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Identification of cell-type-specific mutations in nodal T-cell lymphomas

Nguyen, T B, Sakata-Yanagimoto, M, Asabe, Y, Matsubara, D, Kano, J, Yoshida, K, Shiraishi, Y, Chiba, K, Tanaka, H, Miyano, S, Izutsu, K, Nakamura, N, Takeuchi, K, Miyoshi, H, Ohshima, K, Minowa, T, Ogawa, S, Noguchi, M, Chiba, S·2017·Blood Cancer Journal
DOI 10.1038/bcj.2016.122PMC PMC5301031
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Abstract

Recent genetic analysis has identified frequent mutations in ten-eleven translocation 2 (TET2), DNA methyltransferase 3A (DNMT3A), isocitrate dehydrogenase 2 (IDH2) and ras homolog family member A (RHOA) in nodal T-cell lymphomas, including angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma, not otherwise specified. We examined the distribution of mutations in these subtypes of mature T-/natural killer cell neoplasms to determine their clonal architecture. Targeted sequencing was performed for 71 genes in tumor-derived DNA of 87 cases. The mutations were then analyzed in a programmed death-1 (PD1)-positive population enriched with tumor cells and CD20-positive B cells purified by laser microdissection from 19 cases. TET2 and DNMT3A mutations were identified in both the PD1+ cells and the CD20+ cells in 15/16 and 4/7 cases, respectively. All the RHOA and IDH2 mutations were confined to the PD1+ cells, indicating that some, including RHOA and IDH2 mutations, being specific events in tumor cells. Notably, we found that all NOTCH1 mutations were detected only in the CD20+ cells. In conclusion, we identified both B- as well as T-cell-specific mutations, and mutations common to both T and B cells. These findings indicate the expansion of a clone after multistep and multilineal acquisition of gene mutations.

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Figures

Figure 1 Targeted sequencing result of 87 nodal T-cell lymphoma samples. TET2-, RHOA-, IDH2- and DNMT3A-mutated cases are indicated by blue, red, orange and green boxes, respectively. Other recurrently mutated genes are in purple. The laser-microdissected samples are indicated in red letters.
Figure 1 Targeted sequencing result of 87 nodal T-cell lymphoma samples. TET2-, RHOA-, IDH2- and DNMT3A-mutated cases are indicated by blue, red, orange and green boxes, respectively. Other recurrently mutated genes are in purple. The laser-microdissected samples are indicated in red letters.CC BY · PubMed Central
Figure 2 RHOA mutations are specific to PD1+ cells. (a) An example of the immunostaining pattern for PD1 and CD20 in AITL. Left, PD1+ cells; right, CD20+ cells. (b) Sequences of G17V RHOA mutations in whole tumor, PD1+ cells and CD20+ cells. The numeric values indicate allele frequencies of mutations defined by amplicon-based deep sequencing. The AITL samples are indicated in black letters. The nodal PTCL with TFH phenotype sample is indicated in red letters *: RHOA c.A51T:p.G17V, silent mutation. The filled and dashed red arrows indicate mutations and no mutations, respectively.
Figure 2 RHOA mutations are specific to PD1+ cells. (a) An example of the immunostaining pattern for PD1 and CD20 in AITL. Left, PD1+ cells; right, CD20+ cells. (b) Sequences of G17V RHOA mutations in whole tumor, PD1+ cells and CD20+ cells. The numeric values indicate allele frequencies of mutations defined by amplicon-based deep sequencing. The AITL samples are indicated in black letters. The nodal PTCL with TFH phenotype sample is indicated in red letters *: RHOA c.A51T:p.G17V, silent mutation. The filled and dashed red arrows indicate mutations and no mutations, respectively.CC BY · PubMed Central
Figure 3 Distributions of TET2/DNMT3A/RHOA/IDH2/NOTCH1 mutations and IgH VDJ status. Allele frequencies of TET2/DNMT3A/RHOA/IDH2/NOTCH1 mutations in whole tumor, PD1+ cells and CD20+ cells are shown. The blue boxes represent positive TET2 mutations; the green boxes, positive DNMT3A mutations; the red boxes, positive RHOA mutations; the orange boxes, positive IDH2 mutations; the purple boxes, positive NOTCH1 mutations; the yellow boxes, no mutations; and the white boxes, not examined. The numeric values indicate allele frequencies of mutations defined by deep sequencing, except for that in the box surrounded by bold red lines which was estimated by Sanger sequencing. IgH VDJ status indicates the IgH VDJ rearrangement status in whole-tumor-derived DNA. The AITL samples are indicated in black letters. The nodal PTCL with TFH phenotype sample is indicated in red letters. The PTCL-NOS/nodal PTCL with TFH phenotype sample is indicated in blue letters. MC, monoclonality; OC, oligoclonality; Pos: positivity was evaluated only by Sanger sequencing. Multiple TET2 mutations were identified in PTLC2, 8, 60, 63, 77, 136, 121, 123, 127 and 129.
Figure 3 Distributions of TET2/DNMT3A/RHOA/IDH2/NOTCH1 mutations and IgH VDJ status. Allele frequencies of TET2/DNMT3A/RHOA/IDH2/NOTCH1 mutations in whole tumor, PD1+ cells and CD20+ cells are shown. The blue boxes represent positive TET2 mutations; the green boxes, positive DNMT3A mutations; the red boxes, positive RHOA mutations; the orange boxes, positive IDH2 mutations; the purple boxes, positive NOTCH1 mutations; the yellow boxes, no mutations; and the white boxes, not examined. The numeric values indicate allele frequencies of mutations defined by deep sequencing, except for that in the box surrounded by bold red lines which was estimated by Sanger sequencing. IgH VDJ status indicates the IgH VDJ rearrangement status in whole-tumor-derived DNA. The AITL samples are indicated in black letters. The nodal PTCL with TFH phenotype sample is indicated in red letters. The PTCL-NOS/nodal PTCL with TFH phenotype sample is indicated in blue letters. MC, monoclonality; OC, oligoclonality; Pos: positivity was evaluated only by Sanger sequencing. Multiple TET2 mutations were identified in PTLC2, 8, 60, 63, 77, 136, 121, 123, 127 and 129.CC BY · PubMed Central
Figure 4 Distribution of newly identified gene mutations in nodal T-cell lymphomas. The results of Sanger sequencing and/or amplicon-based deep sequencing for some newly identified gene mutations in whole tumor, PD1+ cells and CD20+ cells are shown. The numeric values indicate allele frequencies of mutations defined by deep sequencing. The AITL samples are indicated in black letters. The PTCL-NOS/nodal PTCL with TFH phenotype sample is indicated in blue letters. NA, not analyzed by deep sequencing. The filled and dashed red arrows indicate mutations and no mutations, respectively.
Figure 4 Distribution of newly identified gene mutations in nodal T-cell lymphomas. The results of Sanger sequencing and/or amplicon-based deep sequencing for some newly identified gene mutations in whole tumor, PD1+ cells and CD20+ cells are shown. The numeric values indicate allele frequencies of mutations defined by deep sequencing. The AITL samples are indicated in black letters. The PTCL-NOS/nodal PTCL with TFH phenotype sample is indicated in blue letters. NA, not analyzed by deep sequencing. The filled and dashed red arrows indicate mutations and no mutations, respectively.CC BY · PubMed Central
Figure 5 B-cell-specific mutations in nodal T-cell lymphomas. The results of Sanger sequencing and/or amplicon-based deep sequencing for some newly identified gene mutations in whole tumor, PD1+ cells and CD20+ cells are shown. The numeric values indicate allele frequencies of mutations defined by deep sequencing. The AITL samples are indicated in black letters. The PTCL-NOS/nodal PTCL with TFH phenotype sample is indicated in blue letters. NA, not analyzed by deep sequencing. The filled and dashed red arrows indicate mutations and no mutations, respectively. NOTCH1 is marked by red letters because this is repetitive.
Figure 5 B-cell-specific mutations in nodal T-cell lymphomas. The results of Sanger sequencing and/or amplicon-based deep sequencing for some newly identified gene mutations in whole tumor, PD1+ cells and CD20+ cells are shown. The numeric values indicate allele frequencies of mutations defined by deep sequencing. The AITL samples are indicated in black letters. The PTCL-NOS/nodal PTCL with TFH phenotype sample is indicated in blue letters. NA, not analyzed by deep sequencing. The filled and dashed red arrows indicate mutations and no mutations, respectively. NOTCH1 is marked by red letters because this is repetitive.CC BY · PubMed Central

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Citations

Cites

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Metadata

Authors
Nguyen, T. B., Sakata-Yanagimoto, M., Asabe, Y., Matsubara, D., Kano, J., Yoshida, K., Shiraishi, Y., Chiba, K., Tanaka, H., Miyano, S., Izutsu, K., Nakamura, N., Takeuchi, K., Miyoshi, H., Ohshima, K., Minowa, T., Ogawa, S., Noguchi, M., & Chiba, S.
ORCID
Takeuchi, K
Venue
Blood Cancer Journal
Publisher
Springer Science and Business Media LLC
Published
2017-01-06
Volume
7
Issue
1
Pages
e516-e516
ISSN
2044-5385
DOI
10.1038/bcj.2016.122
PMC
PMC5301031
Cited by
93
References
7
Language
en
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