Ras gene mutation and amplification in human nonmelanoma skin cancers

Abstract

Our previous studies have shown that human skin cancers occurring on sun-exposed body sites frequently contain activated Ha-ras oncogenes capable of inducing morphologic and tumorigenic transformation of NIH 3T3 cells. In this study, we analyzed human primary squamous cell carcinomas (SCCs) and basal cell carcinomas (BCCs) occurring on sun-exposed body sites for mutations in codons 12, 13, and 61 of Ha-ras, Ki-ras, and N-ras oncogenes by amplification of genomic tumor DNAs by the polymerase chain reaction, followed by dot-blot hybridization to synthetic oligonucleotide probes designed to detect single base-pair mutations. In addition to the primary human skin cancers, we also analyzed Ha-ras-positive NIH 3T3 transformants for mutations in the Ha-ras oncogene. The results indicated that all three NIH 3T3 transformants, 11 of 24 (46%) SCCs, and 5 of 16 (31%) BCCs contained mutations at the second position of Ha-ras codon 12 (GGC----GTC), predicting a glycine-to-valine amino acid substitution, whereas only 1 of 40 skin cancers (an SCC) displayed a mutation in the first position of Ki-ras codon 12 (GGT----AGT), predicting a glycine-to-serine amino acid change. In addition, three of the SCCs contained highly amplified copies of the N-ras oncogene in their genomic DNA. Interestingly, two of the SCCs containing amplified N-ras sequences also had G----T mutations in codon 12 of the Ha-ras oncogene. These studies demonstrate that mutations in codon 12 of the Ha-ras oncogene occurred at a high frequency in human skin cancers originating on sun-exposed body sites, whereas mutation in codon 12 of Ki-ras or amplification of N-ras occurred at a low frequency. Since the mutations in the Ha-ras and Ki-ras oncogenes were located opposite potential pyrimidine dimer sites (C-C), it is likely that these mutations were induced by ultraviolet radiation present in sunlight.

Development of Keratoacanthomas and Squamous Cell Carcinomas in Transgenic Rabbits with Targeted Expression of EJras. Oncogene in Epidermis

“…5 Another study reported that 40% of the human skin cancers studied contained mutations in codon 12 of Ha-ras. 6 These results clearly indicate the involvement of activated Ha-ras genes in the development of both benign and malignant skin tumors. The roles of activated Ha-ras in skin tumor development are further supported by animal studies, including carcinogen-treated animals [7][8][9][10][11] and transgenic animals.…”

An inactivating CYLD mutation promotes skin tumor progression by conferring enhanced proliferative, survival and angiogenic properties to epidermal cancer cells

“…This mutant carries the 601 C/S point mutation in the cysteine box of the deubiquitinase domain, resulting in a catalitically inactive protein that is able to compete with the endogenous CYLD (Brummelkamp et al, 2003;Trompouki et al, 2003;Massoumi et al, 2006Massoumi et al, , 2009. The PDVC57 cells were chosen because they bear a Ha-ras mutation carried by all the chemically induced mouse skin tumors and some human skin carcinomas (Pierceall et al, 1991;Spencer et al, 1995). PDVC57 cells were stably transfected with the mouse CYLD C/S complementary DNA tagged with a hemagglutinin-A epitope under the control of the b-actin promoter ( Figure 1a) or with the empty vector.…”

Absence of BRAF Gene Mutation in Non-Melanoma Skin Tumors

“…[6][7][8][9][10][11][12] Mutation of BRAF has been proposed to play a role in cancer growth, including primary and metastatic melanoma. [13][14][15][16] The identification of BRAF alteration in BCC may represent a new approach for both diagnosis and treatment of this non-melanoma skin tumor.…”

“…Now, an overall RAS mutation frequency of 10-20% is suggested for squamous cell carcinoma (SCC) and BCCs. [6][7][8][9][10][11][12] Moreover, mutation of BRAF has been proposed to contribute to cancer development. 13 B-RAF is a kinase that activates the RAF/MEK/ERK signal transduction cascade.…”