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B. Schuhmacher et al.
Table 1. Clinical information on nodular lymphocyte-predominant Hodgkin lymphoma and T-cell/histiocyte-rich large B-cell lymphoma patients.
Case Former Diagnosis number case number*
Fan pattern#
Estimated tumor cell content
15%
5% 10% 15% 10% 1% 10% 3% 5% 1% 1% 1% 3% 5% 3% 3% 1% 1% 3% 1% 3% 3%
1% 3% 3% 3%
Gender Age
Stage
1
2 3 4 5 6 7 8 9 10 11 12 13 14 15
16 6
17 7
18 8
19 9
20 10
21 11
22 5
23
24 12
25 13
26 17
THRLBCL
THRLBCL
THRLBCL
THRLBCL
THRLBCL
THRLBCL
THRLBCL
THRLBCL
THRLBCL
Variant NLPHL
Variant NLPHL
Variant NLPHL
Variant NLPHL
Variant NLPHL
Variant NLPHL
Typical NLPHL
Typical NLPHL
Typical NLPHL
Typical NLPHL
Typical NLPHL
Typical NLPHL
Variant NLPHL , part of
composite lymphoma Variant NLPHL Variant NLPHL Variant NLPHL
Variant NLPHL
pattern E pattern E pattern E pattern E pattern E pattern E pattern A pattern A pattern A pattern A pattern A pattern B pattern D
pattern C pattern C pattern D pattern D
M 20 IVB
M 47 IVB F 50 IVB M 40 IVB M 50 n.a. F 89 IVA M 27 IVA M 31 IVB F 75 IIIA M 59 IVB M 46 IVA F 85 IIIB M 40 IVB M 23 IIIA M 46 IVA M 10 IIA M 72 n.a. M 64 n.a.
M 13 IA M 52 n.a. F 53 n.a. M 35 n.a.
M 64 n.a. M 15 IIA M 31 IA M 75 n.a.
* These cases were included in a previous study of nodular lymphocyte-predominant Hodgkin lymphoma.12 # Histopathological patterns were determined according to Fan et al.10 THRLBCL:T-cell/histiocyte-rich large B-cell lymphoma; NLPHL: nodular lymphocyte-predominant Hodgkin lymphoma; n.a.: Information on Ann Arbor stage was not available.
Supplementary Table S3). A total of 33 genes (53%) were recurrently affected by mutations in at least two cases (Figure 1A). Specifically in THRLBCL, 31 genes (50%) were mutated, and 13 of these showed recurrent muta- tions in at least two cases, indicating a considerable muta- tional overlap between THRLBCL and NLPHL. The genes with the highest overall mutation frequency (≥20% of all 26 cases) were JUNB, DUSP2, SGK1, SOCS1, CREBBP, FN1 and TRRAP (Figure 1A). Mutation frequencies in JUNB, SGK1, CREBBP and TRRAP were higher, albeit not significantly so, in both THRLBCL and the NLPHL vari- ants C/D/E than in typical NLPHL A/B (Figure 1A).
The median number of mutated genes per case was comparable between typical NLPHL (median 3.5; range, 2- 13), histopathological NLPHL variants C/D/E (median 5.0; range, 1-11) and THRLBCL (median 4.0; range, 2-20) (Figure 1B). However, the median number of SNVs per case was slightly increased in THRLBCL (median 12; range, 2-30) when compared with that in typical NLPHL (median 7; range, 2-14) and NLPHL variants C/D/E (medi- an 8; range, 1-20) (Figure 1C). Notably, the number of SNVs per case was specifically increased in the four genes JUNB, DUSP2, SGK1 and SOCS1 (1-5 SNVs/case) when compared to CREBBP, FN1 and TRRAP (1-2 SNVs/case),
particularly in regard to the shorter coding sequence of the first four genes (<1.3 kb versus >7.3 kb) (Figure 1D). The higher number of SNVs per case found in THRLBCL was, therefore, related to the higher number of SNVs in these four genes.
SOCS1 was the only gene in which mutations occurred significantly more frequently in THRLBCL than in typical NLPHL A/B (4/9 cases versus 0/6 cases, respectively; P=0.010, χ2-test) and in NLPHL in general (4/9 cases versus 3/17 cases, respectively; P=0.035, χ2-test).
Furthermore, the number of SNVs per case was signifi- cantly increased in SOCS1 in THRLBCL (median 5.0; range, 3-6) when compared with that in histopathological NLPHL variants C/D/E (median 1.5; range, 1-2; P=0.048, Mann-Whitney test). JUNB was the gene with the highest number of nonsense mutations, which were present in both NLPHL (2/15 mutations) and THRLBCL (2/12 muta- tions).
The genes with the highest mutation frequency are targets of aberrant somatic hypermutation
Regarding the distribution of mutations in the seven most recurrently mutated genes, SNVs were generally dis- tributed throughout the coding sequence with no differ-
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