This year, an estimated 239,300 new cases of breast cancer will be diagnosed in the U.S., and 40,200 will die of the disease.

A much rarer cancer-connected affliction, Fanconi anemia (FA), occurs in only some 500 American households. FA strikes one in 360,000 live births. The disease makes itself known at 7 years of age, on average, and death usually takes its small FA victims between their third and 13th birthday.

Until this year there was no obvious link between widespread breast cancer - mammary carcinoma - and the seldom-seen pediatric disorder, Fanconi anemia.

Now there is such a connection.

Today's issue of Science, nominally dated June 14, 2002, but released online June 13, carries the title: "Biallelic inactivation of BRCA2 in Fanconi anemia." Its senior author is pediatric oncologist Alan D'Andrea, a professor of medicine at Harvard Medical School and its affiliated Dana-Farber Cancer Institute, both in Boston.

"We report that an error in any of the half-dozen genes involved in Fanconi anemia," D'Andrea told BioWorld Today, "can increase an individual's chances of developing breast cancer. Our discovery raises the prospect that the ranks of known breast cancer susceptibility genes - BRCA1 and BRCA2 - may soon rise from two to eight. So we now know that these eight genes - two breast, six FA - cooperate in a common cellular pathway. We can use this information for new diagnostic, and potentially therapeutic, purposes in cancer.

"My laboratory has been studying this rare disease, Fanconi anemia, for about 10 years now," he continued, "and we've identified six genes that cause FA. The children who have this disease are prone to developing cancers at a young age. They usually contract leukemia, but also solid tumors, occasionally even breast cancer - if they live long enough. They usually die from complications of bone marrow failure."

Adult Cancer In Pediatric Patient Hints At FA

"I think it's the kind of disease," D'Andrea pointed out, "that has to be considered when a young child develops a cancer that one normally sees in adults. Sometimes small patients with FA develop cancer of the esophagus. And when one sees a child with a cancer like that, one has to contemplate the possibility that they have an underlying genetic cause for this disease - like FA.

"We made the observation a few months ago, surprising for us," D'Andrea said, "that breast cancer tumor cells we took from a woman in the general population had a striking resemblance to cells from FA patients. Under the microscope both cells had a very characteristic pattern of chromosome breakage and DNA damage. On the basis of this microscopic similarity between breast cancer cells and Fanconi anemia cells from a patient with FA, we realized that these genes were closely connected biologically and genetically.

"As we reported in Science, we had a few patients whom we'd followed with FA who did not fall into any of the traditional six gene subtype groups," he said. "So we took a lucky chance and sequenced their BRCA1 and BRCA2 genes. Amazingly, we found that while there were no mutations in BRCA1, there were biallelic mutations in the BRCA2 gene, one allele from the mother and one from the father. What that meant to us then was that the rare children with FA are in fact BRCA2 homozygotes. They got one mutant BRCA2 gene from the mother, who's a carrier, and another mutant BRCA2 gene from the father, also a carrier.

"That's a startling finding," D'Andrea observed. "It's the first time anyone has found mutations in both chromosome copies of the BRCA2 gene. In fact, until now, people were assuming that such homozygosity would be lethal. But in fact it's not lethal; these children lived, albeit a few years, before they succumbed to cancer.

"I think the significance of this finding," he said, "is that it clearly connects all of these genes in a very discrete function in the cell. What that means to me - and what I think it's going to mean to other investigators in the field - is that these six Fanconi anemia genes may themselves be breast cancer genes as well. So we should now begin screening the general population not only for mutations in BRCA1 and BRCA2, but for mutations in all of these FA genes, with the idea of trying to identify families who are at risk of developing new cancers.

"This has pretty broad diagnostic implications," he observed. "The therapeutic implications are perhaps a bit more remote. The therapeutic implications are that perhaps if one knew that an individual had an error in one of the genes in this pathway, one could conceivably design drugs to target and strengthen these pathways to stall the onset of a cancer - perhaps even to treat an early malignancy.

"Just as women today can be tested for BRCA1 and BRCA2 mutations to determine if they have an inherited predisposition for breast cancer, testing for mutations in these other six FA genes may soon become routine in gauging inherited breast cancer risk," he said.

Six New Drug Targets Await Commercialization

"So my hope is that now that we have eight target genes for breast cancer, perhaps pharmaceutical or biotech companies will recognize for drug design all of the genes in the pathway of this potential target," D'Andrea said. "People in the breast cancer field are going to find this pretty exciting. It's actually an example of working on a rare disease in a pediatric setting. Fanconi anemia is a pretty obscure disorder. Most people don't even know how to spell its name.

"The BRCA2 mutations that we've found in these patients are a little atypical," he said. "The children who have FA and biallelic BRCA2 mutations, one mutation - say from the mother or father - is usually quite severe. And that's one of the known BRCA2 mutations that have been found in breast cancer patients in the general population. The other mutation, though, tends to be more mild. That allows the FA patient to survive. Because if he or she had two extremely severe mutations in BRCA2, then that would be embryonically lethal. They probably would not even be born.

"Guido Fanconi [1892-1979] was a very famous pediatrician in Italy," D'Andrea recalled. "He studied at the University of Zurich in Switzerland, for many years. It was Fanconi who originally - in the early part of the 20th century, perhaps in the 1930s - described the blood disease, which now bears his name."