Genotype-phenotype and outcome associations in patients with Fanconi anemia: the National Cancer Institute cohort

Abstract

Fanconi anemia (FA) is caused by pathogenic variants in the FA/BRCA DNA repair pathway genes, and is characterized by congenital abnormalities, bone marrow failure (BMF) and increased cancer risk. We conducted a genotype-phenotype and outcomes study of 203 patients with FA in our cohort. We compared across the genes, FA/BRCA DNA repair pathways (upstream, ID complex and downstream), and type of pathogenic variants (hypomorphic or null). We explored differences between the patients evaluated in our clinic (clinic cohort) and those who provided data remotely (field cohort). Patients with variants in upstream complex pathway had less severe phenotype [lacked VACTERL-H (Vertebral, Anal, Cardiac, Trachea-esophageal fistula, Esophageal/duodenal atresia, Renal, Limb, Hydrocephalus) association and/or PHENOS (Pigmentation, small-Head, small-Eyes, Neurologic, Otologic, Short stature) features]. ID complex was associated with VACTERL-H. The clinic cohort had more PHENOS features than the field cohort. PHENOS was associated with increased risk of BMF, and VACTERL-H with hypothyroidism. The cumulative incidence of severe BMF was 70%, solid tumors (ST) 20% and leukemia 6.5% as the first event. Head and neck and gynecological cancers were the most common ST, with further increased risk after hematopoietic cell transplantation. Among patients with FANCA, variants in exons 27-30 were associated with higher frequency of ST. Overall median survival was 37 years; patients with leukemia or FANCD1/BRCA2 variants had poorest survival. Patients with variants in the upstream complex had better survival than ID or downstream complex (p=0.001 and 0.016, respectively). FA is phenotypically and genotypically heterogeneous; detailed characterization provides new insights towards understanding this complex syndrome and guiding clinical management.

Figure 1.

Study flow chart. (A) The distribution of patients with Fanconi anemia (FA) in the field cohort and clinic cohort. Phenotype information was not available for seven patients in the field cohort. (B) The distribution of patients with FANCA variants according to the location of the variants on the FANCA protein. *The sum of the numbers with BRCA1 interaction region, exons 27-30 and FAAP-20 binding domain variants exceeds 86 because some patients had variants in multiple regions of the FANCA protein.

Figure 2.

Distribution of patients according to genotypes, mutation pathways and type of variants in the field cohort and the clinic cohort. (A) Distribution of Fanconi anemia genes, including gene unknown patients. *Patients with unknown genotype were more common in the field cohort than in the clinic cohort (P=0.001); (B) Distribution by mutation pathways; (C) Distribution by hypomorphic and null genotypes. Panels (B) and (C) include only patients with available pathway and genotype data, respectively.

Figure 3.

Physical abnormalities in field cohort patients versus clinic cohort patients. Blue: field cohort; orange: clinic cohort. Horizontal axis: types of abnormalities; vertical axis: percentage of patients with abnormalities. VACTERL-H: vertebral, anal, cardiac, tracheo-esophageal fistula, esophageal or duodenal atresia, renal, upper limb, hydrocephalus; PHENOS: skin pigmentation, small head, small eyes, structural nervous system, otology, short stature; TEF: tracheo-esophageal fistula; FA: Fanconi anemia; GI: gastrointestinal. Comparisons were performed by the Fisher exact test, *P<0.05.

Figure 4.

Cumulative incidence of adverse events and increased cancer risk in patients with variants within/involving exons 27-30 of FANCA. (A) Cumulative incidence of bone marrow failure leading to hematopoietic cell transplantation or death (red), acute myeloid leukemia (green) and solid tumors (blue) in the presence of competing risks. (B) Cumulative incidence of solid tumors by age in non-transplanted (solid line) and transplanted patients (dotted line) in the absence of competing risks. HCT: hematopoietic cell transplantation; AML: acute myeloid leukemia. (C) Cumulative incidence of solid tumors in patients with (green) and without (orange) variants within/involving exons 27-30 of FANCA protein. (D) Distribution of variants in the FANCA. Shaded areas; orange: BRCA1 interaction region; yellow: exons 27-30; blue: FAAP20-binding domain. Numbers in circles represent the number of alleles for each variant. Horizontal gray bars represent multi-exon deletions and colored circles represent single nucleotide variants/small indels. Red stars highlight the variants observed in patients who developed solid tumors.

Figure 5.

Survival estimates in patients with Fanconi anemia.