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p53 mutation and cancer

Giglia-Mari, G. and Sarasin, A. (2003) TP53 mutations in human skin cancers. Hum Mutat, 21, 217-228. Download

Skin Cancer

Basal cell carcinoma is the most common form of skin cancer. The second most common type of skin malignancy is squamous cell carcinoma. Although these 2 types of skin cancer are the most common of all malignancies, they account for less than 0.1% of patient deaths due to cancer. Both of these types of skin cancer are more likely to occur in individuals of light complexion who have had significant exposure to sunlight, and both types of skin cancers are more common in the southern latitudes of the Northern hemisphere. The overall cure rate for both types of skin cancer is directly related to the stage of the disease and the type of treatment employed. However, since neither basal cell carcinoma nor squamous cell carcinoma of the skin are reportable diseases, precise 5-year cure rates are not known. Although basal cell carcinoma and squamous cell carcinoma are by far the most frequent types of skin tumors, the skin can also be the site of a large variety of malignant neoplasms. These other types of malignant disease include malignant melanoma, cutaneous T-cell lymphomas (mycosis fungoides), Kaposi's sarcoma, extramammary Paget's disease, apocrine carcinoma of the skin, and metastatic malignancies from various primary sites

Basal cell carcinoma and squamous cell carcinoma are both of epithelial origin. They are usually diagnosed on the basis of routine histopathology. Squamous cell carcinoma is graded 1 to 4 based on the proportion of differentiating cells present, the degree of atypicality of tumor cells, and the depth of tumor penetration. Apocrine carcinomas, which are rare, are associated with an indolent course and usually arise in the axilla.

Basal cell carcinoma

Basal cell carcinoma is at least 3 times more common than squamous cell carcinoma in nonimmunocompromised patients. It usually occurs on sun exposed areas of skin, and the nose is the most frequent site. Although there are many different clinical presentations for basal cell carcinoma, the most characteristic type is the asymptomatic nodular or nodular ulcerative lesion that is elevated from the surrounding skin and has a pearly quality and contains telangiectatic vessels. It is recognized that basal cell carcinoma has a tendency to be locally destructive. High-risk areas for tumor recurrence include the central face (periorbital region, eyelids, nasolabial fold, nose-cheek angle), postauricular region, pinna, ear canal, forehead, and scalp. A specific subtype of basal cell carcinoma is the morphea-form type. It typically appears as a scar-like, firm plaque and because of indistinct clinical tumor margins, it is difficult to treat adequately with traditional treatments.

Squamous cell carcinoma

Squamous cell tumors also tend to occur on sun-exposed portions of the skin such as the ears, lower lip, and dorsa of the hand. However, squamous cell carcinomas that arise in areas of non-sun-exposed skin or that originate de novo on areas of sun-exposed skin are prognostically worse since they have a greater tendency to metastasize. Chronic sun damage, sites of prior burns, arsenic exposure, chronic cutaneous inflammation as seen in long standing skin ulcers, and sites of previous x-ray therapy are predisposed to the development of squamous cell carcinoma.

Actinic keratosis

Actinic keratoses are potential precursors of squamous cell carcinoma. These typical red scaly patches usually arise on areas of chronically sun-exposed skin, and are likely to be found on the face and dorsal aspects of the hand. Although the vast majority of actinic keratoses do not become squamous cell carcinomas, it is thought that as many as 5% of actinic keratoses will evolve into this locally invasive carcinoma. Due to this premalignant potential, the destruction of actinic keratoses is advocated.

UV Mutations

UV radiation-induced mutations have been studied in various animal models. The majority of the mutations are found to be located at dipyrimidine sites (i.e. (T-T, C-C, C-T or T-C) and correspond to a C to T transition. More than 20% correspond to tandem mutations involving the two adjacent nucleotides of the dipyrimidine sites (C-C to T-T).

Ultraviolet light is absorbed by the nucleic acid bases, and the resulting influx of energy can induce chemical changes. The most frequent photoproducts are the consequences of bond formation between adjacent pyrimidines within one strand, and, of these, the most frequent are cyclobutane pyrimidine dimers (CPDs). T-T CPDs are formed most readily, followed by T-C or C-T; C-C dimers are least abundant. One can obtain an idea of the extent of distortion of DNA chain structure caused by CPDs by noting that, in the diagram of a T-T CPD on the left, the cyclobutane ring, shaded in light green, should have sides of approximately equal length. Thus the two adjacent pyrimidines must be pulled closer to each other than in normal DNA

Several human genetic syndromes are associated with DNA repair deficiency. Among them, xeroderma pigmentosum (XP) is an autosomal, recessively inherited disease. Patients with XP show clinical and cellular hypersensitivity to UV radiation, resulting in a very high incidence of skin cancer. In these subjects, the median age of onset of skin cancer is 8 years, nearly 50 years younger than in the general population.

Brash et al. showed that, in skin spinocellular cancer, C ---> T mutations predominate in pyrimidine dimers. It is well known that ultraviolet radiation, an etiological agent of most skin cancers, acts directly on these dimers. A particular characteristic of the action of UV radiation is the change in the bases CC ---> TT, observed in Brash's series but also in other skin cancer series such as basocellular cancers (Rady et al. 1992). In patients with genetic DNA repair deficiencies, such as xeroderma pigmentosum (XP), the phenotype is much more marked. All mutations found in skin cancers are located on the pyrimidine dimers and 55 % are tandem mutations CC ---> TT (Dumaz et al. 1994). This type of mutation is only very rarely found in internal cancers (less than 1 %). In skin cancers from XP patients, more than 95 % of the mutations are located on the noncoding strand of the p53 gene, while in other skin tumors and in internal cancers, no special trends are observed. This result therefore suggests that there is preferential repair of the coding strand, which has been confirmed by Toranaletti and Pfeifer, who showed that the repair rate of pyrimidine dimers in the p53 gene is highly variable, with an especially low rate in the codons that are often mutated in skin cancer. Such p53 mutations seem to be very early events as they can be found both in precancerous lesions such as actinic keratosis (Ziegler et al. 1994) and in normal skin exposed to UV (Jonason et al. 1996). Recent work have demonstrated that human epidermal cancer and accompanying precursors have identical p53 mutations different from p53 mutations in adjacent areas of clonally expanded non-neoplastic keratinocytes (Ponten et al. 1997; Ren et al. 1997; Ren et al. 1996; Ren et al. 1997; Ren et al. 1996).

These results taken together (predominance of CC -> TT lesions on the non coding strand) were experimentally confirmed in animals carrying UV-induced tumors (Dumaz et al. 1997; Kress et al. 1992).

Spectrum of p53 mutations in skin cancer

Distribution of GC to AT transitions at Py-Py (+) and non Py-Py (–) sites. The blue and red columns correspond to mutations at non CpG and CpG sites respectively. BCC, basal cell carcinoma; SCC, squamous cell carcinoma of the skin; AK, actinic keratosis; XP, xeroderma pigmentosum patients.

Distribution of tandem mutations in various cancers types. BCC, basal cell carcinoma; SCC, squamous cell carcinoma of the skin; AK, actinic keratosis; XP, xeroderma pigmentosum patients.

DISTRIBUTION OF p53 MUTATIONS IN SKIN SCC

MUTATIONAL EVENTS IN SKIN SCC

DISTRIBUTION OF p53 MUTATIONS IN SKIN BCC

MUTATIONAL EVENTS IN SKIN BCC

DISTRIBUTION OF p53 MUTATIONS IN SKIN ACTINIC KERATOSIS

MUTATIONAL EVENTS IN SKIN ACTINIC KERATOSIS

Key References

• Ziegler A, Leffell DJ, Kunala S et al. Mutation hotspots due to sunlight in the p53 gene of nonmelanoma skin cancers. Proc Natl Acad Sci USA. 1993; 90: 4216-20
• Brash DE, Rudolph JA, Simon JA et al. A Role for sunlight in skin cancer - UV-induced p53 mutations in squamous cell carcinoma. Proc Natl Acad Sci USA. 1991; 88: 10124-8
• Rady P, Scinicariello F, Wagner RF, and Tyring SK. p53 Mutations in Basal Cell Carcinomas. Cancer Res. 1992; 52: 3804-6
• Sato M, Nishigori C, Zghal M, Yagi T, and Takebe H. Ultraviolet-Specific mutations in p53 gene in skin tumors in Xeroderma-Pigmentosum patients. Cancer Res. 1993; 53: 2944-6
• Dumaz N, Drougard C, Sarasin A, and Dayagrosjean L. Specific UV-Induced mutation spectrum in the p53 gene of skin tumors from DNA-Repair-Deficient Xeroderma-Pigmentosum patients. Proc Natl Acad Sci USA. 1993; 90: 10529-33
• Dumaz N, Stary A, Soussi T, Dayagrosjean L, and Sarasin A. Can we predict solar ultraviolet radiation as the causal event in human tumours by analysing the mutation spectra of the p53 gene? Mutat Res. 1994; 307: 375-86
• Tornaletti S and Pfeifer GP. Slow repair of pyrimidine dimers at p53 mutation hotspots in skin cancer. Science. 1994; 263: 1436-8
• Ziegler A, Jonason AS, Leffell DJ et al. Sunburn and p53 in the onset of skin cancer. Nature. 1994; 372: 773-6
• Jonason AS, Kunala S, Price GJ, Restifo RJ, Spinelli HM, Persing JA, Leffell DJ, Tarone RE and Brash DE (1996) Frequent clones of p53-mutated keratinocytes in normal human skin. Proc Natl Acad Sci USA 93: 14025-14029.
• Kress S, Sutter C, Strickland PT, Mukhtar H, Schweizer J, and Schwarz M. Carcinogen-Specific mutational pattern in the p53 gene in Ultraviolet-B Radiation-Induced squamous cell carcinomas of mouse skin. Cancer Res. 1992; 52: 6400-3
• Ren ZP, Ahmadian A, Ponten F, Nister M, Berg C, Lundeberg J, Uhlen M and Ponten J (1997) Benign clonal keratinocyte patches with p53 mutations show no genetic link to synchronous squamous cell precancer or cancer in human skin. Am J Pathol 150: 1791-1803.
• Ren ZP, Hedrum A, Ponten F, Nister M, Ahmadian A, Lundeberg J, Uhlen M and Ponten J (1996) Human epidermal cancer and accompanying precursors have identical p53 mutations different from p53 mutations in adjacent areas of clonally expanded non-neoplastic keratinocytes. Oncogene 12: 765-773.
• Ren ZP, Ponten F, Nister M and Ponten J (1997) Reconstruction of the two-dimensional distribution of p53 positive staining patches in sun-exposed morphologically normal skin. Int J Oncol 11: 111-115.
• Ren ZP, Ponten F, Nister M and Ponten J (1996) Two distinct p53 immunohistochemical patterns in human squamous-cell skin cancer, precursors and normal epidermis. Int J Cancer 69: 174-179.
• Dumaz N, vanKranen HJ, deVries A, Berg RJW, Wester PW, vanKreijl CF, Sarasin A, DayaGrosjean L and deGruijl FR (1997) The role of UV-B light in skin carcinogenesis through the analysis of p53 mutations in squamous cell carcinomas of hairless mice. Carcinogenesis 18: 897-904.
• Ponten F, Berg C, Ahmadian A, Ren ZP, Nister M, Lundeberg J, Uhlen M and Ponten J (1997) Molecular pathology in basal cell cancer with p53 as a genetic marker. Oncogene 15: 1059-1067.