Page 73 - Haematologica Vol. 109 - July 2024

ARTICLE - Familial germline pathogenic alleles and hematologic malignancies Q. Feng et al.
Black (NLB) families, 2 (33%) were found in non-Latino Asian/Pacific Islander (NLAPI) families, and one (11%) was found in a non-Latino American Indian/Alaskan Native (NLAIAN) family. Among the VUS, 41 (39%) were found in LAT families, 21 (22%) were found in NLW families, 10 (10%) were found in NLB families, 27 (28%) were found in NLAPI families, and one (1%) was found in a NLAIAN family (Table 2). In the LAT families, P/LP variants were detected in ATM (NM_000051.3:c.3158dup; one sibling had T-cell leukemia and the other had diffuse large B-cell lymphoma) in fam- ily #27. For NLW families, P/LP variants were detected on TP53 (family #6, NM_000546.5:c.586C>T; one sibling with acute leukemia, not otherwise specified [NOS], and the other with signet ring carcinoma), and NOD2 (family #25, NM_022162.2:c.1515dup; both siblings diagnosed with HL NOS). For NLB families, P/LP variants were detected on GATA2 (family #15, NM_001145661.1:c.1009C>T; one sibling AMML-M4 and second sibling, AMKL-M7) and NOD2 (family #35, NM_022162.2:c.1515dup; both siblings with Burkitt cell leukemia). In separate NLAPI families, P/LP variants were detected on FLG (family #2, NM_002016.1:c.3321del; HL and AMKL-M7), and CBLB (family #21, NM_170662.4:c.2307del; large B-cell lymphoma and neuroblastoma). The siblings in this family also shared an additional nonsense variant in HABP2. For one NLAIAN family (#29), a P/LP variant was detected on SBF2 (NM_030962.3:c.4400del; one sibling with acute lymphoblastic leukemia NOS and the other sibling
with hepatoblastoma) (Online Supplementary Table S4). In addition, we identified 7 rare P/LP variants that are not shared between the 2 siblings. In 4 LAT subjects without any P/LP variants shared with siblings, these included a nonsense variant in AMER1 (NM_152424.3:c.28C>T), a frameshift deletion in HLTF (NM_003071.3:c.1967del), and missense variants in GJB2 (NM_004004.5:c.596C>T) and PINK1 (NM_032409.2:c.1040T>C) (Online Supplementary Table S5). In one NLW subject diagnosed with a malignant teratoma, we found a non-shared nonsense variant in SMARCA4 (NM_001128849.1:c.4038G>A). In an NLB subject who developed acute megakaryoblastic leukemia (AMKL), and who also shared a P/LP variant in GATA2 with their sibling who developed acute myeloid leukemia (family #15), a non-shared nonsense variant was identified in FAT1 (NM_005245.3:c.10957G>T). Finally, in a NLAPI subject who developed AMKL, and shared a P/LP variant in FLG with their sibling who developed HL (family #2), a non- shared rare P/LP variant was identified in exon 2 of GATA1 (NM_002049.3:c.115G>T) (Online Supplementary Table S5), in which somatic mutations are known drivers of AMKL. Of note, this GATA1 variant had an allele fraction of 71.4% and was detected in the subject identified with trisomy 21 (sub- ject #534; see above); thus, it is likely to be a somatic GATA1 mutation that would be indicative of transient abnormal myelopoiesis (TAM), which occurs frequently in newborns with DS and is a precursor to AMKL in some cases.20
Table 1. Demographics of the 32 proband-sibling pairs, California Cancer Registry, 1989-2015.
Overall N=64
Proband N=32
Affected sibling N=32
Self-reported race/ethnicity, N (%) Latino, all races
NLW
NLB
NLAPI NLAIAN
24 (37.5) 20 (31.3) 6 (9.4) 12 (18.8) 2 (3.1)
12 (37.5) 10 (31.3) 3 (9.4) 6 (18.8) 1 (3.1)
12 (37.5) 10 (31.3) 3 (9.4) 6 (18.8) 1 (3.1)
Cancer site, N (%) Leukemias Lymphomas Brain tumors Neuroblastoma Retinoblastoma Renal tumors Hepatic tumors Bone tumors Sarcomas
Germ cell tumors Neoplasms and melanomas
27 (42.2) 17 (26.6) 5 (7.8) 1 (1.6) 1 (1.6) 1 (1.6) 1 (1.6) 1 (1.6) 5 (7.8) 3 (4.7) 2 (3.1)
12 (37.5) 9 (28.1) 3 (9.4) 1 (3.1) 1 (3.1) 1 (3.1) 0 (0)
0 (0)
3 (9.4) 2 (6.2) 0 (0)
15 (46.9%) 8 (25.0) 2 (6.2)
0 (0)
0 (0)
0 (0)
1 (3.1)
1 (3.1)
2 (6.2)
1 (3.1)
2 (6.2)
Sex of child, N (%) Male
Female
38 (59.4) 26 (40.6)
16 (50.0) 16 (50.0)
22 (68.8) 10 (31.2)
Age in years, mean (SD)
9.75 (7.10)
6.22 (5.45)
13.3 (6.86)
N: number; NLW: non-Latino White; NLB: non-Latino Black; NLAPI: non-Latino Asian/Pacific Islander; NLAIAN: non-Latino American Indian/ Alaskan Native; SD: Standard Deviation.
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