did not demonstrate additional mutations (in collaboration with Dr. Brigitte Bressac-de Paillerets, Service de Génétique, Institut Gustave Roussy, Villejuif, France).
Melanoma – Neural system tumors Syndrome: A familial association of melanoma (MM) and Neural system tumors (NST) has been recognized as a rare autosomal dominant familial cancer syndrome and was designated as the Melanoma and Neural System Tumor syndrome (MM-NST, OMIM 155755). Our group has described 15 Jewish families and 10 seemingly sporadic cases with the MM-NST syndrome, with additional confirmatory publications from France and Scandinavia following. We have recently genotyped a series of 24 Jewish families with the MM-NST syndrome for germline mutations and/or deletions in the CDKN2A/ARF and CDK4 loci (in collaboration with Dr. Brigitte Bressac-de Paillerets). No germline alterations were detected in any of these loci among these families. This negative finding suggests that the search for alterations predisposing to MM-NST familial syndrome in Jewish families should focus on other loci in the human genome (manuscript submitted for publication). We are currently extending the research to conduct a comprehensive genetic analysis for MC1R allele polymorphism in Jewish families with MM-NST syndrome compared with ethnically matched Jewish MM patients and unaffected controls.
The Jewish Melanoma group’s (Emanuel Yakobson) interest is familial melanoma and germline mutation detection in Jews. Active collaborations have been established with Brigitte Bressac (France) and David Hogg (Canada) groups. We have also initiated a large case control study of up to 1000 “sporadic” malignant melanoma families in Israel, with an additional intent to explore the level and the nature of DNA repair enzyme activity as a risk factor for melanoma development together with Prof. Zvi Livneh at the Weizmann Institute and Prof. David Goldstein at UCL, London.
The role of host and environmental factors in the pathogenesis of nevi- ongoing research
The strong association between multiple nevi and melanoma, suggests that identification of the pathogenesis of nevi may help clarify the evolution of melanoma and lead to prevention strategies. We have studied the prevalence of nevi and freckles in a cohort of young Israeli males (n=3,040) [2] and noted that the risk of multiple nevi was significantly associated with family history of melanoma, and ethnic melanoma risk group. There was an increased risk of multiple nevi among second- compared with first-generation, native-born recruits of migrant families, indicating an environment-related effect.
Childhood is a period of particular susceptibility to the adverse effects of sun exposure. Sun exposure in early years contributes to the proliferation of nevi and to the subsequent melanoma risk. Among a study population of 974 Israeli schoolchildren use of sunscreen was unexpectedly linked with elevated nevi counts [3]. These findings may indicate that sunscreens do not modify the genetic predisposition and natural history of nevi proliferation during childhood and adolescence.
Kaposi Sarcoma
A strong association is known to exist between HHV-8 seropositivity and the development of Kaposi sarcoma (KS) [4]. Ethiopian immigrants in Israel may have some protective mechanism against the development of KS despite HHV-8 seropositivity. Among 249 Israeli Ethiopians analyzed, a total of 39.1% and 57% of the HIV-negative and HIV-positive Ethiopians, respectively, were infected with HHV-8 (p<0.03). However, none of the Ethiopians examined and none of the other HIV-negative Ethiopians among about 45,000 immigrants, had KS [5]. The mechanism behind this population's unique protection requires further study. |
