Fanconi anemia and the development of leukemia

Abstract

Fanconi anemia (FA) is a rare autosomal recessive cancer-prone inherited bone marrow failure syndrome, due to mutations in 16 genes, whose protein products collaborate in a DNA repair pathway. The major complications are aplastic anemia, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and specific solid tumors. A severe subset, due to mutations in FANCD1/BRCA2, has a cumulative incidence of cancer of 97% by age 7 years; the cancers are AML, brain tumors, and Wilms tumor; several patients have multiple events. Patients with the other genotypes (FANCA through FANCQ) have cumulative risks of more than 50% of marrow failure, 20% of AML, and 30% of solid tumors (usually head and neck or gynecologic squamous cell carcinoma), by age 40, and they too are at risk of multiple adverse events. Hematopoietic stem cell transplant may cure AML and MDS, and preemptive transplant may be appropriate, but its use is a complicated decision.

Keywords: Fanconi anemia; bone marrow failure; leukemia; myelodysplastic syndrome; stem cell transplant.

Figure 1

Chromosome breakage. Metaphases from blood T-lymphocytes following culture with phytohemagglutinin and a DNA crosslinking agent such as diepoxybutante or mitmycin C. Figure shows breaks, gaps, rearrangements and endoreduplications.

Figure 2

Fanconi anemia genes, indicating the majority are FANCA, followed by FANCC and FANCG, and others less frequent. The ones marked with an asterisk are associated with breast cancer in heterozygotes, and FA when mutations occur in both alleles. Adapted from Leiden Open Variation Database, http://chromium.liacs.nl/LOVD2/FANC/home.php.

Figure 3

FA/BRCA DNA damage response pathway. Following DNA damage, the proteins represented by A, B, C, E, F, G, L and M form the core complex, which is required for ubiquitination of the I and D2 proteins, which are in turn required for the downstream complex of D2-ubi, I-ubi, and D1/BRCA2, J/BRIP1, N/PALB2, BRCA1, O/RAD51C, P/SLX4, Q/ERCC4, and BRCA1 to form DNA repair foci. Only BRCA1 has not yet been proven to be a Fanconi gene. Adapted from Shimamura and Alter [1]. Reprinted from Blood Reviews, Volume 24/Edition 3, Shimamura A, Alter BP, Pathophysiology and management of inherited bone marrow failure syndromes, Pages 101-22, 2010, with permission from Elsevier.

Figure 4

The types and frequencies of cancer in FA reported in the literature from 1927 through 2012. There were 188 cases of leukemia, of which 84% were acute myeloid leukemia, and 286 solid tumors, in 413 of 2190 people with FA. Forty-seven had 2–4 cancers.

Figure 5

The relative risk of cancer compared with the general population (using SEER data) in a combination of four independent cohorts. The Y axis shows the observed/expected ratio on a log scale. The risk of any cancer was ~50-fold, solid tumors ~40-fold, HNSCC ~550-fold, vulvar 3000-fold, AML 700-fold, and MDS 6600-fold. Data from [–7].

Figure 6

Annual hazard rate and cumulative incidence of competing adverse events by age in patients with Fanconi Anaemia (FA). Adverse events are severe bone marrow failure (BMF, blue), leukemia (AML, black), or solid tumors (ST, red). Results are combined from the cohorts cited in Figure 5. Left, Annual hazard rate in percent per year. Right, cumulative incidence by age (cumulative percentage experiencing each event as initial cause of failure) and 95% confidence intervals (CI) (shaded areas). From Alter et al [4]. Reprinted from Alter BP, Giri N, Savage SA, et al. Malignancies and survival patterns in the National Cancer Institute inherited bone marrow failure syndromes cohort study. Br J Haematol 2010;150:179–188, with permission from John Wiley and Sons.

Figure 7

Outcomes in patients with FA due to mutations in FANCD1/BRCA2. (A) Probability of any type of leukemia. (B) Probability of a brain tumor, associated with a mutation in 886delGT compared with other mutations. The relative hazard due to 886delGT is 4 (CI 2 – 12). (C) Probability of any solid tumor. (D) Probability of leukemia associated with a mutation in IVS7 compared with other mutations. The relative hazard due to IVS7 is 4 (CI 1.3 – 13). (E) Probability of Wilms tumor. (F) Probability of any cancer is 97% by age 7 years. Adapted and updated from Alter et al [9,10]. Reproduced from J Med Genet, Alter BP, Rosenberg PS, Brody LC, volume 44, pages 1–9, 2007, with permission from BMJ Publishing Group Ltd.