Fanconi anemia gene-associated germline predisposition in aplastic anemia and hematologic malignancies

Abstract

Whether Fanconi anemia (FA) heterozygotes are predisposed to bone marrow failure and hematologic neoplasm is a crucial but unsettled issue in cancer prevention and family consulting. We retrospectively analyzed rare possibly significant variations (PSVs) in the five most obligated FA genes, BRCA2, FANCA, FANCC, FANCD2, and FANCG, in 788 patients with aplastic anemia (AA) and hematologic malignancy. Sixty-eight variants were identified in 66 patients (8.38%). FANCA was the most frequently mutated gene (n = 29), followed by BRCA2 (n = 20). Compared with that of the ExAC East Asian dataset, the overall frequency of rare PSVs was higher in our cohort (P = 0.016). BRCA2 PSVs showed higher frequency in acute lymphocytic leukemia (P = 0.038), and FANCA PSVs were significantly enriched in AA and AML subgroups (P = 0.020; P = 0.008). FA-PSV-positive MDS/AML patients had a higher tumor mutation burden, higher rate of cytogenetic abnormalities, less epigenetic regulation, and fewer spliceosome gene mutations than those of FA-PSV-negative MDS/AML patients (P = 0.024, P = 0.029, P = 0.024, and P = 0.013). The overall PSV enrichment in our cohort suggests that heterozygous mutations of FA genes contribute to hematopoietic failure and leukemogenesis.

Keywords

Fanconi anemia / aplastic anemia / hematologic malignancy / germline predisposition

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Acknowledgements

This work was partially supported by a grant from the Shandong Nature Science Fund (No. ZR2016HP02).

Compliance with ethics guidelines

Daijing Nie, Jing Zhang, Fang Wang, Xvxin Li, Lili Liu, Wei Zhang, Panxiang Cao, Xue Chen, Yang Zhang, Jiaqi Chen, Xiaoli Ma, Xiaosu Zhou, Qisheng Wu, Ming Liu, Mingyue Liu, Wenjun Tian, and Hongxing Liu have no conflict of interest to declare. All procedures followed were in accordance with the ethical standards of the Ethical Committee of Hebei Yanda Lu Daopei Hospital on human experimentation and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients for participation in the study.

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-021-0841-x and is accessible for authorized users.

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