Studies of Familial Melanoma
- Determine the incidence and etiologic significance of variants of known melanoma
susceptibility genes (MSGs) in families with multiple cases of melanoma.
- Determine the proportion of multiple-case families that are explained by
high-penetrance mutations in known MSGs.
- Determine the proportion of multiple-case families that are explained by these
mutations and whether it varies with latitude, as a surrogate for ultraviolet exposure,
with number of affected relatives, with average age at onset of melanoma in relatives,
with presence of multiple primary melanoma, or with other family-specific variables.
- Determine the penetrance of MSG mutations in these families.
- Determine if the penetrance varies with age, sex, or birth cohort.
- Determine if the penetrance varies with the gene involved or nature of the mutation.
- Assess the penetrance in mutations that also have a deleterious effect on the
alternative splice product, p14ARF.
- Determine whether carriers of MSGs have an increased susceptibility to other types of
- Determine the risk of other types of cancers for mutation carriers.
- Determine environmental exposures, in particular sun exposure, that modify risk of
melanoma in MSG mutation carriers.
- Determine the cutaneous phenotypes that correlate with melanoma risk in these families.
- Correlate cutaneous phenotypes with the presence of MSG variants.
- Determine the effect of other covariates, such as sun exposure or the presence of
alleles of putative modifying genes (e.g., MC1R or CDKN2A), on phenotype.
- Determine if modifier genes, such as those controlling pigmentation of the skin, and
therefore sun susceptibility, modify risk in MSG mutation carriers.
- Identify any histopathological correlates of MSG status in primary tumors arising in
melanoma-susceptible individuals in these families.
- Identify any histopathological correlates of primary melanomas in carriers of MSG
mutations with other covariates.
OUTLINE: This is a case-control, multicenter study.
Participants complete 2 questionnaires and assist in the creation and expansion of a family
pedigree. Blood samples are examined for melanoma susceptibility gene mutations, including
CDK4 and CDKN2A.
Participants are also examined for moles and photographed. Physical variables (e.g., skin,
eye, and hair pigmentation) and sun damage (solar lentigines and freckling) are also noted.
If available, tissue samples are examined for Clark level, Breslow thickness, and frequency
of mitoses. Peri-lesional skin from tumors is examined by p53 staining.
Participants are followed periodically to monitor cancer development.
Peer reviewed and funded or endorsed by Cancer Research UK
PROJECTED ACCRUAL: A total of 5,000 participants will be accrued for this study.
Predictive significance of melanoma susceptibility gene (MSG) mutations in the CDKN2A gene
Julia Newton Bishop, MD
Leeds Cancer Centre at St. James's University Hospital