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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

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Front. Med.    2022, Vol. 16 Issue (3) : 459-466    https://doi.org/10.1007/s11684-021-0841-x
RESEARCH ARTICLE
Fanconi anemia gene-associated germline predisposition in aplastic anemia and hematologic malignancies
Daijing Nie1,2, Jing Zhang1, Fang Wang1, Xvxin Li1, Lili Liu1, Wei Zhang1, Panxiang Cao1, Xue Chen1, Yang Zhang1, Jiaqi Chen1, Xiaoli Ma1, Xiaosu Zhou2, Qisheng Wu3, Ming Liu1, Mingyue Liu1, Wenjun Tian4, Hongxing Liu1,2,3()
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
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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     
Corresponding Author(s): Hongxing Liu   
Just Accepted Date: 06 August 2021   Online First Date: 08 November 2021    Issue Date: 18 July 2022
 Cite this article:   
Daijing Nie,Jing Zhang,Fang Wang, et al. Fanconi anemia gene-associated germline predisposition in aplastic anemia and hematologic malignancies[J]. Front. Med., 2022, 16(3): 459-466.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-021-0841-x
https://academic.hep.com.cn/fmd/EN/Y2022/V16/I3/459
Median age ?(year, range) Sex ratio ?(male/female) Case number
AA 10 (1–63) 1.19 243
MDS 27 (1–65) 1.44 61
AML 14.5 (1–65) 1.34 208
ALL 6 (1–53) 1.38 276
Total 10 (1–65) 1.31 788
Tab.1  Demographics
Fig.1  Profile of rare possibly significant variants (PSVs) of each gene in this cohort. (A) PSV distribution. (B) PSV types. (C) Schematic diagram of PSVs in each gene. Exons are represented by colored rectangles; PSV types are represented by colored patterns.
Gene AA MDS AML ALL ExAC_EAS
?VAF
VAF OR 95% CI P VAF OR 95% CI P VAF OR 95% CI P VAF OR 95% CI P
BRCA2 0.62 0.69 0.22–2.20 0.800 1.64 1.87 0.45–7.80 0.301 1.20 1.36 0.54–3.40 0.426 1.81 2.08 1.06–4.06 0.038 0.89
FANCA 1.85 2.41 1.19–4.89 0.020 2.46 3.24 0.99–10.59 0.075 2.16 2.83 1.39–5.76 0.008 1.45 1.87 0.89–3.93 0.135 0.78
FANCC 0.62 1.79 0.54–5.91 0.255 0.82 2.39 0.32–17.79 0.353 0.48 1.39 0.33–5.86 0.657 0.18 0.52 0.07–3.83 1.000 0.35
FANCD2 0.62 0.76 0.24–2.43 1.000 0.82 1.01 0.14–7.42 1.000 0.48 0.59 0.14–2.42 0.773 0.54 0.67 0.21–2.14 0.801 0.81
FANCG 0.21 0.71 0.10–5.27 1.000 0 – – 1.000 0.24 0.83 0.11–6.16 1.000 0.18 0.63 0.08–4.64 1.000 0.29
Total 3.91 1.20 0.73–1.97 0.496 5.74 1.64 0.70–3.84 0.278 4.57 1.51 0.93–2.46 0.108 4.17 1.37 0.88–2.13 0.163 3.12
Tab.2  Variant distribution and odd ratio
Fig.2  Cumulative age-related disease incidence of FA-PSV+ and FA-PSV− cases in each disease subgroup. Horizontal axis represents age (year). Vertical axis represents cumulative incidence. Red lines indicate FA-PSV+ cases. Green lines indicate FA-PSV− cases. The correlation between FA-PSV status and disease incidence in the four disease subgroups is not significant. AA, aplastic anemia; MDS, myelodysplastic syndrome; AML, acute myeloid leukemia; ALL, acute lymphocytic leukemia. FA-PSV+, Fanconi anemia-possibly significant variant positive; FA-PSV−, Fanconi anemia-possibly significant variant negative.
Fig.3  Somatic mutation landscapes. (A) Somatic mutation landscape of patients with myeloid neoplasms. Data for each patient are represented by columns of the matrix. The first row indicates diagnosis, and the second row represents the five FA genes as a group (red). The subsequent rows represent recurrently mutated genes in myeloid neoplasms (blue), fusion genes (orange), and karyotypes (purple). (B) Somatic mutation landscape of patients with acute lymphoblastic leukemia. Data for each patient are represented by columns of the matrix. The first row indicates lineages, and the second row represents the five FA genes as a group (red). The subsequent rows represent recurrently mutated genes (blue), genetic markers indicate Ph-like/Ph+ acute lymphocytic leukemia (orange), fusion genes (green), and karyotypes (purple). KMT2A-r, KMT2A rearrangement.
1 M Swift. Fanconi’s anaemia in the genetics of neoplasia. Nature 1971; 230(5293): 370–373
https://doi.org/10.1038/230370a0 pmid: 4927726
2 SH Swerdloow, E Campo, NL Harris, ES Jaffe, SA Pileri, H Stein, J Thiele, DA Arber, RP Hasserjian, MM Le Beau, A Orazi, R Siebert. WHO classification of tumours of haematopoietic and lyphoid tissues. 4th ed. International Agency for Research on Cancer, 2017
3 N Rahman. Realizing the promise of cancer predisposition genes. Nature 2014; 505(7483): 302–308
https://doi.org/10.1038/nature12981 pmid: 24429628
4 MB Daly, R Pilarski, MB Yurgelun, MP Berry, SS Buys, P Dickson, SM Domchek, A Elkhanany, S Friedman, JE Garber, M Goggins, ML Hutton, S Khan, C Klein, W Kohlmann, AW Kurian, C Laronga, JK Litton, JS Mak, CS Menendez, SD Merajver, BS Norquist, K Offit, T Pal, HJ Pederson, G Reiser, KM Shannon, K Visvanathan, JN Weitzel, MJ Wick, KB Wisinski, MA Dwyer, SD Darlow. NCCN guidelines insights: genetic/familial high-risk assessment: breast, ovarian, and pancreatic, Version 1.2020. J Natl Compr Canc Netw 2020; 18(4): 380–391
https://doi.org/10.6004/jnccn.2020.0017 pmid: 32259785
5 CG Mathew. Fanconi anaemia genes and susceptibility to cancer. Oncogene 2006; 25(43): 5875–5884
https://doi.org/10.1038/sj.onc.1209878 pmid: 16998502
6 M Berwick, JM Satagopan, L Ben-Porat, A Carlson, K Mah, R Henry, R Diotti, K Milton, K Pujara, T Landers, S Dev Batish, J Morales, D Schindler, H Hanenberg, R Hromas, O Levran, AD Auerbach. Genetic heterogeneity among Fanconi anemia heterozygotes and risk of cancer. Cancer Res 2007; 67(19): 9591–9596
https://doi.org/10.1158/0008-5472.CAN-07-1501 pmid: 17909071
7 M Tischkowitz, DF Easton, J Ball, SV Hodgson, CG Mathew. Cancer incidence in relatives of British Fanconi anaemia patients. BMC Cancer 2008; 8(1): 257
https://doi.org/10.1186/1471-2407-8-257 pmid: 18786261
8 B Przychodzen, H Makishima, MA Sekeres, SK Balasubramanian, S Thota, BJ Patel, M Clemente, C Hirsch, B Dienes, JP Maciejewski. Fanconi anemia germline variants as susceptibility factors in aplastic anemia, MDS and AML. Oncotarget 2017; 9(2): 2050–2057
https://doi.org/10.18632/oncotarget.23328 pmid: 29416752
9 KZY Maung, PJ Leo, M Bassal, DA Casolari, JX Gray, SC Bray, S Pederson, D Singhal, SE Samaraweera, T Nguyen, G Cildir, M Marshall, A Ewing, EL Duncan, MA Brown, R Saal, V Tergaonkar, LB To, P Marlton, D Gill, I Lewis, AJ Deans, AL Brown, RJ D’Andrea, TJ Gonda. Rare variants in Fanconi anemia genes are enriched in acute myeloid leukemia. Blood Cancer J 2018; 8(6): 50
https://doi.org/10.1038/s41408-018-0090-7 pmid: 29891941
10 D Nie, P Cao, F Wang, J Zhang, M Liu, W Zhang, L Liu, H Zhao, W Teng, W Tian, X Chen, Y Zhang, H Nan, Z Wei, T Wang, H Liu. Analysis of overlapping heterozygous novel submicroscopic CNVs and FANCA-VPS9D1 fusion transcripts in a Fanconi anemia patient. J Hum Genet 2019; 64(9): 899–909
https://doi.org/10.1038/s10038-019-0629-x pmid: 31239491
11 Y Zhang, F Wang, X Chen, Y Zhang, M Wang, H Liu, P Cao, X Ma, T Wang, J Zhang, X Zhang, P Lu, H Liu. CSF3R mutations are frequently associated with abnormalities of RUNX1, CBFB, CEBPA, and NPM1 genes in acute myeloid leukemia. Cancer 2018; 124(16): 3329–3338
https://doi.org/10.1002/cncr.31586 pmid: 29932212
12 NU Potter, C Sarmousakis, FP Li. Cancer in relatives of patients with aplastic anemia. Cancer Genet Cytogenet 1983; 9(1): 61–65
https://doi.org/10.1016/0165-4608(83)90025-0 pmid: 6839307
13 M Swift, RJ Caldwell, C Chase. Reassessment of cancer predisposition of Fanconi anemia heterozygotes. J Natl Cancer Inst 1980; 65(5): 863–867
pmid: 6933255
14 DI Kutler, B Singh, J Satagopan, SD Batish, M Berwick, PF Giampietro, H Hanenberg, AD Auerbach. A 20-year perspective on the International Fanconi Anemia Registry (IFAR). Blood 2003; 101(4): 1249–1256
https://doi.org/10.1182/blood-2002-07-2170 pmid: 12393516
15 M Castella, R Pujol, E Callén, MJ Ramírez, JA Casado, M Talavera, T Ferro, A Muñoz, J Sevilla, L Madero, E Cela, C Beléndez, CD de Heredia, T Olivé, JS de Toledo, I Badell, J Estella, Á Dasí, A Rodríguez-Villa, P Gómez, M Tapia, A Molinés, Á Figuera, JA Bueren, J Surrallés. Chromosome fragility in patients with Fanconi anaemia: diagnostic implications and clinical impact. J Med Genet 2011; 48(4): 242–250
https://doi.org/10.1136/jmg.2010.084210 pmid: 21217111
16 EK Flynn, A Kamat, FP Lach, FX Donovan, DC Kimble, N Narisu, E Sanborn, F Boulad, SM Davies, AP Gillio 3rd, RE Harris, ML MacMillan, JE Wagner Jr, A Smogorzewska, AD Auerbach, EA Ostrander, SC Chandrasekharappa. Comprehensive analysis of pathogenic deletion variants in Fanconi anemia genes. Hum Mutat 2014; 35(11): 1342–1353
https://doi.org/10.1002/humu.22680 pmid: 25168418
[1] FMD-20092-OF-LHX_suppl_1 Download
[2] FMD-20092-OF-LHX_suppl_2 Download
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