ena-STUDY-The Maria Sklodowska-Curie National Research Institute of Oncology-02-02-2021-10:32:51:487-507
Cryptic MYC insertions in Burkitt lymphoma: New data and a review of the literature
Burkitt lymphoma (BL) is a highly aggressive B-cell lymphoma and is the fastest growing human tumor. The genetic hallmark of BL  is the MYC rearrangement (MYCR). This aberration is present  in near all BL cases, mainly as a result of chromosomal translocation t(8;14)(q24;q32), less often as a variant translocations t(2;8)(p12;q24) or t(8;22)(q24;q11) (Bertrand et al., Bernheim et al.,  Kaiser-McCaw B et al.). The molecular consequence of  these translocations is deregulated expression of the MYC oncogene. Deregulated expression arises as a result of juxtaposition of the MYC to the enhancer elements of one of the immunoglobulin (IG) genes: the IGH (14q32), the IGK (2p12) or the IGL (22q11) (Shiramizu B et al.). Recent study have described lymphomas, which morphologically and phenotypically resemble BL but without the MYCR instead with unique chromosome 11q aberrations (11q gain/loss).  For these lymphomas, the term „Burkitt-like lymphoma with 11q aberration” (BLL,11q) was proposed as a new provisional entity in the Revised 4th Edition of the World Health Organization (WHO) classification of Tumors of Hematopoietic and Lymphoid Tissues (Swerdlow S et al, 2016). Some rare cases with 11q gain/loss have also the MYCR (BL, MYCR /11q)  and are diagnosed as BL or high-grade B-cell lymphoma, not otherwise specified (HGBL,NOS) or even double hit lymphoma (DHL) (Grygalewicz et al, 2017 Rymkiewicz G et al, 2018). The MYCR is also observed in other aggressive mature B-cell lymphomas (BCL) as HGBLs and diffuse large B-cell lymphomas (DLBCL).Breakpoints of the MYC are widely dispersed on the  large > 1 Mb region, and depend on lymphoma subtype and translocation partner. In sporadic BL (sBL) with the MYC- IGH fusion, breakpoints of the MYC are mapped within the MYC  or immediately 5' to the MYC, and very rare 50-350 kb 3' of the MYC (Cory S, 1986;  Haralambieva E, 2004). On the other hand, most breakpoints within the IGH region are located within switch regions and only a minority within the joining locus (Busch K, 2007).In almost all BLs, and other BCLs, the MYC-IGH is a result of karyotypically  visible translocation. However, there are few literature data regarding cryptic MYC insertion  in lymphomas (May PC, 2010; Haralambieva 2004; Peterson JF , 2019; King RL 2019; Wagener R, 2020).Phenomenon of the MYC insertion seems to be very rare, however detection of every type of the MYCR is important in the diagnosis of BCL, particularly in the proper diagnosis of BL. Recently we showed significant differences between MYC-positive BL and MYC-negative BLL,11q in the expression of CD38 by flow cytometry (FCM), that may contribute to the differential diagnosis between BL and BLL,11q and other MYC-positive BCL (Rymkiewicz G et al 2018).We herein present two cases of BL without typical, chromosomal  MYC translocations and without 11q alterations out of 108 patients with BL/BLL,11q diagnosis. In these cases, with clinicopathologic characteristics of classical BL, karyotypically invisible insertion of the MYC  into the IGH locus  or the IGH into the MYC region were detected and  we present molecular features of these fusions characterized by next  generation sequencing (NGS). We also confirm the rarity of cryptic MYC fusions in BL and BLL,11q patients with frequency of 1.9 % in patients with suspected BL diagnosis.  The authors also discuss the significant role of FCM evaluation of CD38 expression, in establishing the final diagnosis of BL with the MYCR/ insertion.
Burkitt lymphoma (BL) is a highly aggressive B-cell lymphoma and is the fastest growing human tumor. The genetic hallmark of BL  is the MYC rearrangement (MYCR). This aberration is present  in near all BL cases, mainly as a result of chromosomal translocation t(8;14)(q24;q32), less often as a variant translocations t(2;8)(p12;q24) or t(8;22)(q24;q11) (Bertrand et al., Bernheim et al.,  Kaiser-McCaw B et al.). The molecular consequence of  these translocations is deregulated expression of the MYC oncogene. Deregulated expression arises as a result of juxtaposition of the MYC to the enhancer elements of one of the immunoglobulin (IG) genes: the IGH (14q32), the IGK (2p12) or the IGL (22q11) (Shiramizu B et al.). Recent study have described lymphomas, which morphologically and phenotypically resemble BL but without the MYCR instead with unique chromosome 11q aberrations (11q gain/loss).  For these lymphomas, the term „Burkitt-like lymphoma with 11q aberration” (BLL,11q) was proposed as a new provisional entity in the Revised 4th Edition of the World Health Organization (WHO) classification of Tumors of Hematopoietic and Lymphoid Tissues (Swerdlow S et al, 2016). Some rare cases with 11q gain/loss have also the MYCR (BL, MYCR /11q)  and are diagnosed as BL or high-grade B-cell lymphoma, not otherwise specified (HGBL,NOS) or even double hit lymphoma (DHL) (Grygalewicz et al, 2017 Rymkiewicz G et al, 2018). The MYCR is also observed in other aggressive mature B-cell lymphomas (BCL) as HGBLs and diffuse large B-cell lymphomas (DLBCL).Breakpoints of the MYC are widely dispersed on the  large > 1 Mb region, and depend on lymphoma subtype and translocation partner. In sporadic BL (sBL) with the MYC- IGH fusion, breakpoints of the MYC are mapped within the MYC  or immediately 5' to the MYC, and very rare 50-350 kb 3' of the MYC (Cory S, 1986;  Haralambieva E, 2004). On the other hand, most breakpoints within the IGH region are located within switch regions and only a minority within the joining locus (Busch K, 2007).In almost all BLs, and other BCLs, the MYC-IGH is a result of karyotypically  visible translocation. However, there are few literature data regarding cryptic MYC insertion  in lymphomas (May PC, 2010; Haralambieva 2004; Peterson JF , 2019; King RL 2019; Wagener R, 2020).Phenomenon of the MYC insertion seems to be very rare, however detection of every type of the MYCR is important in the diagnosis of BCL, particularly in the proper diagnosis of BL. Recently we showed significant differences between MYC-positive BL and MYC-negative BLL,11q in the expression of CD38 by flow cytometry (FCM), that may contribute to the differential diagnosis between BL and BLL,11q and other MYC-positive BCL (Rymkiewicz G et al 2018).We herein present two cases of BL without typical, chromosomal  MYC translocations and without 11q alterations out of 108 patients with BL/BLL,11q diagnosis. In these cases, with clinicopathologic characteristics of classical BL, karyotypically invisible insertion of the MYC  into the IGH locus  or the IGH into the MYC region were detected and  we present molecular features of these fusions characterized by next  generation sequencing (NGS). We also confirm the rarity of cryptic MYC fusions in BL and BLL,11q patients with frequency of 1.9 % in patients with suspected BL diagnosis.  The authors also discuss the significant role of FCM evaluation of CD38 expression, in establishing the final diagnosis of BL with the MYCR/ insertion.