Are there known downsides to removing UV mutation hotspots to prevent some skin cancers (Genetic sunblock)?

Question

Khavari et al. recently demonstrated that a significant fraction of one of the major forms of skin cancer (cutaneous squamous cell carcinomas) are associated with a mutated KNSTRN gene (a protein associated with the kinetochore). They identify a specific region of the gene as being a hotspot for UV induced mutation and suggest that these mutations may be an early event in the development of this type of skin cancer.(1)Abstract from their nature paper (paywalled):>Here we report the discovery of recurrent mutations concentrated at an ultraviolet signature hotspot in KNSTRN, which encodes a kinetochore protein, in 19% of cutaneous squamous cell carcinomas (SCCs). Cancer-associated KNSTRN mutations, most notably those encoding p.Ser24Phe, disrupt chromatid cohesion in normal cells, occur in SCC precursors, correlate with increased aneuploidy in primary tumors and enhance tumorigenesis in vivo. These findings suggest a role for KNSTRN mutagenesis in SCC development.(2)My question:Scientists could theoretically alter the nucleotide sequence of the KNSTRN gene to remove the mutation hotspot, potentially lowering the incidence of this type of skin cancer. But are there any downsides to doing so? Are there any cases where a UV mutatable hotspot has shown to have some useful function in a cell or organism? Thanks! 1. http://www.sciencedaily.com/releases/2014/09/140907181722.htm2. http://www.nature.com/ng/journal/vaop/ncurrent/full/ng.3091.html

Answer 1

Firstly, it is important to understand what a "hot spot" is: a single or cluster of nucleotides in a gene that are commonly mutated in cancer(s). Generally, a mutational hot spot exists in a portion of a gene which is key to functionality, whether it be for transcriptional regulation of for actual protein activity. The concept of removing these hot spots poses a variety of problems, namely that, if feasible, its removal would almost certainly compromise the gene's activity in normal cellular function. Removing nucleotides would result in a frameshift which would interrupt the codons following the site, changing the amino acid sequence of the protein product. Alternatively, replacing the nucleotide hotspot with a different nucleotide so as not to disrupt the reading frame would work in theory, but it would not prevent the mutation from reoccurring. This would also require large-scale gene therapy in which every cell in the organ of interest (in this case the skin) would need to be effectively genetically altered; this level of precision is not yet possible and would be incredibly costly as purely a preventative measure. Another important factor is that many key driver genes in carcinogenesis are systemically important, which is why many targeted cancer therapies have severe side effects. In this case, the kinetochore is a key structure to mitosis, and, while this intuitively may seem like a good target as a hallmark of cancer is uncontrolled division, it is not specific to cancer, and is important for normal cellular division throughout the entire body. Thus, wiping out the activity of this gene as a preventative measure would severely compromise the cell population targeted. The current focus of cancer therapy is targeting such key genes in cancer without the treatment interacting with healthy tissue; this is not done in a preventative manner as you cannot effectively target the subpopulation of cells with the initial mutation of interest. The best way to prevent skin cancer is to stop it at the source: wear sunscreen!