New gene linked to familial cancer

Apr 20 2005

Scientists have identified a new gene that appears to be linked to a small but significant percentage of familial cancer cases – as well as seemingly randomly occurring malignancies.

The finding has scientists re-examining commonly held beliefs about the nature and frequency of genetic mutation as a cause of cancer. Familial cancer, in contrast to inherited cancer, is defined as multiple cases of cancer in one family that cannot be accounted for by classic rules of inheritance.

The findings are published in the April 21 issue of the New England Journal of Medicine.

“The findings suggest that a lot of cancer we once thought of as random may not be so random after all,” says George Calin, an adjunct assistant professor and research scientist in molecular virology, immunology and medical genetics and the first author of the study. He added that the findings hold important diagnostic and economic implications, as well.

Most geneticists believe that less than 5 percent of cancer is inherited, primarily through mutation in a relatively small number of well-known genes. Calin says that this new gene, however, dubbed ARLTS1, (ADP – Ribosylation Factor-Like Tumor Suppressor 1) can also increase a person’s chances of developing cancer, but only a little.

“ARLTS1 is one of an emerging set of genes whose effects are subtle, but which still play an important and predictable role in the development of cancer in some people.”

Researchers have known for years that a handful of well-known genes (like BRCA1 and BRCA2, for example) can, when mutated, dramatically increase a person’s risk of developing cancer. This “second tier” of genes, on the other hand, may heighten the risk of cancer for a much larger group of patients, says Carlo Croce, director of the Human Cancer Genetics Program at Ohio State and senior author of the study.

“Detecting alterations in such genes may more clearly predict who is predisposed to getting cancer, and who is not,” he adds.

Calin and Croce, both members of Ohio State’s Comprehensive Cancer Center, working with an international team of colleagues, had long suspected that a particular stretch of DNA on chromosome 13 – known as a rich source of mutations linked to various malignancies – might be the location of other genes important in carcinogenesis. Multiple tests with a portion of that DNA yielded ARLTS1 as a specific new gene.

ARLTS1 belongs to the Ras superfamily of genes that regulates cell growth. Most of the genes in that family are oncogenes, meaning that when activated, they cause cells to grow out of control. ARLTS1, on the other hand, is a tumor suppressor gene – a gene that normally helps the body identify and destroy suspicious-looking cells before they undergo malignant transformation and spread. When ARLTS1 is altered, it loses that ability, giving tumors a chance to establish themselves and grow.

To determine the extent to which ARLTS1 appears in various populations, researchers compared tumor tissue or blood samples from 325 patients with different forms of familial or sporadic cases of cancer to the blood of 475 healthy donors or patients with diseases other than cancer. The families, from the United States, France, Italy and Romania, included patients with chronic myeloid leukemia, or thyroid, colorectal, breast, lung or early stage pancreatic cancer.

Through multiple experimental and computational methods, researchers found that mutated ARLTS1 is three times more likely to be present in patients with familial cancers, and two times more likely to be present in random cases of cancer, than it is in the general population.

Calin says normal ARLTS1 activity can be compromised through deletion, mutation or alteration by a chemical change called methylation, adding that defective ARLTS1 also leads to inhibition of apoptosis, or normal cell death.

“We feel this discovery is significant on several levels. First, it adds one more player to the growing number of genes that are known to be active in the development of some forms of cancer,” says Croce.

“We also see this same gene mutated in small number of cancers that we once thought were randomly occurring in the general population. This is important for patients because one day in the near future, we will be able to incorporate a test for this gene – and others – into a simple screening tool that may reveal the extent to which a person is at risk for developing cancer.”

Calin says such tests could mean earlier detection of disease “which is not only good health, but good business.”

Grants from the National Cancer Institute, the Italian Ministry of Public Health and the Italian Association for Cancer Research supported the project.

Researchers from many cancer centers contributed to the study, including scientists from the Kimmel Cancer Center, Fox Chase Cancer Center; University of California at San Diego; Dana Farber Institute; University of Ferrara, Italy; Aarhus University, Denmark; Fundeni Hospital, Romania; University La Sapienza, Italy; Pasteur Institute, Paris; University of Catanzaro, Italy; Kyushu University, Japan; and Instituto Dermopatico dell’Immacolata, Italy.