Basal Cell Carcinoma and the Carcinogenic Role of Aberrant Hedgehog Signaling

Anna Saran

Disclosures

Future Oncol. 2010;6(6):1003-1014. 

In This Article

DNA Damage Repair & BCC

Ultraviolet radiation (UVR) DNA damage, characterized by C–T transition at dipyrimidine sites and CC–TT tandem mutations, is a major etiologic factor for BCC, demonstrated by the fact that the mutations in Ptch1 identified in sporadic BCC are frequently UVR specific.[110] In addition, this type of damage is found in a very high percentage of BCCs arising in the skin of patients with xeroderma pigmentosum.[111]TP53 gene mutations are also associated with BCC, the majority being UVR-specific nucleotide changes.[39,110,112] Thus, genetic variability in DNA repair genes may contribute to differences in DNA repair capacity and susceptibility to BCC.

The available body of data indicates that polymorphisms in DNA repair genes may contribute to sporadic BCC. Polymorphisms in the xeroderma pigmentosum group D gene (XPD), whose gene product functions in nucleotide excision repair, may contribute to sporadic BCC development.[113] Numerous studies have demonstrated overall risk modulation of BCC by variant alleles for DNA strand break repair genes, including XRCC1, which encodes a protein directly involved in the repair of DNA base damage that is recruited to sites of single-strand break repair by poly-(ADP-ribose) polymerase (PARP)-1.[114,115] While UVB exposure does not directly cause DNA double-strand breaks (DSBs), UV-induced photoproducts cause replication arrest, which can lead to the formation of DSBs.[116] This suggests a role for the DSB repair pathways in BCC development. In the homologous recombination pathway acting in the repair of DSBs in mammalian cells, XRCC2 and XRCC3, as RAD51 gene paralogues, facilitate the formation of RAD51 foci at the sites of repair. Polymorphisms in these genes are studied for their association with BCC risk. However, thus far, contradictory results have been published as to the protective role of one of the most widely studied of such polymorphisms, the T241M substitution in XRCC3.[117–120] Along the same lines, the 4044T and 4062T alleles of the Ligase IV gene were associated with decreased BCC risk,[118] although this awaits confirmation by further studies. Experimental studies using mouse models of Hh-driven tumorigenesis have the potential to provide mechanistic insights. The effects of introducing genomic instability on BCC induction and progression were investigated in Ptch1+/- mice carrying mutant Blm, the gene that is defective in Bloom's syndrome, an autosomal recessive hereditable condition characterized by chromosomal instability.[121] Human cells lacking functional BLM show tenfold-elevated rates of sister chromatid exchange. Ptch1+/- mice carrying Blm inactivation developed significantly more microscopic BCCs at 7 months from a 5-Gy dose of x-rays compared with Ptch1+/- mice, and also demonstrated a markedly increased rate of rhabdomyosarcoma (another Hh-dependent tumor) development. We have recently demonstrated that inactivation of PARP-1, a DNA strand break-sensing molecule, strikingly accelerates BCC development in Ptch1+/- mice exposed to x-rays.[122] Multiple tumors developed with highly reduced latency in the double knockouts, and characterization of this striking BCC phenotype was accomplished in spite of concurrent high mortality for medulloblastoma. Thus, the high BCC frequency detected was nevertheless underestimated. Whether this phenotype was owing to the absence of PARP-1 function as a suppressor of chromosomal recombination,[123,124] leading to Ptch1 loss of heterozygosity and driving a switch to malignancy in early proliferative BCC lesions,[22] or to other nuclear processes in which PARP-1 is implicated that were compromised, remains to be determined. However, poly(ADP-ribosylation) represents a major mechanism to regulate genomic stability both when DNA is damaged by exogenous agents and during cell division,[125] pointing to genomic instability as a key element in the development of Hh-associated tumors. Loss of p53, which prevents the accumulation of genetic mutations by inducing cell cycle arrest, apoptosis or senescence of somatic cells after genotoxic and oncogenic stresses, also markedly enhances Hh-driven tumorigenesis in mice.[126] Similarly, irradiation of newborn Ptch1 heterozygous mice results in dramatic enhancement of Hh-induced medulloblastoma, indicating that ionizing radiation-induced damage and genomic instability may cooperate with Ptch1 germline mutations to induce medulloblastoma.[127]

In summary, these studies reinforce the hypothesis that genes controlling the extent of DNA damage/repair and their genetic variants are very likely to modulate individual BCC susceptibility/resistance.

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