Fanconi anemia (FA) is an autosomal recessive disorder in which affected subjects have great susceptibility to neoplasia early in life, including acute myeloid leukemia and squamous cell carcinoma.  Bone marrow failure is also frequent, as well as mutations in at least 8 groups of FA patients (A, B, C, D₁, D₂, E, F and G) and germline mutations in six of these have been identified in 6 genes (A, C, D₂, E, F and G).  The FA cells manifest many broken and misshapen chromosomes reflecting that FA proteins participate in the repair of DNA damage, either stimulating or inhibiting normal repairs.  Five of the 6 genes previously described combine in a multi-subunit nuclear complex which activates by ubiquitination of the protein product of a sixth gene (FANCD2) which is involved in the process of DNA repair.  Howlett et al¹ identified a 7th gene by demonstrating that homozygous “loss of function” mutations occurring in the BRCA2 gene (causing breast cancer as does the BRCA1 gene) occurs in a subset of patients with FA. 

Witt and Ashworth² stated in the introduction of their commentary; “Important discoveries are so neat and satisfying that, in retrospect, they seem obvious.  Howlett et al disclosed that the inheritance of two defective copies of the BRCA2 breast cancer susceptibility gene can lead to FA.  The BRCA2 protein is thought to be important in the repair of DNA damage.  Cells lacking BRCA2 inaccurately repair damaged DNA leading to gene mutation and progression of tumors and are particularly sensitive to DNA cross-linking agents.  Howlett et al demonstrated that one of the previously unidentified FA genes (FANCD1) is BRCA2.”  No BRCA1 mutations were found in the patients studied by Howlett et al.  However, all the authors of all three papers speculatively agreed that the 6 previously cloned genes are linked in a common pathway with BRCA1 and BRCA2 genes.^1-3

Venkitaraman³ in his closing comments stated; “The network which connects BRCA and FA proteins in DNA repair includes at least two other molecules - ATM (mutated in ataxia telangiectasia) and CHEK2 - whose inactivation is also associated with carcinogenesis in several tissues.  Although the precise functional connections between the molecules in this network remain obscure, it is clear we are glimpsing an important tumour suppressor pathway whose disruption may underlie many different types of human cancer.”

1.    Howlett NG, et al. Science 2002;297:606-609.

2.    Witt E, Ashworth A.  Science 2002;297:534.

3.    Venkitaraman AR.  Lancet 2002;369:1343-1345.

First Editor’s Comment:  Heterozygous inactivating germline mutations in BRCA1 and BRCA2 have been linked to increased susceptibility to breast and ovarian cancer in women.¹  In the tumors that develop in these patients, there is loss of heterozygosity of BRCA1 or BRCA2.  Both BRCA1 and BRCA2 are important for repair of DNA damaged by exposure to ionizing radiation and cross-linking, and do so by interrupting the cell cycle while promoting repair of the damaged DNA strands.^{1-3  The} carboxyl-terminal domain of BRCA2 likely binds to single strands of DNA at the site(s) of a double stranded DNA break and facilitates the binding of other repair factors such as RAD51, an important member of this family.  This article is of interest because it demonstrates the difference in phenotypes that result from heterozygous as compared to homozygous germline mutations in BRCA2.  How this mutation affects somatic growth and the reproductive endocrine system is unclear. However, Wajnrajch et al⁴ found aberrations of endocrine function in 44/54 primarily prepubertal patients with FA.⁴ Abnormalities included short stature with mean height SDS -2.35 (due to growth hormone insufficiency in 44%), hypothyroidism (36%), hyperinsulinemia (72%), impaired glucose tolerance (25%), and diabetes mellitus (2%).  Skeletal maturation was approximately one year delayed behind chronologic age; predicted adult height in 22 subjects was -1.24 SDS.

References

1.    Wilson JH, Elledge SJ. Science 2002;297:1822-1823.

2.    Yang H, et al. Science 2002;297:1837-1848.

3.    Witt E, Ashworth A. Science 2002;297:534.

4.    Wajnrajch MP, et al. Pediatrics 2001;107:744-754.

Allen W. Root, MD

Second Editor’s Comment: The phenomena described in the papers given as references are phenomenal.  The first 3 references read as a package will permit any reader not informed about such matters to advance into the upper elementary levels, both in respect to understanding the physiology and pathophysiology of Fanconi Anemia, breast cancer, and to the interactions of genes and gene products.

Robert M. Blizzard, MD