Melanoma Clinical Trial
Official title:
Family Study of Melanoma in Italy
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.
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.
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