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Fanconi Anemia Research Opens New Doors in Understanding of Cancer

Jeanne Erdmann

When oncologist Alan D’Andrea M.D., of the Dana-Farber Cancer Institute, Boston, began sorting through Fanconi anemia genes for connections to other cancer genes, he was heading down a well-trodden path in cancer biology. Although Fanconi anemia is uncommon, hereditary diseases that predispose people to early cancers or to rare cancers have helped scientists understand tumor suppressor genes such as p53 and the retinoblastoma (Rb) gene.



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The above pathway proposed by Alan D’Andrea, M.D., shows how seven Fanconi anemia proteins respond to DNA damage using homologous recombination, a signaling pathway common to other diseases marked by chromosome breakage, such as ataxia telangiectasia. (Reprinted from Curr Biol. 2003;13:R546 with permission from Elsevier.)

 
D’Andrea noticed a striking resemblance between breast tumor cells carrying BRCA mutations and the cells of his Fanconi patients. Cells from both conditions were sensitive to chromosome breakage.

Could there be a connection? Indeed there was. He and his colleagues found that BRCA2, a major breast and ovarian cancer gene, is also a Fanconi anemia gene called FANCD1. This finding has uncovered a common DNA repair pathway among seemingly dissimilar conditions and has scientists wondering whether mutations in Fanconi anemia genes might predispose the general population to certain cancers.

A Rare Disease

The Fanconi Research Fund Web site lists approximately 500 Fanconi families worldwide. The birthrate for those affected with this autosomal recessive disorder is roughly 1 in 300,000. In the general population, the carrier rate for Fanconi mutations is roughly in 1 in 300, but the rate can be as high as 1 in 90 in populations that intermarry, such as Ashkenazi Jews.

Thus far, scientists have identified at least 10 Fanconi anemia genes, said Blanche Alter, M.D., expert in the Clinical Genetics Branch at the National Cancer Institute.

Alter has cared for Fanconi anemia patients her entire career and has seen a gradual increase in their life span from childhood until age 30 or so. But this longer life brings a dramatic increase in cancers, many of which are not easily explained.

When aplastic anemia, the hallmark of this disease, is treated with a bone marrow transplant, the marrow may be cured of Fanconi anemia, but not the rest of the body. Cells with defective Fanconi anemia genes sit in all tissues and may lead to an increased rate of solid tumors, such as vulvar and head and neck cancers, perhaps because of defective DNA repair, said Alter.

She and her NCI colleagues recently used a retrospective cohort for a time-dependent risk analysis of cancer formation in Fanconi patients. The work, published this year in Blood, found that people with Fanconi anemia have a 50-fold higher combined risk of solid tumors than the general population. When this risk was broken down into individual tumors, the range increased from several hundred to more than one thousand-fold.

Because these patients have high rates of oral and gynecologic cancers, Alter and collaborators are studying the possible link between the human papillomavirus and Fanconi anemia. Alter and other scientists in the field hypothesize that mutations in these genes may also be involved in specific cancers in the general population.

A Common Repair Pathway

Cells that carry Fanconi anemia mutations also carry a weak spot: They are sensitive to chemicals that cause crosslinks in DNA strands. This vulnerability is used diagnostically when the chemotherapy drug mitomycin C is added in a laboratory test, a chromosome breakage test, to confirm the disease.

In cancer treatment, this Achilles’ heel is exploited when cisplatin, also a DNA cross-linker, is used as chemotherapy against some tumors such as ovarian cancer.

Although little is known about the normal function of individual Fanconi genes, they are activated when cells divide and when DNA damage occurs. In normal cells, five of the Fanconi proteins form a nuclear complex and activate another Fanconi protein, which interacts in the nucleus with BRCA1 and BRCA2, said D’Andrea.

The Fanconi-BRCA pathway is activated in response to certain kinds of DNA damage, particularly DNA agents that cause double-strand breaks in DNA such as ultraviolet light, ionizing radiation, and cisplatin. Patients with Fanconi anemia and with mutations in the Fanconi genes cannot repair this type of damage because this pathway is disrupted, he said.

"This seems to be a very selective DNA repair pathway which perhaps has evolved in humans because we live longer and are exposed to a lot of toxins," said D’Andrea.

Fanconi-BRCA and Ovarian Cancer

After D’Andrea and his colleagues found that BRCA2 and FANCD1 were identical genes, they turned their attention to sporadic ovarian tumors, which are also sensitive to cisplatin and chromosome breakage but can become resistant to the drug during treatment. They knew that sporadic cancers did not have mutations in BRCA1 and BRCA2, but the Fanconi genes and BRCA1 and 2 do work together in a common signaling pathway. They sorted through this pathway in ovarian tumor cell lines sensitive to cisplatin.

In research published this year in Nature Medicine, D’Andrea and Toshiyasu Taniguchi, M.D., Ph.D., of the Dana-Farber Cancer Institute, found that one of the genes, Fanconi F, was silenced by methylation, which shuts down the gene and renders the pathway of Fanconi genes inoperative. That methylation gives the cell a Fanconi phenotype, said D’Andrea, because it is sensitive to cisplatin and chromosome breakage—and it is prone to cancer.

Once the cancerous cell has been exposed to cisplatin, that gene becomes reactivated, which helps the cell disguise itself and "hide" from the treatment. It is still cancer but now it’s resistant to cisplatin, said D’Andrea.

Identification of this gene silencing in the Fanconi-BRCA pathway could be used for diagnostics, therapeutics, or drug discovery, he added. For example, women with sporadic or hereditary ovarian cancer could be screened for a defect in the Fanconi-BRCA pathway in the tumor, which may predict a clinical course before treatment.

Scientists are finding possible connections between the Fanconi-BRCA pathway and other conditions marked by chromosome breakage and predisposition to cancer. Proteins in the hereditary diseases ataxia telangiectasia and Nijmegen breakage syndrome interact with some parts of this pathway.

The implications of these findings could reach far from rare hereditary diseases and far from hereditary breast and ovarian cancers. Because everyone carries normal Fanconi genes and 1 in 300 people carry mutations in those genes, could those mutations cause certain cancers in the general population?

That’s been one problem with the Fanconi-BRCA model. Until recently, said D’Andrea, scientists thought that carriers of mutated genes do not seem to get cancer.

Scott Kern, M.D., professor of oncology at Johns Hopkins Kimmel Cancer Center, Baltimore, and a specialist in pancreas cancer, thinks otherwise.

"Many people still remember the 5 or 7 years when we didn’t know what BRCA2 was really doing in the cell and they think of BRCA2 as just another tumor suppressor gene. But it’s not. It’s a Fanconi anemia gene, and it’s been looking us right in the face all of these years. We haven’t realized there’s a tie between Fanconi anemia and common cancers," said Kern.

That realization caused Kern—who participated in the original search for BRCA2, a mutation that is also important in familial pancreas cancer—to think of this cancer as a manifestation of Fanconi genes.

When he looked into the connection by studying tumors from patients with early-onset pancreatic cancers, he found specific mutations in two Fanconi genes, FANCC and FANCG. The work published recently in Cancer Research found that one of these mutations is common in people with German descent, and the other is a somatic mutation acquired when the cell became cancerous.

Kern said it may take 10 years to sort out the implications of these two mutations. He and his colleagues also found many other mutations, should scientists identify them in other cancers.

Research stemming from the BRCA-Fanconi pathway may be the tip of the iceberg in identifying cancer risk if people who carry mutations in these genes face an increased risk of cancer that is not definable by our current knowledge, Kern said.

Understanding the Cell Cycle

In the meantime, these discoveries are helping scientists understand the cell cycle and recognize how the cell copes with damage to its DNA, one of the fundamental mechanisms that leads to cancer.

"Cancer is a multi-step pathway. One gene might get knocked out and that may create instability within the cell, which might then lead to mutations in other genes occurring. Eventually, it escalates and reaches a critical point, and control over the cell cycle is lost and the cell become cancerous," explained Marc Tischkowitz, Ph.D., Institute of Child Health, London and an author on D’Andrea’s Nature Medicine paper.

For now though, not all scientists agree on whether the Fanconi proteins work by interacting with damaged DNA during the repair process or through detection of DNA damage at cell-cycle checkpoints. NCI’s Alter noted that DNA repair pathways are complicated and have incredibly large numbers of proteins and much still needs to be sorted through.

"The other thing that we all have to keep in mind is that these proteins probably have other actions besides getting together in this complex and triggering the downstream pathway. They may interact with other proteins," said Alter. "So we have to be open-minded right now about what they do."

Tischkowitz said it is likely that some Fanconi proteins work outside the DNA repair pathway. For example, scientists do not know why some children with Fanconi anemia have many congenital abnormalities, such as skeletal malformations. The challenge now, he said, is to take the basic elements of our inheritance that have been broken down by the Human Genome Project and use it to build an understanding of these pathways.

"The more genes you have to work with, the more different ways they have to interact. It increases exponentially. But often what we do is quite reductionist, finding genes and breaking everything down into individual components," said Tischkowitz. "So it’s nice to put them all together in a common pathway."



             
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