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Associations of complementation group, ALDH2 genotype, and clonal abnormalities with hematological outcome in Japanese patients with Fanconi anemia

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Abstract

Fanconi anemia (FA) is a genetically and clinically heterogeneous disorder that predisposes patients to bone marrow failure (BMF), myelodysplastic syndromes (MDS), and acute myeloid leukemia (AML). To study which genetic and phenotypic factors predict clinical outcomes for Japanese FA patients, we examined the FA genes, bone marrow karyotype, and aldehyde dehydrogenase-2 (ALDH2) genotype; variants of which are associated with accelerated progression of BMF in FA. In 88 patients, we found morphologic MDS/AML in 33 patients, including refractory cytopenia in 16, refractory anemia with excess blasts (RAEB) in 7, and AML in 10. The major mutated FA genes observed in this study were FANCA (n = 52) and FANCG (n = 23). The distribution of the ALDH2 variant alleles did not differ significantly between patients with mutations in FANCA and FANCG. However, patients with FANCG mutations had inferior BMF-free survival and received hematopoietic stem cell transplantation (HSCT) at a younger age than those with FANCA mutations. In FANCA, patients with the c.2546delC mutation (n = 24) related to poorer MDS/AML-free survival and a younger age at HSCT than those without this mutation. All patients with RAEB/AML had an abnormal karyotype and poorer prognosis after HSCT; specifically, the presence of a structurally complex karyotype with a monosomy (n = 6) was associated with dismal prognosis. In conclusion, the best practice for a clinician may be to integrate the morphological, cytogenetic, and genetic data to optimize HSCT timing in Japanese FA patients.

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Acknowledgements

We would like to thank the patients and family members who made this work possible. We also thank all of the clinicians who provided precise data and the Support Center for Medical Research and Education, Tokai University.

Funding

This work was supported by Research Grants for Intractable Diseases from the Japanese Ministry of Health, Labor, and Welfare to E.I., S.K. and M.Y.

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Authors and Affiliations

  1. Department of Cell Transplantation and Regenerative Medicine, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan

    Miharu Yabe & Hiromasa Yabe

  2. Department of Pediatrics, Tokai University School of Medicine, Isehara, Japan

    Takashi Koike, Keisuke Ohtsubo, Eri Imai, Tsuyoshi Morimoto & Hiromitsu Takakura

  3. Department of Hematology/Oncology, Saitama Children’s Medical Center, Saitama, Japan

    Katsuyoshi Koh

  4. Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Kenichi Yoshida & Seishi Ogawa

  5. Department of Pediatrics, Hirosaki University Graduate School of Medicine, Hirosaki, Japan

    Etsuro Ito

  6. Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Yusuke Okuno, Hideki Muramatsu & Seiji Kojima

  7. Division of Molecular and Clinical Epidemiology, Aichi Cancer Center Research Institute, Nagoya, Japan

    Keitaro Matsuo

  8. Laboratory of DNA Damage Signaling, Department of Late Effects Studies, Radiation Biology Center, Kyoto University, Kyoto, Japan

    Minako Mori, Asuka Hira & Minoru Takata

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  1. Miharu Yabe
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  2. Takashi Koike
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Correspondence to Miharu Yabe.

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The authors declare that they have no conflict of interest.

Ethical approval

This study was approved by the Research Ethics Committees of Tokai University and Kyoto University, and all procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Yabe, M., Koike, T., Ohtsubo, K. et al. Associations of complementation group, ALDH2 genotype, and clonal abnormalities with hematological outcome in Japanese patients with Fanconi anemia. Ann Hematol 98, 271–280 (2019). https://doi.org/10.1007/s00277-018-3517-0

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