Childhood brain tumors associated with rarely inherited BRCA2 gene mutations

New research led by scientists at Memorial Sloan-Kettering Cancer Center and The Rockefeller University shows that pediatric brain tumors and Fanconi anemia can develop among children in the rare instance that both parents carry mutations of the BRCA2 gene. The work will be published in the October 15 issue of the Journal of the National Cancer Institute.

The report describes four families in which both parents carried BRCA2 mutations. The families were part of The International Fanconi Anemia Registry, a unique, prospectively collected database of approximately 1,000 patients with Fanconi anemia, a rare inherited disorder characterized by a severe deficiency of red blood cells, bone marrow failure, and a predisposition to cancer. The registry was established at The Rockefeller University in 1982 to address questions relating to diagnosis, prognosis, treatment, natural history of the disease, and cancer incidence in a large number of patients with this disorder.

According to the study, individual children from three of the families, and two distant cousins from the fourth family were born carrying two mutations of the BRCA2 gene, one inherited from each of their parents. In all four cases, the children were affected not only with Fanconi anemia, but also with brain tumors diagnosed at an average age of 3.5 years.

“These findings are the first to establish childhood brain cancers, predominantly medulloblastoma, as among the diseases that can occur if both parents carry BRCA2 mutations,” said the study’s lead author Kenneth Offit, MD, Chief of the Clinical Genetics Service at Memorial Sloan-Kettering Cancer Center (MSKCC).

“It has been known that in rare cases, BRCA2 mutations can be inherited and cause Fanconi anemia,” commented the study’s senior author Arleen Auerbach, PhD, Director of the International Fanconi Anemia Registry at The Rockefeller University.

“While brain tumors are extremely unusual in these patients, these results suggest that BRCA2 mutations may provide an important clue to the origin of these tumors,” she said.

In the study, two of the four families with affected children carried a particular mutation of BRCA2 – the identical mutation in BRCA2 that is most frequency associated with an increased risk of breast and ovarian cancer in those of Ashkenazi Jewish ancestry. That mutation was first described by Dr. Offit’s group in 1996.

In the study, the authors recommend that individuals with BRCA2 mutations consider additional genetic counseling if their spouse is also at increased risk for having a BRCA2 mutation. In the rare circumstance that their partner also carries a BRCA2 mutation, there is the possibility that their offspring may be affected by Fanconi anemia and brain tumors.

However, according to the researchers, such cases are extremely rare. The chances of someone in the general population having a BRCA2 mutation are about 1 in 800; the risk is higher among individuals of Ashkenazi Jewish descent, approximately 1 in 100. In addition, while the total number of Fanconi anemia patients is not documented worldwide, scientists estimate that the likelihood of being a carrier for this disorder is somewhere between 1 in 300 and 1 in 100, the carrier frequency varying by ethnic group. If both parents carry a mutation in the same Fanconi anemia gene, each of their children has a 25 percent chance of inheriting the defective gene from both parents, which would cause the child to have the disorder.

“By studying the occurrence of very rare tumors in genetically defined populations, we have been able to learn much about the mechanisms of tumor development,” said Dr. Auerbach.

Additional experiments are underway to analyze whether BRCA2 mutations are involved in other cases of childhood brain cancer among families in the registry.

“Our goal is to translate these findings regarding cancers of the brain and breast into better prevention and treatment strategies for these malignancies,” said Dr. Offit.

The work was supported by the National Institutes of Health; the Lymphoma Foundation; the Danziger Foundation; the Koodish Fellowship; the Goldsmith Research Project; the Lomangino, Weissenbach, Southworth, and Niehaus Family Research Funds; the Elterninitiative Kinderkrebsklinik e. V.; and the Kinderstem e. V.

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