These days many of us have taken to slapping on sunscreen to the exposed parts of our bodies before we participate in outdoor activities in fine weather. The rationale seems good given the alarming incidence of skin cancers among outdoor workers in sunny places like Australia and the association of ultra-violet light, which causes sunburn to the unprotected, with DNA damage and mutation. The most common of human skin cancers, but fortunately one of the less lethal and easily treatable, is the basal cell carcinoma (BCC). It occurs sporadically, mostly on exposed areas of the skin and most frequently among fair-skinned people (presenting up to 750,000 cases per year in USA).
Recent studies of the genomic alterations (indicators of DNA damage) presenting in BCC tumors indicate a range of chromosomal differences in comparison with the same person’s “normal” white blood cells. However, consistently among them are changes to chromosome 9 which span a region containing a locus (a gene in modern parlance) called patched*. This finding is consistent with several previous investigations which have established association between changes at the patched gene and the occurrence of BCC. One of these associations represents a rare heritable disorder known as Nevoid Basal Cell Carcinoma Syndrome (NBCCS) which is characterised by developmental abnormalities and high frequencies of BCC even on unexposed skin. In functional terms, patched appears to correspond to a protein which is sited part on the outside and part inside cells which acts as a receptor to a developmental signalling molecule called sonic hedgehog. Patched is also classified as a tumor suppressor suggesting that deficiency in patched function will promote tumor development, and implying that NBCCS may correspond to severe malfunction of patched.
Taken together these associations and functional assignments raise the question of whether inherited alterations at the patched locus have a direct deterministic role in BCC and whether patched determines the need for sunscreen. Or, to put the question more reasonably, do fully functional patched alleles allow some fair-skinned people to risk sunburn without risking BCC? Of course, as with all incomplete causal explanations the question is slightly farcical, as illustrated by another finding. In sufferers of Xeroderma pigmentosum, a rare genetic inability to repair DNA damage in the skin, BCC is more common and occurs much earlier in life than in the general population. So perhaps the fair sunburn-prone skin is more significant than is patched per se, emphasising that the “gene for” discourse would be better replaced by the discussion of combinations of contributory factors. At the same time we have to recognise that the popular discourse on genomics and health, whether it be in justificatory press releases from the major genomics programmes such as the human HapMap or in news-media accounts, depends upon the concept that we can define genes for and that such things are worthy of a social quest. A consequence of this is that we could tend to play down the effects of other contributory factors or trigger fatalistic responses and this is why I have talked about the gene for sunscreen rather than the gene for skin cancer.
Either way, systematic exploration of genome-wide changes in BCC cells, made possible by the massively parallel analysis of the distribution of markers known as SNPs (single nucleotide polymorphisms) carried out on DNA microarrays (often referred to in microelectronics language as DNA chips), does begin to help clarify the nature of events leading to the above mentioned changes on chromosome 9 as well as other chromosomes. It seems that in a high proportion of BCCs the alterations correspond to the acquisition of an extensive uniparental disomy across the affected chromosome. That is to say that for one of the parental pair of chromosomes a whole segment has been replaced by material from the other, leading to loss of the contribution from one parent and duplication of that from the other, via an aberrant chromosomal-cutting-copying-and-pasting event. This is one route to loss of heterozygosity a phenomenon which would cause a weak parental allele at patched to be exposed and by implication the tumor suppressor activity corresponding to patched to be diminished. Another route to loss of the original heterozygosity is by the acquisition of new mutations at patched, and these are also found. While extensive chromosomal changes are a signature of many of the cellular transformations leading to cancer, the convergence of different mechanisms of genomic change on the patched locus does suggest that changes and allelic differences at this locus are a deterministic effecter rather than a passive consequence of BCC and as a predisposing factor to shade-seeking or sunscreen.
Steve Hughes, Egenis
* Some of us who have been patched with skin grafts up to cover the disfigurements of surgical intervention to remove BCCs may find the term patched somewhat ironic but the name comes from that assigned originally to the corresponding gene locus in the fruit fly.