BRCA Mutations and Childhood Cancer

Mutation of the Breast Cancer 1 and 2 genes were identified in 1993 and 1994 respectively as the underlying genetic cause for a significant number of familial breast and ovarian cancers.¹ Patients carrying germline, heterozygous mutations in either the BRCA1 or BRCA2 genes demonstrate highly penetrant breast and ovarian cancer phenotypes. The tumors arising in these patients exhibit loss of heterozygosity (LOH) at the wildtype allele and retention of the mutated copy. Females with a family history of breast and/or ovarian cancer are screened for mutations in their BRCA1 and BRCA2 genes. This diagnostic modality has real clinical significance as large studies have conclusively demonstrated >90% reductions in breast and ovarian cancer incidence in BRCA1 and BRCA2 carriers that have undergone prophylactic mastectomy and salpingo-oophorectomy.^2,3

Despite a predilection for suppressing breast and ovarian epithelial cancers, both BRCA1 and BRCA2 play essential roles in the error free repair of DNA double strand break in all proliferating cell types, thus it seems reasonable to postulate a broader spectrum of tumor suppression exists for both genes. Indeed, it has been more recently demonstrated that hematopoietic and brain malignancies occur in pediatric patients afflicted with a particularly severe form of Fanconi anemia syndrome due to inherited, biallelic BRCA2 mutations.⁴ BRCA1 interacts with and coordinates the DNA repair activities of multiple other tumor suppressor proteins including two Fanconi anemia gene products, BRCA2 (FANCD1) and the Brip1 helicase (FANCJ).⁵ Moreover, transgenic mice engineered to carry mutations in their BRCA1 or BRCA2 genes develop cancer in multiple organ systems in addition to mammary gland cancers.⁶

Given the association of BRCA1 and BRCA2 mutations with cancer in multiple organ systems and in pediatric patients with Fanconi Anemia, Domchek and coworkers address the question of whether heterozygosity for either BRCA1 or BRCA2 mutation predisposes to childhood cancer as defined by malignancy prior to the age of 21 years. This is a particularly important question given the prevalence of BRCA1 and 2 mutations in the general population and the availability of highly sensitive and specific screening tests to detect germline mutation of either gene. Should a positive association be detected between BRCA mutation and an increased overall risk of childhood malignancy, recommendations for early screening of offspring from BRCA mutation carriers may be instituted.

The authors report in this issue a retrospective analysis of the prevalence of childhood cancers from families evaluated at a high-risk breast cancer clinic that have been either confirmed or ruled out as having BRCA1 or BRCA2 germline mutations. The data demonstrate nonsignificant differences between the prevalence of childhood cancers in high-risk patient families and kindred of BRCA mutation carriers (20 cases of cancer in 379 families with BRCA mutations vs 35 cases in 426 families with wildtype BRCA1 and BRCA2 genes p = 0.12). The spectrum of tumors observed was also not significantly affected by BRCA mutations, with leukemia and CNS tumors being most common for both groups, suggesting heterozygosity for BRCA1 or BRCA2 mutation does not contribute to either the prevalence or tissue specificity of childhood malignancy.

Although these differences did not reach statistical significance, as the authors point out, due to both the retrospective design and the size of this study, BRCA1 and BRCA2 mutation cannot be completely excluded as a cause of childhood cancer. As cancers arising in BRCA1 and BRCA2 heterozygous adults in the breast and ovary typically exhibit loss of the wt allele, it would also be worthwhile in future studies to examine childhood cancers in BRCA1 carriers for evidence of LOH. In the absence of LOH, a contribution to malignancy becomes less likely. Conversely, frequent LOH at the wildtype locus in BRCA carriers would be consistent with a causative role in the development of malignancy.

In conclusion, this is an important study that argues against a widespread strategy of testing children for the presence of germline BRCA1 and BRCA2 mutations, but rather supports current practice recommendations of BRCA testing only in adult patients.