The goal of this project is to determine the role of p16, a tumor-suppressor gene in the retinoblastoma cell-cycle regulation pathway, in familial melanoma kindreds. Malignant melanoma is the most lethal of the skin cancers, and unlike most malignancies, often affects younger patients in their third and fourth decades. Several risk factors have been associated with melanoma, including sun exposure, genetic predisposition, total number of nevi present on an individual, and characteristics of nevi. The overall proportion of cutaneous melanoma attributable to genetic predisposition is reported to be about 10- 15%, but evaluation of cancer incidence data from the Utah Population Database suggests that the fraction of melanoma occurring in a familial setting may be as high as 30%. The applicant proposes to re-examine members of Utah melanoma kindreds, first studied 15 years ago at the UUSM, that helped establish the presence of a melanoma susceptibility locus on 9p21 and later confirm the association of p16 mutations with familial melanoma. A five-year mentored program is proposed to investigate the global hypothesis that carriage of a germline p16 mutation results in measurable clinical, histologic, and cellular changes that lead to familial susceptibility to melanoma. This program will incorporate both didactic and research training and will be guided by a research oversight committee composed of four established scientists at the UUSM and the Huntsman Cancer Institute.
Three specific aims are proposed. First, clinical differences between carriers and non-carriers of a p16 mutation will be examined in the Familial Melanoma Research Clinic (FMRC) at the Huntsman Cancer Institute. Kindred members studied 15 years ago will be re-examined to measure differences in photodamage, number of nevi, size of nevi, characteristics of nevi, and distribution of nevi among p16 carrier and noncarrier kindred members. Second, I will determine whether p16 mutation carriage results in decreased senescence or apoptosis of nevus cells utilizing B-galactosidase levels and TUNEL staining, respectively. Third, I will determine whether nevi and melanomas from p16 mutation carriers have acquired additional mutations that could lead to increased risk of malignant transformation.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23RR017525-03
Application #
6846036
Study Section
National Center for Research Resources Initial Review Group (RIRG)
Program Officer
Wilde, David B
Project Start
2003-02-15
Project End
2008-01-31
Budget Start
2005-02-01
Budget End
2006-01-31
Support Year
3
Fiscal Year
2005
Total Cost
$134,730
Indirect Cost
Name
University of Utah
Department
Dermatology
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Pershing, Lynn K; Tirumala, Vidyanath P; Nelson, Joel L et al. (2008) Reflectance spectrophotometer: the dermatologists'sphygmomanometer for skin phototyping? J Invest Dermatol 128:1633-40
Florell, Scott R; Smoller, Bruce R; Boucher, Kenneth M et al. (2008) Sampling of melanocytic nevi for research purposes: a prospective, pilot study to determine effect on diagnosis. J Am Acad Dermatol 59:814-21
Florell, Scott R; Meyer, Laurence J; Boucher, Kenneth M et al. (2008) Increased melanocytic nevi and nevus density in a G-34T CDKN2A/p16 melanoma-prone pedigree. J Invest Dermatol 128:2122-5
Thomas, Joshua; Liu, Tong; Cotter, Murray A et al. (2007) Melanocyte expression of survivin promotes development and metastasis of UV-induced melanoma in HGF-transgenic mice. Cancer Res 67:5172-8
Cotter, Murray A; Thomas, Joshua; Cassidy, Pamela et al. (2007) N-acetylcysteine protects melanocytes against oxidative stress/damage and delays onset of ultraviolet-induced melanoma in mice. Clin Cancer Res 13:5952-8
Cotter, Murray A; Florell, Scott R; Leachman, Sancy A et al. (2007) Absence of senescence-associated beta-galactosidase activity in human melanocytic nevi in vivo. J Invest Dermatol 127:2469-71
McKenna, Jeffrey K; Florell, Scott R (2007) Cost-effective dynamic telepathology in the Mohs surgery laboratory utilizing iChat AV videoconferencing software. Dermatol Surg 33:62-8;discussion 68
Wada, David A; Perkins, Sherrie L; Tripp, Sheryl et al. (2007) Human herpesvirus 8 and iron staining are useful in differentiating Kaposi sarcoma from interstitial granuloma annulare. Am J Clin Pathol 127:263-70
Florell, Scott R; Cessna, Melissa; Lundell, Ryan B et al. (2006) Usefulness (or lack thereof) of immunophenotyping in atypical cutaneous T-cell infiltrates. Am J Clin Pathol 125:727-36
Florell, Scott R; Boucher, Kenneth M; Garibotti, Gilda et al. (2005) Population-based analysis of prognostic factors and survival in familial melanoma. J Clin Oncol 23:7168-77

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