Genetic predisposition to mesothelioma discovered

Asbestos is still used as a building material in much of the world, despite incontrovertible evidence that inhalation of its fibrous crystals causes malignant mesothelioma. Yet, only a small proportion of those exposed develop this deadly cancer. Each year, 3,000 die of mesothelioma in the United States, but between 1949 and 1979, 27 million US workers were exposed to asbestos.

An international team of researchers led by Michele Carbone at the University of Hawaii, including Umran Dogan at King Fahd University of Petroleum and Minerals in Dhahran, Saudi Arabia, searched the genomes of two US families with a high incidence of the disease, among other malignancies, and publish their findings in Nature Genetics.

First, Joseph Testa's laboratory at the Fox Chase Cancer Center in Philadelphia, Pennsylvania, conducted array-comparative genomic hybridization, a technique used to detect gene copy number variation, in a tumour from a member of each family. This work identified alternations to the gene BAP1, known to encode a nuclear protein that binds to the tumour suppressor BRCA1 — notorious because its mutants can promote the development of breast cancer. The BAP1 gene encodes a novel ubiquitin hydrolase that has been shown to regulate the expression of multiple genes via deubiquitination of targets, and BAP1 mutations lead to abnormal cell proliferation.

Next, the team sequenced BAP1 in the blood cells of both families. They found that five members in one family (each with a mutated form of BAP1) had malignant mesothelioma, breast, ovarian or renal cancer. In the second family, they found a BAP1 mutation in six members with mesothelioma, two with uveal melanoma, and several others with skin or pancreatic cancers. Otherwise healthy family members did not carry the mutation. Neither family had members who worked with the hazardous material, but they did live in homes containing asbestos, suggesting a modest exposure.

With the link to BAP1 firmly established, the research expanded to 26 people with sporadic mesothelioma who reported exposure to asbestos. They found approximately one fourth had somatic mutations to the BAP1 gene in tumour cells, in line with results of a similar study by another research group. They also found that four individuals had uveal melanoma, three of whom later developed mesothelioma.

The researchers propose that this is a new cancer syndrome characterized by the development of uveal melanoma and mesothelioma, and possibly by other malignancies. In addition, mutated BAP1 renders people vulnerable to the continuing scourge of asbestos.

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