Family Study of Melanoma in Italy
Condition: Melanoma; Dysplastic Nevi; Melanocytic Nevi
MeSH terms: Melanoma; Nevus; Nevus, Pigmented; Dysplastic Nevus Syndrome
Study type: Observational

Summary: 
      During the course of a case-control study of melanoma conducted at the Bufalini Hospital,
      Cesena, Italy in the years 1994-1996, 20 families with 2 or 3 melanoma cases were identified
      and studied. The area where the study was conducted showed the steepest increase in melanoma
      incidence in Mediterranean populations between the years 1987 and 1997.

      Clinical characteristics of melanoma in the families studied were similar to those typically
      described in fair-skinned populations, but no relevant mutations in the coding regions of
      known candidate genes from melanoma have been found. Lack of findings could be due to the
      modest number of families and the small number of affected CMM cases examined. We cannot
      exclude the possibility of alterations in introns, splicing sites or promoter regions. Also
      epigenetic factors could affect the expression of the gene products we studied.
      Alternatively, germline alterations of a gene(s) other than the candidate genes we analyzed
      may play an important role in melanoma predisposition in this population. A large number of
      families is needed to test these hypotheses.

      These additional families could provide an important contribution to the understanding o
      melanoma development. In fact, this population does not generally have the host
      characteristics that are usually associated with higher risk for melanoma (e.g., light skin
      color, red hair, blue eyes, multiple freckles, tendency to sunburn, etc.) but do have a
      relative high frequency of dysplastic nevi and melanoma.

      The main objective of this study is to recruit more families at the Bufalini Hospital,
      Cesena, Italy in order to reach a larger sample size. Recently, 16 potential melanoma-prone
      families have been identified through patient's or physicians' referrals by the
      Dermatologists at the Bufalini Hospital. The dermatologists have maintained close
      relationships with members of these families and are confident that these subjects would be
      willing to participate in a study if contacted. The first goal of our study is to contact
      this family group and verify their willingness to participate in the study. In addition, new
      families could be identified and recruited.

      We propose to conduct a pilot project. We estimate recruitment of approximately 25 families
      with 2 or more melanoma cases in first -degree relatives over a one-year period, including
      the 16 families already identified and approximately 10 new kindreds. At the end of the pilot
      phase we will determine the feasibility of continuing recruitment.
    

Detailed description: 
      To date 557 subjects, including cases of melanoma and unaffected relatives, have been
      recruited in the family study of melanoma at the Bufalini Hospital, Cesena, Italy, University
      ofl'Aquila, L'Aquila, Italy, and the Istituto Valenciano de Oncologia, Valencia, Spain.
      Clinical characteristics of melanoma in the families studied were similar to those typically
      described in fair-skinned populations.

      In the original study from the Bufalini Hospital, only 7% of the families analyzed have been
      shown to carry mutation in the CDKN2A gene, known candidate gene for melanoma, and no other
      mutation in additional susceptibility genes have been identified. The possibility of
      alterations in introns, splicing sites, or promoter regions cannot be excluded. Also,
      epigenetic factors could affect the expression of the gene products we studied.
      Alternatively, germline alterations of a gene(s) other than the candidate genes may play an
      important role in melanoma predisposition in this population. We began genome-wide scanning
      of the first 47 families. There was no evidence for linkage to either chromosome 9 or
      chromosome 1, previously shown to be susceptibility loci for melanoma. We extended the
      samples size also including melanoma-prone families from other Italian investigators. We have
      performed fine mapping of the loci that appeared interesting in the first linkage analysis.
      We did not confirm the previous association with the disease and published a manuscript to
      report the null results. Some of these families were also analyzed together with other
      families worldwide in linkage and genome-wide association studies with the goal of
      identifying loci potentially important for melanoma etiology. Moreover, some individuals from
      this study are being analyzed for presence of variants in susceptibility genes in
      pigmentation, DNA repair, and other pathways together with the melanoma samples from the
      case-control study (02-C- N(35). Finally, some families with three or more affected
      individuals are ongoing exomic sequencing with the goal of identifying novel loci associated
      with melanoma susceptibility. More than 100 subjects have been sequenced to date. We have
      identified a potentially important candidate gene for melanoma and are investigating
      additional families and melanoma cases to verify whether we can replicate this finding.

      This protocol proposes to continue recruitment of families in order to reach a larger sample
      size for future analysis. The additional families could provide an important contribution to
      the understanding of melanoma development.

      In addition, this protocol proposes to continue recruiting subjects for the tissue study
      subgroup at the Bufalini Hospital of Cesena, the Unviersity of I' Aquila, Italy and the
      Istituto Valenciano de Oncologia, Valencia, Spain. To date, 98 subjects have been enrolled in
      this study. The study aims at investigating the progression from nevi to melanoma in a cross
      sectional study of melanoma cases. The tissue study component focuses on the comparison of
      gene expression, somatic mutations, genetic variants, and proteomics profile in normal skin,
      common melanocytic nevi, dysplastic nevi, and melanoma tissue samples from the same
      individuals (familial or sporadic cases). Each subject completes an interview based
      questionnaire on sun exposure, pigmentation, sunsensitivity, family and medical history, and
      other melanoma risk factors and donates a blood sample.
    

Observational model: Family-Based
Time perspective: Other
Sampling method: Non-Probability Sample
Study population: 
        Melanoma-prone families from dermatology clinics.
      
Biospecimen description: 
      whole blood, lymphocytes, tissue sections, plasma
    
Keywords: Genetics; Kindreds; Mediterranean Population; Nevi; Pigmentation; Melanoma-Prone Families; Sun Exposure; Melanoma