Diagnostics & Imaging Week Contributing Writer

A strategy to compare the genomes of cells from human tumors with those of normal body cells to identify genes that initiate the development of cancer has proved successful, allowing scientists to confirm the role of a known gene in the development of basal-cell carcinoma (BCC).

The researchers, funded by Cancer Research UK and the Association for International Cancer Research (AICR), showed that cells in more than 90% of BCC have genetic damage in the same place. The region of the genome affected contains a gene called PTCH (known as “patched”), which already has been linked to skin and other types of cancer.

Muy-Teck Teh, lecturer in oral cancer at Queen Mary’s School of Medicine and Dentistry (London), told Diagnostics & Imaging Week’s sister publication, BioWorld International: “The fact that we found this signature pattern of genetic damage in over 90 percent of samples of BCC in humans suggests that damage to PTCH may be the ‘first hit’ that is required in order for BCC to form.”

Teh and his colleagues reported their work in a paper in the Oct. 1 issue of Cancer Research.

BCC is a form of non-melanoma skin cancer. It develops following genetic damage caused by ultraviolet radiation in, for example, sunlight. Each year, more than 60,000 people in the UK are diagnosed with BCC, but few people die from it.

Teh’s group knew that the PTCH gene was a tumor suppressor gene that had been implicated in BCC before. Researchers had found mutations in PTCH in people with Gorlin syndrome, who suffer from developmental defects and BCC formation. In addition, mice lacking two functional copies of the PTCH gene died during early embryonic life, so the gene is clearly required for normal development. Animals with only one functional copy of the gene survive to adulthood, but they are more prone to cancer, especially skin cancer. But it was not clear if PTCH was the key gene, or if other genes also were involved in BCC formation.

In order to obtain a more detailed picture, the researchers set out to compare the entire genomes of normal cells and cells from BCCs. They embarked on a search for regions in which the genome had undergone changes resulting in a condition called loss of heterozygosity. Such a change means that if a gene (such as a tumor suppressor gene) becomes mutated, there is no wild-type gene to compensate for its loss, and the risks of a tumor developing increase.

David Kelsell, lead researcher of the study, said: “We used a technology called a gene chip array that detects any difference between two sets of genes. It’s a vast improvement on previous technologies, which could not pick up certain differences. By comparing a BCC patient’s tumor cells with their healthy cells, we were able to see all of the genetic events that played a part in the development of disease in that individual.”

Further studies on those patients – the majority – who had lost heterozygosity of the genome on the region of chromosome 9 that contains the PTCH gene, showed that 70% of the tumors had mutations in the PTCH gene itself.

Teh added: “We have identified a ‘signature fingerprint’ for BCC, which has very few genetic changes compared to that seen in non-skin epithelial cancers like breast and colon. However, we have also found other less common genetic changes in the BCC, indicating that other genes may also be involved in BCC development.”

Mark Matfield, Scottish scientific consultant of AIRC, said: “There are over 200 different types of cancer, and each one is caused by a handful of key genetic changes. This new gene-testing technology means we will be able to identify them all and that means we can soon start developing treatments aimed at the actual cause of the cancers. [This discovery] will, we expect, be followed by similar discoveries on many different types of cancer, pushing the study of cancer into the next stage of genetic research.”