Sietse M Aukema1,2,3, Roel van Pel2,4, Inga Nagel1,5, Susanne Bens1,6, Reiner Siebert1,6, Stefano Rosati2, Eva van den Berg7, Anneke G Bosga-Bouwer7, Robby E Kibbelaar8, Mels Hoogendoorn9, Gustaaf W van Imhoff4, Hanneke C Kluin-Nelemans4, Philip M Kluin2, Marcel Nijland4. 1. Institute of Human Genetics, University Hospital Schleswig-Holstein, Campus Kiel/Christian Albrechts University Kiel, Kiel, Germany. 2. Department of Pathology & Medical Biology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands. 3. Institute of Pathology, Division of Haematopathology, University Medical Centre Schleswig-Holstein, Kiel, Germany. 4. Department of Haematology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands. 5. Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany. 6. Institute of Human Genetics, University of Ulm, Ulm, Germany. 7. Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands. 8. Department of Pathology, Pathology Friesland, Leeuwarden, The Netherlands. 9. Department of Internal Medicine, Medisch Centrum Leeuwarden, Leeuwarden, The Netherlands.
Abstract
AIMS: Low-grade follicular lymphoma (FL) (grade 1/2, FL1/2) has an annual risk of transformation of ≈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 RESULTS: We 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. CONCLUSIONS: we show an increase in MYC expression from FL1/2 to tFL. MYC breakpoints were present in ≈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.
AIMS: Low-grade follicular lymphoma (FL) (grade 1/2, FL1/2) has an annual risk of transformation of ≈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 RESULTS: We 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. CONCLUSIONS: we show an increase in MYC expression from FL1/2 to tFL. MYC breakpoints were present in ≈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.
Authors: Sietse M Aukema; Giorgio A Croci; Reiner Siebert; Wolfram Klapper; Susanne Bens; Kathrin Oehl-Huber; Rabea Wagener; German Ott; Andreas Rosenwald; Philip M Kluin; Eva van den Berg; Anneke G Bosga-Bouwer; Mels Hoogendoorn; Eva Hoster; Iris Bittmann; Inga Nagel; Eva M Murga Penas; Markus Kreuz; Julia Bausinger; Wilfried Belder; Ilske Oschlies; Martin J S Dyer; Sandrine Jayne Journal: Virchows Arch Date: 2021-02-02 Impact factor: 4.064
Authors: Henry Loeffler-Wirth; Markus Kreuz; Maria Schmidt; German Ott; Reiner Siebert; Hans Binder Journal: Cancers (Basel) Date: 2022-07-14 Impact factor: 6.575