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All three of the most common forms of skin cancer (melanoma, basal cell carcinoma and squamous cell carcinoma) can be caused by inherited genetic defects, although all hereditary forms of skin cancer are very rare. By studying inherited forms of these cancers, scientists have learned (and are continuing to learn) much about why tumours develop and, hopefully, what can be done to treat and prevent them.

So, what happens in the process from a gene to a cancer? Or vice versa?

Tales of Hedgehogs and Scotsmen

The stories of the hereditary forms of squamous cell carcinoma and basal cell carcinoma illustrate the routes that scientists can take to find¹ the genes that cause particular diseases. As with most rare diseases, both conditions are named after the person who first described them. So, hereditary squamous cell carcinoma is often known as 'Ferguson-Smith disease' and hereditary basal cell carcinoma is called 'Gorlin syndrome'. This is partly to honour the painstaking work and careful observations that were carried out by the doctors in question, but mainly because the scientific names of the diseases verge on the unpronounceable. Ferguson-Smith disease is also known as 'multiple self-healing squamous epithelioma' (MSSE² for short), while Gorlin syndrome should technically be called 'naevoid basal cell carcinoma syndrome (or NBCCS³).

Hedgehogs

People with NBCCS develop numerous basal cell carcinomas, particularly between puberty and 35 years of age. Only a very small number of these tumours become malignant, and patients have frequent check-ups to spot those that do. People with NBCCS often have other signs of the disease, such as pits in the palms of the hands and soles of the feet, and faults in their ribs.

Yes, but... Hedgehogs?

The gene that is altered in NBCCS is known as PATCHED⁴. This is because it is very similar to a gene called patched that was first discovered in fruit flies (or Drosophila, if you prefer). When you knock out the patched gene in a fruit fly, you get fly embryos that look patchy - fruit fly geneticists have limited imaginations and odd senses of humour. Patched was found to be very important in a long and complicated cellular pathway involving a gene called hedgehog (if you knock out the hedgehog gene, you get fly embryos that look... you get the idea. Incidentally, the human equivalent of hedgehog is called SONIC HEDGEHOG. You were warned).

PATCHED was found by two groups of scientists simultaneously, each group working in the opposite direction to the other. One group started with NBCCS. Most families with the condition all seemed to have a fault in the same stretch of DNA (part of chromosome 9). So, the scientists looked at the sequence of this section to see if it matched any genes that were already known, which, of course, it did: patched. The second group's reasoning was slightly different. They started with the fruit fly version of patched and thought 'this is obviously an important gene in flies, I wonder if it's involved in any human diseases'. They used patched to find matching sections of human DNA, and up popped PATCHED. Different routes, the same outcome. But it's not always as easy as that...

And Scotsmen?

MSSE is very rare. Most of the patients who are known to have this condition can trace their ancestry back to one family who lived in the west of Scotland sometime in the 18th Century. People with MSSE generally start to get squamous cell carcinomas on their hands, arms and face shortly after puberty. Unlike ordinary squamous cell carcinomas, however, MSSE tumours eventually disappear. They leave an unpleasant scar, but otherwise do little damage. No-one knows why this happens, yet.

Using similar techniques to those used to find PATCHED, researchers found that the gene that is affected in MSSE also lies within a short stretch of chromosome 9. Unfortunately, this particular region of chromosome 9 is extremely popular with genes for rare diseases:

• Hereditary sensory neuropathy, which involves gradual loss of nerves that sense pain and temperature.

• Fanconi anaemia, a disease in which people gradually lose the ability to produce blood cells, and also develop certain types of cancer.

• Xeroderma pigmentosum, in which people are extremely sensitive to sunlight and develop many different skin cancers.

• Brachydactyly, a condition in which the ends of the fingers and nails are missing.

• Certain diseases of metabolism, including some families with hereditary diabetes.

...and, just to complicate things a little further, this part of chromosome 9 is also the region that contains PATCHED.

Most of these genes have been ruled out, but there are undoubtedly others waiting to be discovered, one of which must be the one involved in MSSE. Fortunately, the publication of the Human Genome Project means that looking for genes is about to become a lot easier. Having said that, finding the gene is only half the battle. You then have to work out what the gene does and why you get a particular type of cancer when it gets damaged. And that's the hard part...

Not all Genes Have Interesting Names

Hereditary melanoma has been linked to alterations in a gene known, rather boringly as P16 or, alternatively and not much more interestingly, INK4A. P16 is involved in the insanely complex chain of command that makes sure that cells multiply only when they absolutely have to. If you damage P16, or any of the hundreds of other genes that do a similar job⁵, then the cell will start multiplying with carefree abandon, and that's when cancer starts to develop. Alterations in P16 have been found in almost all different types of cancers, so why a person should specifically develop melanomas when they inherit an altered form of the gene is still something of a mystery. As much of a mystery as why people develop basal cell carcinomas when they inherit a faulty version of PATCHED, or, indeed, why any gene should be linked to a specific type of inherited cancer. It's mysteries like this, however, that help to keep researchers plugging away to try to understand why cancer develops, what you can do about it when it does and, just maybe, how to stop it happening in the future...