This application requests support for years 4-8 of a project whose goal is the identification of genes the loss of whose function is important in the development of basal cell carcinomas (BCCs), by far the most common human cancer. As in the retinoblastoma paradigm, there is a form of basal cell carcinoma in which, by comparison with the sporadic type, tumors arise at younger age, in greater numbers, and with autosomal dominant inheritance- the basal cell nevus syndrome (BCNS). During the past several years, we assessed linkage of the BCNS phenotype to more than 120 sites in a genome-wide search without identifying the location of the gene. Very recently, other investigators found such linkage at chromosome 9q, a site that we subsequently confirmed in our own kindreds We propose now to characterize more fully allelic loss at this site in BCCs and to search for the BCNS gene itself by a """"""""positional cloning"""""""" strategy that relies heavily on a search for rearrangements disrupting the gene in BCCs or, preferably, in """"""""constitutional"""""""" DNA from BCNS patients. Successful completion of this work should lead not only to fundamental insights into cutaneous carcinogenesis but also to understanding of the relationship of the tumors to the multiple phenotypic abnormalities of the inherited syndrome.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
Project #
Application #
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Francisco
Schools of Medicine
San Francisco
United States
Zip Code
Bonifas, J M; Pennypacker, S; Chuang, P T et al. (2001) Activation of expression of hedgehog target genes in basal cell carcinomas. J Invest Dermatol 116:739-42
Aszterbaum, M; Epstein, J; Oro, A et al. (1999) Ultraviolet and ionizing radiation enhance the growth of BCCs and trichoblastomas in patched heterozygous knockout mice. Nat Med 5:1285-91
Aszterbaum, M; Beech, J; Epstein Jr, E H (1999) Ultraviolet radiation mutagenesis of hedgehog pathway genes in basal cell carcinomas. J Investig Dermatol Symp Proc 4:41-5
Aszterbaum, M; Rothman, A; Johnson, R L et al. (1998) Identification of mutations in the human PATCHED gene in sporadic basal cell carcinomas and in patients with the basal cell nevus syndrome. J Invest Dermatol 110:885-8
Xie, J; Johnson, R L; Zhang, X et al. (1997) Mutations of the PATCHED gene in several types of sporadic extracutaneous tumors. Cancer Res 57:2369-72
Oro, A E; Higgins, K M; Hu, Z et al. (1997) Basal cell carcinomas in mice overexpressing sonic hedgehog. Science 276:817-21
Xie, J; Quinn, A; Zhang, X et al. (1997) Physical mapping of the 5 Mb D9S196-D9S180 interval harboring the basal cell nevus syndrome gene and localization of six genes in this region. Genes Chromosomes Cancer 18:305-9
Bonifas, J M; Bare, J W; Kerschmann, R L et al. (1994) Parental origin of chromosome 9q22.3-q31 lost in basal cell carcinomas from basal cell nevus syndrome patients. Hum Mol Genet 3:447-8