Many families are acutely aware that BRCA1 and BRCA2 are the most important breast and ovarian cancer susceptibility genes. But recently, a team, including researchers at Penn Medicine discovered another risk these genes can pose when both parents carry the mutation.
When I spoke with Roger Greenberg, PhD, about his new paper published online in Cancer Discovery, it came as a surprise to me to learn that these genes are also implicated in Fanconi anemia, a rare, inherited blood disorder that can lead to bone marrow failure. Greenberg is a professor of Cancer Biology, an associate investigator at the Abramson Family Cancer Research Institute, and the basic scientific director for the Basser Research Center for BRCA at Penn.
The study all started with the discovery of a biallelic BRCA1
mutation in a young Finnish woman with Fanconi-like symptoms who was diagnosed with breast cancer at age 23. Biallelic simply means two alleles, or variations of a gene, one from each parent. Most breast cancers originate in women who only have one mutated copy of the gene from a parent, not two.
“We established that biallelic mutations in the breast cancer gene BRCA1 cause a distinct subtype of Fanconi anemia along with extremely early-onset breast cancer, which has implications for counseling families where both parents harbor BRCA1 mutations,” says Roger. According to the National Heart, Lung and Blood Institute, about 1 in 130,000 people are born with Fanconi anemia in the US each year. Two ethnic groups, Ashkenazi Jews and Afrikaners, are more likely than other groups to have the disorder or be a carrier.
Greenberg became involved in this international research effort when Sarah Sawyer, a geneticist from the Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa, Canada, contacted him, “out of the blue” about the 23 year old. A physician in Finland -- Jukka S. Moilanen, from the department of Clinical Genetics and Medical Research, Oulu University Hospital -- had contacted Sawyer to locate the mutation in this patient because of her work with rare genetic diseases.
Known mutated proteins associated with Fanconi anemia interact with the BRCA1 protein during DNA repair. From this, deficiency in DNA repair that depends on BRCA proteins is intimately connected to breast and ovarian cancer susceptibility and now to Fanconi anemia.
In the Finnish patient’s case, the team found that her skin fibroblastcells were deficient in the BRCA1 and Rad51 repair proteins at sites of DNA damage, combined with misformed chromosomes and hypersensitivity to specific DNA damage-inducing agents. The Greenberg team reversed these three characteristics by introducing a normal BRCA1 gene into the patient’s fibroblast cells, thereby providing a proof of principle of their hunches in this human cell-based experiment.
Prior to this study, 16 genes (all for DNA-repair proteins, including BRCA2) were known to be mutated in Fanconi anemia, and all of these alterations are characterized by deficiency in repairing strands of DNA that are mistakenly linked by chemical bonds. These aberrant links can ultimately cause cell death.
Greenberg wasn’t really surprised when he heard from Sawyer about the Finnish patient because of an earlier Penn paper, also in Cancer Discovery, with Susan Domchek MD, a professor of Medicine and director of the Basser Research Center for BRCA. This study described another patient with two BRCA1 mutations who was diagnosed with ovarian cancer when she was 28, which is extremely early, even for patients with BRCA mutations.
The team surmised that in both patients, the BRCA1 protein is hobbled but not completely absent. “This told us that BRCA2 Fanconi patients we already knew about are different compared to this new BRCA1 Fanconi patient,” says Greenberg. The patients differ in this way: The BRCA2 mutations some Fanconi patients have cause a more severe type of disease and different forms of cancer, including brain tumors. On the other hand, the BRCA1 Fanconi patient may have a more mild form of disease that does not cause bone marrow failure, but causes very early onset breast and ovarian cancer.
From the most recent paper, the authors now know there are patients out there who have two mutated copies of BRCA1, and this can help genetic counselors advise these patients to avoid certain types of chemotherapy that induce DNA crosslinks. For example, platinum salts that are typically used in ovarian cancer. These patients cannot stand the DNA damage that these treatments cause and can get extraordinarily sick.
The studies also define the sites within the BRCA1 gene where biallelic mutations are most likely to occur together and associate these changes with the clinical symptoms that arise in these patients. Now, counselors and basic researchers are better able to help families who carry these double-whammy genes.