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

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; Hongxing Liu

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

Author: Daijing NIE ¹ ; Jing ZHANG ¹ ; Fang WANG ¹ ; Xvxin LI ¹ ; Lili LIU ¹ ; Wei ZHANG ¹ ; Panxiang CAO ¹ ; Xue CHEN ¹ ; Yang ZHANG ¹ ; Jiaqi CHEN ¹ ; Xiaoli MA ¹ ; Xiaosu ZHOU ² ; Qisheng WU ³ ; Ming LIU ¹ ; Mingyue LIU ¹ ; Wenjun TIAN ⁴ ; Hongxing LIU ⁵
Author Information

1. Division of Laboratory Medicine, Hebei Yanda Lu Daopei Hospital, Langfang, 065201, China.
2. Beijing Lu Daopei Institute of Hematology, Beijing, 100176, China.
3. Division of Pathology & Laboratory Medicine, Beijing Lu Daopei Hospital, Beijing, 100176, China.
4. Department of Clinical Laboratory Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, 250021, China.
5. Division of Laboratory Medicine, Hebei Yanda Lu Daopei Hospital, Langfang, 065201, China. starliu@pku.edu.cn.
Publication Type:Journal Article
Keywords: Fanconi anemia; aplastic anemia; germline predisposition; hematologic malignancy
MeSH: Anemia, Aplastic/genetics*; Epigenesis, Genetic; Fanconi Anemia/genetics*; Germ Cells; Hematologic Neoplasms/genetics*; Humans; Leukemia, Myeloid, Acute/genetics*; Retrospective Studies
From: Frontiers of Medicine 2022;16(3):459-466
CountryChina
Language:English
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.