MYC expression and translocation analyses in low-grade and transformed follicular lymphoma

Sietse M. Aukema; Roel van Pel; Inga Nagel; Susanne Bens; Reiner Siebert; Stefano Rosati; Eva van den Berg; Anneke G. Bosga-Bouwer; Robby E. Kibbelaar; Mels Hoogendoorn; Gustaaf W. van Imhoff; Hanneke C. Kluin-Nelemans; Philip M. Kluin; Marcel Nijland

doi:10.1111/his.13316

MYC expression and translocation analyses in low-grade and transformed follicular lymphoma

Sietse M. Aukema^*, Roel van Pel, Inga Nagel, Susanne Bens, Reiner Siebert, Stefano Rosati, Eva van den Berg, Anneke G. Bosga-Bouwer, Robby E. Kibbelaar, Mels Hoogendoorn, Gustaaf W. van Imhoff, Hanneke C. Kluin-Nelemans, Philip M. Kluin, Marcel Nijland

^*Corresponding author for this work

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Abstract

AimsLow-grade follicular lymphoma (FL) (grade 1/2, FL1/2) has an annual risk of transformation of approximate to 3%, which is associated with aberrations in CDKN2A/B, TP53, and MYC. As in diffuse large B-cell lymphoma, high MYC expression in transformed FL (tFL) might predict a MYC breakpoint.

Methods and resultsWe quantified MYC expression by immunohistochemistry and digital analysis in 41 paired biopsies from 20 patients with FL1/2 with subsequent transformation and in four isolated biopsies of tFL. As controls, 28 biopsies of FL1/2 without transformation (median follow-up of 105 months) and nine biopsies of FL3A/B were analysed. In the 20 FL1/2-tFL pairs, MYC expression was significantly higher in tFL than in the initial FL1/2 biopsies (median 54% versus 6%; 7% in FL3A, and 35% in FL3B). MYC breaks (MYC-R) were detected in eight of 21 (38%) tFLs analysed by fluorescence in-situ hybridization (FISH), with a median MYC score of 86%. In two of the analysed tFL cases, the translocation was already detected in antecedent FL1/2. MYC partners were immunoglobulin (IG) loci in three of eight cases (one IGL, one IGH, and one IGK) and non-IG in five of eight cases (two PAX5, one BCL6, and two unknown). Of the eight MYC-R+ cases, six were BCL2+/MYC+ double-hit, one was BCL2+/BCL6+/MYC+ triple-hit, and one was MYC+ single-hit. All three IG-MYC+ cases showed a MYC expression level of >85%, whereas the five cases with a non-IG MYC partner had a wider range of expression (median 68%, range 13-86%). Among the 13 MYC-R- tFLs, two groups with almost dichotomous MYC expression could be observed (three cases showed 90% MYC expression), suggesting alternative mechanisms of MYC activation.

Conclusionswe show an increase in MYC expression from FL1/2 to tFL. MYC breakpoints were present in approximate to 40% of the cases, which is markedly higher than in de novo DLBCL. MYC expression was uniformly high in cases with an IG-MYC translocation but much more heterogeneous and in part independent of the presence of a MYC break in non-IG-MYC and MYC-negative cases.

Original language	English
Pages (from-to)	960-971
Number of pages	12
Journal	Histopathology
Volume	71
Issue number	6
DOIs	https://doi.org/10.1111/his.13316
Publication status	Published - Dec-2017

Keywords

double-hit
follicular lymphoma
MYC
MYC translocation partner
transformation
B-CELL LYMPHOMA
BURKITT-LYMPHOMA
PROGNOSTIC-SIGNIFICANCE
CYTOGENETIC ALTERATIONS
C-MYC
REARRANGEMENTS
8Q24
NEOPLASMS
PATHOLOGY
DISTINCT

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MYC expression and translocation analyses in low-grade and transformed follicular lymphomaFinal publisher's version, 892 KBLicence: Taverne

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Aukema, S. M., van Pel, R., Nagel, I., Bens, S., Siebert, R., Rosati, S., van den Berg, E., Bosga-Bouwer, A. G., Kibbelaar, R. E., Hoogendoorn, M., van Imhoff, G. W., Kluin-Nelemans, H. C., Kluin, P. M., & Nijland, M. (2017). MYC expression and translocation analyses in low-grade and transformed follicular lymphoma. Histopathology, 71(6), 960-971. https://doi.org/10.1111/his.13316

@article{7b8150d7acea44279d91fc35449dcdc1,

title = "MYC expression and translocation analyses in low-grade and transformed follicular lymphoma",

abstract = "AimsLow-grade follicular lymphoma (FL) (grade 1/2, FL1/2) has an annual risk of transformation of approximate to 3%, which is associated with aberrations in CDKN2A/B, TP53, and MYC. As in diffuse large B-cell lymphoma, high MYC expression in transformed FL (tFL) might predict a MYC breakpoint.Methods and resultsWe quantified MYC expression by immunohistochemistry and digital analysis in 41 paired biopsies from 20 patients with FL1/2 with subsequent transformation and in four isolated biopsies of tFL. As controls, 28 biopsies of FL1/2 without transformation (median follow-up of 105 months) and nine biopsies of FL3A/B were analysed. In the 20 FL1/2-tFL pairs, MYC expression was significantly higher in tFL than in the initial FL1/2 biopsies (median 54% versus 6%; 7% in FL3A, and 35% in FL3B). MYC breaks (MYC-R) were detected in eight of 21 (38%) tFLs analysed by fluorescence in-situ hybridization (FISH), with a median MYC score of 86%. In two of the analysed tFL cases, the translocation was already detected in antecedent FL1/2. MYC partners were immunoglobulin (IG) loci in three of eight cases (one IGL, one IGH, and one IGK) and non-IG in five of eight cases (two PAX5, one BCL6, and two unknown). Of the eight MYC-R+ cases, six were BCL2+/MYC+ double-hit, one was BCL2+/BCL6+/MYC+ triple-hit, and one was MYC+ single-hit. All three IG-MYC+ cases showed a MYC expression level of >85%, whereas the five cases with a non-IG MYC partner had a wider range of expression (median 68%, range 13-86%). Among the 13 MYC-R- tFLs, two groups with almost dichotomous MYC expression could be observed (three cases showed 90% MYC expression), suggesting alternative mechanisms of MYC activation.Conclusionswe show an increase in MYC expression from FL1/2 to tFL. MYC breakpoints were present in approximate to 40% of the cases, which is markedly higher than in de novo DLBCL. MYC expression was uniformly high in cases with an IG-MYC translocation but much more heterogeneous and in part independent of the presence of a MYC break in non-IG-MYC and MYC-negative cases.",

keywords = "double-hit, follicular lymphoma, MYC, MYC translocation partner, transformation, B-CELL LYMPHOMA, BURKITT-LYMPHOMA, PROGNOSTIC-SIGNIFICANCE, CYTOGENETIC ALTERATIONS, C-MYC, REARRANGEMENTS, 8Q24, NEOPLASMS, PATHOLOGY, DISTINCT",

author = "Aukema, {Sietse M.} and {van Pel}, Roel and Inga Nagel and Susanne Bens and Reiner Siebert and Stefano Rosati and {van den Berg}, Eva and Bosga-Bouwer, {Anneke G.} and Kibbelaar, {Robby E.} and Mels Hoogendoorn and {van Imhoff}, {Gustaaf W.} and Kluin-Nelemans, {Hanneke C.} and Kluin, {Philip M.} and Marcel Nijland",

year = "2017",

month = dec,

doi = "10.1111/his.13316",

language = "English",

volume = "71",

pages = "960--971",

journal = "Histopathology",

issn = "0309-0167",

publisher = "Wiley",

number = "6",

}

TY - JOUR

T1 - MYC expression and translocation analyses in low-grade and transformed follicular lymphoma

AU - Aukema, Sietse M.

AU - van Pel, Roel

AU - Nagel, Inga

AU - Bens, Susanne

AU - Siebert, Reiner

AU - Rosati, Stefano

AU - van den Berg, Eva

AU - Bosga-Bouwer, Anneke G.

AU - Kibbelaar, Robby E.

AU - Hoogendoorn, Mels

AU - van Imhoff, Gustaaf W.

AU - Kluin-Nelemans, Hanneke C.

AU - Kluin, Philip M.

AU - Nijland, Marcel

PY - 2017/12

Y1 - 2017/12

N2 - AimsLow-grade follicular lymphoma (FL) (grade 1/2, FL1/2) has an annual risk of transformation of approximate to 3%, which is associated with aberrations in CDKN2A/B, TP53, and MYC. As in diffuse large B-cell lymphoma, high MYC expression in transformed FL (tFL) might predict a MYC breakpoint.Methods and resultsWe quantified MYC expression by immunohistochemistry and digital analysis in 41 paired biopsies from 20 patients with FL1/2 with subsequent transformation and in four isolated biopsies of tFL. As controls, 28 biopsies of FL1/2 without transformation (median follow-up of 105 months) and nine biopsies of FL3A/B were analysed. In the 20 FL1/2-tFL pairs, MYC expression was significantly higher in tFL than in the initial FL1/2 biopsies (median 54% versus 6%; 7% in FL3A, and 35% in FL3B). MYC breaks (MYC-R) were detected in eight of 21 (38%) tFLs analysed by fluorescence in-situ hybridization (FISH), with a median MYC score of 86%. In two of the analysed tFL cases, the translocation was already detected in antecedent FL1/2. MYC partners were immunoglobulin (IG) loci in three of eight cases (one IGL, one IGH, and one IGK) and non-IG in five of eight cases (two PAX5, one BCL6, and two unknown). Of the eight MYC-R+ cases, six were BCL2+/MYC+ double-hit, one was BCL2+/BCL6+/MYC+ triple-hit, and one was MYC+ single-hit. All three IG-MYC+ cases showed a MYC expression level of >85%, whereas the five cases with a non-IG MYC partner had a wider range of expression (median 68%, range 13-86%). Among the 13 MYC-R- tFLs, two groups with almost dichotomous MYC expression could be observed (three cases showed 90% MYC expression), suggesting alternative mechanisms of MYC activation.Conclusionswe show an increase in MYC expression from FL1/2 to tFL. MYC breakpoints were present in approximate to 40% of the cases, which is markedly higher than in de novo DLBCL. MYC expression was uniformly high in cases with an IG-MYC translocation but much more heterogeneous and in part independent of the presence of a MYC break in non-IG-MYC and MYC-negative cases.

AB - AimsLow-grade follicular lymphoma (FL) (grade 1/2, FL1/2) has an annual risk of transformation of approximate to 3%, which is associated with aberrations in CDKN2A/B, TP53, and MYC. As in diffuse large B-cell lymphoma, high MYC expression in transformed FL (tFL) might predict a MYC breakpoint.Methods and resultsWe quantified MYC expression by immunohistochemistry and digital analysis in 41 paired biopsies from 20 patients with FL1/2 with subsequent transformation and in four isolated biopsies of tFL. As controls, 28 biopsies of FL1/2 without transformation (median follow-up of 105 months) and nine biopsies of FL3A/B were analysed. In the 20 FL1/2-tFL pairs, MYC expression was significantly higher in tFL than in the initial FL1/2 biopsies (median 54% versus 6%; 7% in FL3A, and 35% in FL3B). MYC breaks (MYC-R) were detected in eight of 21 (38%) tFLs analysed by fluorescence in-situ hybridization (FISH), with a median MYC score of 86%. In two of the analysed tFL cases, the translocation was already detected in antecedent FL1/2. MYC partners were immunoglobulin (IG) loci in three of eight cases (one IGL, one IGH, and one IGK) and non-IG in five of eight cases (two PAX5, one BCL6, and two unknown). Of the eight MYC-R+ cases, six were BCL2+/MYC+ double-hit, one was BCL2+/BCL6+/MYC+ triple-hit, and one was MYC+ single-hit. All three IG-MYC+ cases showed a MYC expression level of >85%, whereas the five cases with a non-IG MYC partner had a wider range of expression (median 68%, range 13-86%). Among the 13 MYC-R- tFLs, two groups with almost dichotomous MYC expression could be observed (three cases showed 90% MYC expression), suggesting alternative mechanisms of MYC activation.Conclusionswe show an increase in MYC expression from FL1/2 to tFL. MYC breakpoints were present in approximate to 40% of the cases, which is markedly higher than in de novo DLBCL. MYC expression was uniformly high in cases with an IG-MYC translocation but much more heterogeneous and in part independent of the presence of a MYC break in non-IG-MYC and MYC-negative cases.

KW - double-hit

KW - follicular lymphoma

KW - MYC

KW - MYC translocation partner

KW - transformation

KW - B-CELL LYMPHOMA

KW - BURKITT-LYMPHOMA

KW - PROGNOSTIC-SIGNIFICANCE

KW - CYTOGENETIC ALTERATIONS

KW - C-MYC

KW - REARRANGEMENTS

KW - 8Q24

KW - NEOPLASMS

KW - PATHOLOGY

KW - DISTINCT

U2 - 10.1111/his.13316

DO - 10.1111/his.13316

M3 - Article

SN - 0309-0167

VL - 71

SP - 960

EP - 971

JO - Histopathology

JF - Histopathology

IS - 6

ER -

MYC expression and translocation analyses in low-grade and transformed follicular lymphoma

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Keywords

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