Trial Information

Family Study of Melanoma in Italy

To date 457 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.

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.