Prognostic significance of mutation type and chromosome fragility in Fanconi anemia

Abstract

Fanconi anemia (FA) is a rare genetic disease characterized by high phenotypic and genotypic heterogeneity, and extreme chromosome fragility. To better understand the natural history of FA, identify genetic risk and prognostic factors, and develop novel therapeutic strategies, the Spanish Registry of Patients with FA collects data on clinical features, chromosome fragility, genetic subtypes, and DNA sequencing with informed consent of participating individuals. In this article, we describe the clinical evolution of 227 patients followed up for up to 30 years, for whom our data indicate a cumulative cancer incidence of 86% by age 50. We found that patients with lower chromosome fragility had a milder malformation spectrum and better outcomes in terms of later-onset hematologic impairment, less severe bone marrow failure, and lower cancer risk. We also found that outcomes were better for patients with mutations leading to mutant FANCA protein expression (genetic hypomorphism) than for patients lacking this protein. Likewise, prognosis was consistently better for patients with biallelic mutations in FANCD2 (mainly hypomorphic mutations) than for patients with biallelic mutations in FANCA and FANCG, with the lack of the mutant protein in patients with biallelic mutations in FANCG contributing to their poorer outcomes. Our results regarding the clinical impact of chromosome fragility and genetic hypomorphism suggest that mutant FA proteins retain residual activity. This finding should encourage the development of novel therapeutic strategies aimed at partially or fully enhancing mutant FA function, thereby preventing or delaying bone marrow failure and cancer in patients with FA. Clinical Trial Registration number: NCT06490510.

FIGURE 1

Description and clinical evolution of 227 (living and deceased) Spanish patients with Fanconi anemia (FA). (A) Patients with FA distributed according to sex and age (gray), by hematologic impairment onset, allogenic hematopoietic stem cell transplantation (aHSCT), solid tumor, leukemia or myelodysplastic syndrome (MDS), and malformations (yes: Dark purple; no: Light purple; no clinical data: Pale purple), and by malformations classified as <3 or ≥3 (gray). The vertical dashed line denotes 50% of the population. (B) Patients with each type of malformation, sorted from most to least frequent. (C) Cumulative incidence for hematologic impairment onset (red), aHSCT (green), leukemia and MDS (pink), and solid tumor (blue). (D) Patients with each type of solid tumor, with the different colors indicating the percentage of individuals in each complementation group (FANCA: purple, FANCD2: green, FANCJ: yellow, BRCA2: red; and unknown: gray). Note that only the first solid tumors are shown for four individuals who developed two different solid tumors in their lifetime: Head and neck squamous cell carcinoma (HNSCC) then lung cancer; HNSCC then breast cancer; solid rectal tumor then HNSCC; and breast cancer then colon cancer. (E) No differences were observed in the cumulative incidence of solid tumors between transplanted patients (blue; n = 91) and non‐transplanted patients (red; n = 117). Of the transplanted patients, 8 developed solid tumors, and of the non‐transplanted patients, 21 developed solid tumors. (F) Survival by age is denoted by a black line and the 95% confidence interval (CI) is denoted by the shaded region. Curves were compared using the log‐rank (Mantel–Cox) test. [Color figure can be viewed at wileyonlinelibrary.com]

FIGURE 2

Chromosome fragility as a predictive factor in Fanconi anemia (FA) evolution. Chromosome fragility after diepoxybutane (DEB) treatment is expressed as aberrations/aberrant cell and as percentage aberrant cells. (A and B) No differences in chromosome fragility were observed between controls and monoallelic FA mutation carriers. Patients with FA had greater chromosome fragility than controls and carriers. Three‐way comparisons were performed using the Kruskal–Wallis non‐parametric test (ANOVA; p < .0001), and two‐way comparisons were performed using Dunn's non‐parametric multiple comparison test. (C and D) Patients with malformations showed greater chromosome fragility than patients without malformations (p = .0194), while no chromosome fragility differences were observed between patients with <3 and with ≥3 malformations (p = .1352). Comparisons between the groups were performed using the Mann–Whitney non‐parametric test. (E and G) Patients with FA classified, according to aberrations/aberrant cell after DEB treatment, in a low or high chromosome fragility group (≤4.07 and >4.07 aberrations/aberrant cell, respectively), where 4.07 is the median aberrations/aberrant cell distribution for the Spanish FA population (see Figure S1). (E) Cumulative incidence for hematologic impairment onset. Patients with low chromosome fragility (light purple) showed later onset (p = .0031) than patients with high chromosome fragility (dark purple). (F) Cumulative incidence for allogenic hematopoietic stem cell transplantation (aHSCT). Patients with low chromosome fragility (light purple) had less need for aHSCT (p < .0001) than patients with high chromosome fragility (dark purple). (G) Cumulative incidence of solid tumors. Patients with low chromosome fragility (light purple) had a lower risk than patients with high chromosome fragility (dark purple). Curves were compared using the log‐rank (Mantel–Cox) test (GraphPad Prism software). [Color figure can be viewed at wileyonlinelibrary.com]

FIGURE 3

Patients with some mutant FANCA protein expression have better outcomes than patients with total protein absence. Cumulative incidence for 135 patients classified according to predicted protein expression based on FANCA mutation type: Total FANCA protein absence (dark purple), and some FANCA protein expression (light purple). (A) Hematologic impairment onset. (B) Allogenic hematopoietic stem cell transplantation (aHSCT). (C) Leukemia and myelodysplastic syndrome (MDS). (D) Solid tumor. (E) Survival. Curves for the two groups were compared using the log‐rank (Mantel–Cox) test (GraphPad Prism software). [Color figure can be viewed at wileyonlinelibrary.com]

FIGURE 4

Patients with biallelic mutations in FANCD2 have better outcomes than patients with biallelic mutations in FANCA or FANCG. (A) Percentage aberrant cells after diepoxybutane (DEB) treatment in the peripheral blood of patients with FANCA (light purple), FANCD2 (dark purple), and FANCG (intermediate purple). Two‐way comparisons were performed using the Mann–Whitney non‐parametric test (GraphPad Prism software). (B) Survival curves for patients with FANCA (light purple), FANCD2 (dark purple), and FANCG (intermediate purple). Curves were compared using the log‐rank (Mantel–Cox) test (GraphPad Prism software). (C) Percentage of alleles in patients with FANCA, FANCD2, and FANCG according to mutation type: Duplication (light pink), large deletion (intermediate pink), missense mutation (dark pink), small deletion (light purple), and nonsense mutation (dark purple). Patients with mutations in FANCD2 had more alleles with missense mutations and fewer alleles with nonsense mutations compared to patients with mutations in FANCA and FANCG. Comparisons were made using the chi‐square test. (D) Percentage patients with FANCA, FANCD2, and FANCG with mutations leading to total protein absence (dark purple) or some mutant protein expression (light purple). [Color figure can be viewed at wileyonlinelibrary.com]