A genetic profling guideline to support diagnosis and clinical management of lymphomas

Vol.:(0123456789) 1 3 Clinical and Translational Oncology https://doi.org/10.1007/s12094-023-03307-1 REVIEW ARTICLE A genetic profiling guideline tosupport diagnosis andclinical management oflymphomas MargaritaSánchez‑Beato1,2 · MiriamMéndez1,2,3 · MaríaGuirado2,4· LucíaPedrosa1 · SilviaSequero2,5 · NataliaYanguas‑Casás1 · LuisdelaCruz‑Merino2,6· LauraGálvez2,7· MartaLlanos2,8· JuanFernandoGarcía9 · MarianoProvencio1,2,10 Received: 27 June 2023 / Accepted: 9 August 2023 © The Author(s) 2023 Abstract The new lymphoma classifications (International Consensus Classification of Mature Lymphoid Neoplasms, and 5th World Health Organization Classification of Lymphoid Neoplasms) include genetics as an integral part of lymphoma diagnosis, allowing better lymphoma subclassification, patient risk stratification, and prediction of treatment response. Lymphomas are characterized by very few recurrent and disease-specific mutations, and most entities have a heterogenous genetic landscape with a long tail of recurrently mutated genes. Most of these occur at low frequencies, reflecting the clinical heterogeneity of lymphomas. Multiple studies have identified genetic markers that improve diagnostics and prognostication, and nextgeneration sequencing is becoming an essential tool in the clinical laboratory. This review provides a “next-generation sequencing” guide for lymphomas. It discusses the genetic alterations of the most frequent mature lymphoma entities with diagnostic, prognostic, and predictive potential and proposes targeted sequencing panels to detect mutations and copy-number alterations for B- and NK/T-cell lymphomas. Keywords Lymphoma· Next-generation sequencing· Diagnosis· Prognosis * Margarita Sánchez-Beato [email protected] 1 Servicio de Oncología Médica, Grupo de Investigación en Linfomas, Hospital Universitario Puerta de Hierro- Majadahonda, IDIPHISA, Madrid, Spain 2 Grupo Oncológico para el Tratamiento y Estudio de los Linfomas-GOTEL, Madrid, Spain 3 Servicio de Oncología Médica, Hospital Universitario Puerta de Hierro-Majadahonda, IDIPHISA, Madrid, Spain 4 Servicio de Oncología Médica, Hospital General Universitario de Elche, Alicante, Spain 5 Servicio de Oncología Médica, Hospital Universitario San Cecilio, Granada, Spain 6 Servicio de Oncología Médica, Facultad de Medicina, Hospital Universitario Virgen Macarena, Universidad de Sevilla, Instituto de Biomedicina de Sevilla (IBID)/CSIC, Seville, Spain 7 Unidad de Gestión Clínica Intercentros de Oncología Médica, Hospitales Universitarios Regional y Virgen de la Victoria, Málaga, Spain 8 Servicio de Oncología Médica, Hospital Universitario de Canarias, LaLaguna,Sta.CruzdeTenerife, Spain 9 Servicio de Anatomía Patológica, Hospital MD Anderson Cancer Center, Madrid, Spain 10 Servicio de Oncología Médica, Departamento de Medicina, Facultad de Medicina, Hospital Universitario Puerta de Hierro-Majadahonda, Universidad Autónoma de Madrid, IDIPHISA, Madrid, Spain Clinical and Translational Oncology 1 3 Introduction Mature lymphoid malignancies (Hodgkin (HL) and non- Hodgkin lymphomas (NHL)) are the most common hematological solid neoplasias. Thanks to the implementation of high-throughput molecular analysis, our knowledge of the molecular characteristics of lymphomas has been strengthened. Lymphoma classification is still mainly based on morphology, immunophenotype, and a few genetic characteristics. However, the new classifications of mature lymphoid neoplasms, the International Consensus Classification (ICC) of Mature Lymphoid Neoplasms [1] and the 5th World Health Organization (WHO) Classification of Lymphoid Neoplasms [2], have incorporated newly developed technologies to improve lymphoma classification and genetic alterations are now part of the criteria applied to lymphoma diagnosis. Standardizing these high-throughput techniques to enable their full and successful clinical application is ongoing, but much controversy persists about the sequencing approach. One of the most critical issues is the method of choice and the composition of the sequencing panel. An ideal panel should be helpful in diagnosis, prognostication, therapy selection, and monitoring but small enough to be broadly and uniformly used. The ability to sequence the whole exome or genome is growing steadily. Nevertheless, a custom panel is currently the most accessible option to broaden the applicability of this approach. These targeted panels enable the analysis of a small number of genes in greater depth, with increased sensitivity and at a lower cost. Amplicon or capture-based sequencing panels could be used. The capture-based ones enable detection not only of single nucleotide variations (SNVs) and indels (insertions and deletions) but also of copy-number alterations (CNAs) and some structural variants. However, the detection of structural alterations needs further improvement. Additionally, standardization of sample management, panel composition, sequencing procedures, bioinformatic analysis, and variant interpretation is essential to produce a useful clinical tool. This review aims to summarize the fundamental molecular characteristics of the various lymphoma types and to describe the genes relevant to each subtype that could be included in a massive sequencing or next-generation sequencing (NGS) panel. Mature B‑cell lymphomas Chronic lymphocytic leukemia Chronic lymphocytic leukemia (CLL) is a low-grade lymphoproliferative disorder characterized by the clonal proliferation and accumulation of mature, typically CD5 + B-cells within the blood, bone marrow, lymph nodes, and spleen [1–4]. More than 80% of CLL cases feature some cytogenetic abnormality and their detection by fluorescence insitu hybridization (FISH) stratify the patients into different risk groups [5]: deletion on the long arm of chromosome 13 (del(13q)), occurs in approximately 55% of cases [6, 7]; trisomy 12 is the second most frequent recurrent chromosomal aberration (10–20% of cases) [6, 8]; deletions on the long arm of chromosome 11 (del(11q)) are found in approximately 25% of chemotherapy-naïve patients with advanced disease and 10% of patients with early disease [9]; and deletion on the short arm of chromosome 17 (del(17p)) occurs in 5–8% of chemotherapy-naïve patients. Only the latter abnormality is considered a significantly negative prognostic factor [10–12]. Other frequent, recurrent abnormalities in CLL include 6q deletion (5%) and 2p gain (5–16%), among others [1, 13]. Somatic hypermutation (SHM) of the immunoglobulin heavy chain variable region (IGHV; < 98% similarity of the IGHV sequence, mutated CLL, M-CLL) confers a better prognosis than the absence of mutation (unmutated CLL, U-CLL) [5, 14, 15]. Recently, the mutation IGLV3-21R110 found in around 5–15% of CLL, can confer a poor prognosis, independently of the IGHV mutational status [16]. TP53 mutations are found in 4–37% of CLL cases. They may occur alone or, more frequently, in combination with del(17p). They have been associated with chemo-refractoriness and reduced overall survival (OS) [17, 18]. NGS studies have helped identify mutations in other genes with prognostic relevance, such as BIRC3, NOTCH1, SF3B1, MYD88, ATM, FBXW7, POT1, NFKBIE, CHD2, RPS15, IKZF3, ZNF292, ZMYM3, ARID1A, and PTPN11 [5, 19–22]. Richter transformation is defined as a transformation of CLL into aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL). These patients typically have a poor response to traditional chemotherapy than de novo DLBCL. Moreover, their pattern of mutations is different from that of DLBLC-not otherwise specified (NOS). The risk of Richter transformation has been associated with prior therapy, U-CLL, NOTCH1 mutations, del(17p) and del(11q) [23–25]. Mutations in BTK, PLCG2, and CARD11 have been associated with resistance to BTK inhibitors [26, 27], Clinical and Translational Oncology 1 3 whereas mutations in BCL2 have been linked to venetoclax resistance [28]. Therefore, choosing between immunochemotherapy and targeted therapies for CLL heavily depends on 17p/TP53 and IGHV status. Even though the treatment choice does not strictly require sequencing data, these data should be integrated into the decision and follow-up. As mentioned above, several genetic aberrations negatively impact prognosis, seem to confer a poorer response to conventional chemotherapy, and could be helpful when considering other treatment options based on BTK or BCL2 inhibition. An ideal NGS panel for CLL should integrate the detection of IGHV SHM, gene mutations and CNAs (Table1 and Fig.1). Lymphoplasmacytic lymphoma/Waldenström macroglobulinemia Lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) is an uncommon low-grade B-cell lymphoma, with an annual incidence of 3–4 cases per million people, characterized by bone marrow infiltration of clonal lymphoplasmacytic cells and the hypersecretion of immunoglobulin M [1, 2]. The lack of specific morphological, immunophenotypic, or chromosomal features requires the diagnosis to be made after excluding other small B-cell lymphomas. Despite its rarity, our understanding of the biology of this disease has improved significantly in recent years with the identification of recurrent mutations in the MYD88 and CXCR4 genes [29]. More than 90% of LPL/MW cases bear the MYD88L265P mutation. However, this is neither necessary nor specific for a diagnosis and can be seen in other B-cell lymphomas such as non-germinal center (GC) DLBCL, CLL, splenic marginal zone lymphomas, primary cutaneous DLBCL, leg type DLBCL, primary central nervous system DLBCL, or testicular DLBCL [30]. However, the co-occurrence of both mutations is highly suggestive of LPL/WM [31]. MYD88L265P triggers tumor-cell growth through BTK, a target of ibrutinib [32]. CXCR4 is mutated in 30% of patients with LPL/WM, is associated with shorter treatment-free survival, and confers resistance to ibrutinib [32–34]. Patients with MYD88 and CXCR4 mutations have important differences in disease presentation and response to therapy with ibrutinib: overall response rates are 100% for those with MYD88L265P and without CXCR4, 85.7% for patients with both mutations and 71.4% for those without any mutation [32]. Other reported genetic alterations include deletion of 6q (40–60% of cases), mutations in PRDM2 and BTG1 (approximately 90% of cases), HIVEP2, MKLN1, PLEKHG1, LYN, ARID1B, FOXP1, and ARID1A [32]. Molecular mutational diagnostic approaches, especially NGS, have helped refine the diagnostic criteria for LPL/WM. Molecular testing can be used for risk stratification and treatment planning of LPL/ WM, beyond diagnostic purposes (Table1 and Fig.1). Marginal zone lymphoma Marginal zone lymphomas (MZLs) constitute a group of indolent B-cell lymphomas that arise from B lymphocytes in the marginal zone. They mainly compromise splenic MZL (SMZLs), with or without villous lymphocytes, nodal MZLs (NMZLs), and extranodal MZLs of mucosal-associated lymphoid tissue (EMZLs or MALTs). These are distinct clinical entities with specific diagnostic criteria and different genetic features, clinical behavior, and therapeutic implications [1, 2, 35]. MZLs account for approximately 10% of all NHLs derived from post-GC memory B-cells in the marginal zone of lymph nodes. The genomic landscape of MZL has been studied, revealing considerable overlap between mutated genes across distinct entities [1, 2, 36] (Table1 and Fig.1). The most widely mutated genes in SMZL are KLF2 and NOTCH2. Other frequent mutations affect TP53 and NOTCH1. Other mutations leading to NF-κB pathway activation involving TNFAIP3, CARD11, MYD88 (outside the p.265 hotspot), or TRAF3 have been reported alongside alterations in chromatin remodelers such as KMT2D, ARID1A, and SIN3A [37, 38]. More than 30% of splenic MZLs are characterized by the deletion of 7q31–32 [36, 37, 39, 40]. NMZL and SMZL have several common alterations. Trisomies of chromosomes 3 and 18 co-occur in around 25% of SMZL and NMZL cases. The mutational profile of NMZL shows other recurrent clonal abnormalities like trisomies 7 and 12, and 6qdeletion. Mutational analysis has identified mutations in KLF2, PTPRD, KMT2D, NOTCH2, LRP1B, TET2, and TNFRSF14. Other less frequent genetic alterations in NMZL include mutations in BRAF, EZH2, and HIST1H1E [38, 41]. The pathogenesis of EMZL/MALT is linked to several recurrent chromosomal aberrations, such as trisomies of 3, 12, and 18, which are found in 20–30% of cases. EMZL also presents recurrent chromosomal translocations. The most common is t(11;18)(p21;q21), which results in a functional chimeric fusion product between BIRC3 and MALT1 [36, 42]. It is associated with a low probability of response to antibiotics, Helicobacter pylori-negative, more advanced disease, and a lower risk of transforming to DLBCL. This translocation is specific for EMZL, since it has not been reported in SMZL or NMZL. Other common translocations are t(3;14)(p14;q32) (FOXP1::IGH), which is found in around 10% of EMZL cases; t(14;18)(q32;q21) (IGH::MALT1), which is present in 15–20% non-gastroin- testinal EMZLs; and t(1;14)(p22;q32) (BCL10::IGH), which is a rare translocation found in 1–2% of EMZLs [1, 2, 43]. Clinical and Translational Oncology 1 3 Table 1 Summary of genetic alterations in B-cell lymphomas and their clinical utility B-cell Lymphoma Genetic alterations Clinical significance Refs. Chronic lymphocytic leukemia (CLL) IGVH SHM, Del(17p)/TP53, Del(11q), Del(13q), trisomy 12, NOTCH1, SF3B1, ATM, BIRC3, NFKBIE, EGR2, MYD88, XPO1, CHD2 DIAGNOSTIC/PROGNOSTIC [5, 15, 17, 19, 22] BTK, PLCG2, BCL2, TP53, CARD11 PREDICTIVE [26–28] Lymphoplasmacytic lymphoma (LPL) MYD88L265P#, CXCR4 DIAGNOSTIC/PROGNOSTIC/PREDICTIVE [29, 32, 33] Marginal zone lymphoma (MZL) Spleenic MZL KLF2, NOTCH2, TP53, NOTCH1, MLL2, ARID1A, SIN3A, TNFAIP3, MYD88, CARD11, trisomies 3, 18, Del(7q) DIAGNOSTIC [35, 37, 40] Nodal MZL KLF2, NOTCH2, KMT2D, PTPRP, trisomies 3, 18, 7, 12 DIAGNOSTIC [38, 41] Extranodal MZL trisomies 3, 18, 12, T(11;18)#, T(1;14), T(3;14), T(14;18) (IGH::MALT1); TNFAIP3, CD79A, CD79B, CARD11, BIRC3, TRAF3, TNFRSF11A DIAGNOSTIC/PROGNOSTIC(m7-FLIPI)/ THERAPY [42–45] Follicular lymphoma (FL) FL T(14;18); KMT2D, EZH2*#, CREBBP#, EP300#, MEF2B#, ARID1A#, FOXO1#, CARD11# DIAGNOSIS/PROGNOSTIC#/THERAPY* [54, 56] NOTCH2, DTX1, UBE2A, HIST1H1E, MYC, TP53, CCND3, GNA13, S1PR2, P2RY8, POU2AF1, CDKN2A/B loss PROGNOSTIC (HT) [58–61] Diffuse FL TNFRSF14, STAT6, CREBBP, EZH2 DIAGNOSTIC [47] Pediatric TFL TNFRSF14, MAP2K1 DIAGNOSTIC [50] Duodenal type FL TNFRSF14, CREBBP, EZH2 DIAGNOSTIC [49] Mantle cell lymphoma (MCL) T(11;14), CCND2 and CCND3 rearr DIAGNOSTIC [1, 2] IGVH SHM, Del(17p)/TP53, ATM, NOTCH1/2, KMT2D PROGNOSTIC [64] Del(17p)/TP53, BIRC3, TRAF2, NSD2, CARD11 PREDICTIVE [66–68] Diffuse large B-cell lymphoma, not otherwise specified (DLBCLNOS) NOTCH2, BCL10, TNFAIP3, UBE2A, CD70, CCND3, DTX1, BCL2, EZH2, CREBBP, TNFRSF14, KMT2D, IRF8, EP300, GNA13, MYD88, CD79B, PIM1, PIM2, PRDM1, BTG1, CD58, NOTCH1, SGK1, SOCS1, TET2, STAT3, TP53; MYC rear., BCL2 rearr., BCL6 rear DIAGNOSTIC/PROGNOSTIC [73–77] Large B-cell lymphoma with IRF4 rearrangement IRF4 rear, IRF4, CARD11, MYD88, CD79B DIAGNOSTIC [69] Large B-cell lymphoma with 11q aberration 11q aberration, GNA13 DIAGNOSTIC [83] High grade B-cell lymphoma (HGBCL) HGBCL-DH-BCL2 MYC rear., BCL2 rear., BCL2, KMT2D, CREBBP, TNFRS14, EZH2 DIAGNOSTIC/PROGNOSTIC [1, 2] HGBCL-DH-BCL6 MYC rear., BCL6 rear DIAGNOSTIC [1, 2] HGBCL-NOS MYD88, CD79B, TBL1XR1, TP53, KMT2D DIAGNOSTIC [1, 2] Clinical and Translational Oncology 1 3 Homozygous deletion of the chromosomal band 6q23, involving TNFAIP3 (A20), has been described in EMZL and may contribute to lymphomagenesis by inducing constitutive NF-κB activation [44]. MYD88 mutation is detected in ocular adnexal MALT lymphoma (5% of cases) and can activate NF-κB, STAT3, and AP1 transcription factors [43]. Apart from the mutations of TNFAIP3 and MYD88, other alterations in NF-κB regulators have been identified (CD79A, CD79B, CARD11, BIRC3, TRAF3, and TNFRSF11A) [43]. The result of the recurrent genetic alterations mentioned above in the activation of the NF-κB activation pathway represents a possible therapeutic target for MALT lymphomas [45]. Follicular lymphoma Follicular lymphoma (FL) is a malignancy derived from GC B-cells and the most common indolent B-cell lymphoma. It remains an incurable malignancy, but OS may last 20years [46]. A key hallmark of FL is the t(14;18)(q32;q21) IGH::BCL2 translocation, the first hit in its oncogenesis. Recently, the new WHO and ICC classifications, recognized unique FL entities, such as insitu follicular B-cell neoplasm, duodenal-type FL, primary cutaneous follicle cell lymphoma, pediatric-type FL, and testicular FL. A distinctive diffuse follicular lymphoma (dFL) variant lacking t(14;18) was first described in 2009 [47]. In a recent study, NGS analysis identified two molecular clusters: one was characterized by TNFRSF14 mutations, and the other showed few genetic alterations, a subgroup with STAT6 mutations concurrent with CREBBP mutations without TNFRSF14 and EZH2 mutations [48]. These findings suggest dFL might represent a subtype of t(14;18)-negative FL. Gastrointestinal FL, especially duodenal-type FL (DTFL), frequently occurs as extranodal FL. This lymphoma is commonly found in the second part of the duodenum and exhibits indolent clinical behavior. It is morphologically and immunophenotypically indistinguishable from typical FL. More widespread use of NGS has identified that the mutation frequencies of recurrently mutated genes, including TNFRSF14, CREBBP, and EZH2, were not significantly different from typical FL, but KMT2D was less commonly mutated in DTFL [49]. Pediatric-type FL (PTFL) occurs in younger patients and shows a preference for the head and neck. Some studies have used NGS technologies to describe a specific mutational profile in PTFL distinct from those of other lymphomas, including typical FL. TNFRSF14 and MAP2K1 are the genes most frequently reported to be mutated in PTFL. One or the other is present in about 80% of cases, but they do not usually cooccur. This finding indicates that both genes are essential for the pathogenesis of PTFL [50]. Table 1 (continued) B-cell Lymphoma Genetic alterations Clinical significance Refs. Burkitt Lymphoma (BL) EBV + MYC rear., MYC aSHM, CDKN2A, DDX3X DIAGNOSTIC [100, 101] TP53 PROGNOSTIC [102] EBV - MYC rear., TCF3, ID3, CDKN2A, DDX3X DIAGNOSTIC [100, 101] TP53 PROGNOSTIC [102] Hodgkin Lymphoma (HL) XPO1, EP300, CREBBP, TP53, B2M, NFKBIE, TNFAIP3, STAT3, STAT6, PTPN1, ITPKB, GNA13, ARID1A, KTM2D, IGLL5, CSFR2B, BTK FUTURE [108–110] The most relevant alterations are indicated in bold Del deletion; SHM somatic hypermutation; EBV Epstein–Barr virus; DH double hit; NOS not otherwise specified HT: Histological transformation; rear.: rearrangement. Refs.: references. The most relevant alterations are indicated in bold Clinical and Translational Oncology 1 3 In 2011, Morin et al. described frequent mutations of KMT2D and other chromatin-modifying genes (CMGs)[51]. These genes code for histone methyltransferases (EZH2, KMT2D) or histone acetylases (MEF2B, CREBBP, EP300) [30]. Alterations in these genes have been established as a central genetic hallmark of FL and are critical for determining GC and post-GC B-cell fate. The characteristic distinguishing FL from other B-cell Fig. 1 Mature B-cell malignancies: cell of origin and main genetic alterations. Schematic representation of B-cell maturation process throughout the germinal center from naïve B-cells to memory and plasma B-cells, and their derived mature B-cell lymphoma. The recently proposed genetic subtypes for DLBCL are represented in the lower part of the figure, with the genes defining each subtype and the relationship with the DLBCL COO classification. The most relevant mutated genes are indicated in the box associated with each subtype. U-unmutated; M-mutated; CLL chronic lymphocytic leukemia; MCL mantle cell lymphoma; FL follicular lymphoma; MZL marginal zone lymphoma; DLBLC diffuse large B cell lymphoma; BL Burkitt’s lymphoma; DH Double hit; HL Hodgkin lymphoma; LPL/WM lymphoplasmacytic lymphoma/Waldenström macroglobulinemia; FDC follicular dendritic cells; COO cell-of-origin; GCB germinal center B cell; ABC activated B cell Clinical and Translational Oncology 1 3 lymphomas is the high rate of mutations in CMGs. The KMT2D gene is the most recurrently mutated CMG in FL (72%), followed by CREBBP (∼65% of FLs) and EP300 (15%) [52, 53]. Mutations of EZH2 are found in 25% of FLs; it has prognostic relevance and is currently investigated as a druggable target of therapeutic potential. EZH2 is a regulator of the GC phenotype, and mutations in this gene block B-cells and stop their differentiation into plasma cells. Therapeutic targeting of epigenetic deregulation is an attractive concept. However, the most common CMG mutations (KMT2D and CREBBP) are loss of function/loss of protein events, which are difficult to target with drugs. This constraint has led researchers to focus on EZH2 mutations, with various companies developing inhibitors for EZH2 [54]. In a recent phase II study, tazemetostat, an oral inhibitor of EZH2, showed anti-tumor activity in patients with relapsed or refractory FL. Patients with or without mutations in EZH2, received tazemetostat and objective responses were observed in 69% of patients with mutated EZH2, and 35% of patients with wild-type EZH2 [55]. The Follicular Lymphoma International Prognostic Index (FLIPI) is the most widely used risk predictor. For failurefree survival, Pastore etal. proposed a clinicogenetic risk model, the m7-FLIPI score, which included the mutational status of seven genes (ARID1A, EZH2, EP300, FOXO1, MEF2B, CREBBP and CARD11), the Eastern Cooperative Oncology Group (ECOG) performance status and FLIPI [56]. m7-FLIPI defined a high-risk group with a 5-year failure-free survival rate of 38%, compared with 77% for the low-risk group, in patients who received first-line treatment with a combination of rituximab and chemotherapy (CVP or CHOP). But low-risk m7-FLIPI does not indicate a more indolent disease course, as all patients required chemotherapy. However, several studies concluded that the prognostic value of the m7-FLIPI clinicogenetic model seems to be dependent on the therapeutic regimen [57] (Table1 and Fig.1). Histological transformation (HT) is reported to occur in 15–30% of patients with FL. HT refers to the evolution of an FL to a clinically aggressive lymphoma, such as DLBCL or Burkitt lymphoma, which is usually associated with poor prognosis and chemotherapy resistance. HT has been associated with alterations deregulating cell-cycle progression and DNA-damage responses (CDKN2A/B, MYC, and TP53) [58, 59], or other genes more commonly mutated in transformed samples than in FL tumors (CCND3, GNA13, S1PR2, and P2RY8) [60]. A study of FL samples from patients who did or did not transform discovered that the presence of mutations in four genes (NOTCH2, DTX1, UBE2A, and HIST1H1E) [61] was associated with a shorter time to transformation when mutated in the FL biopsies at diagnosis. This study also identified mutated genes enriched at transformation, like POU2AF1, which has roles in GC architecture and migration [61]. Mantle cell lymphoma Mantle cell lymphoma (MCL) accounts for about 6% of NHL cases. The disease has two clinical presentations: common conventional MCL (cMCL) (90% of patients), which usually has an aggressive clinical course (SOX-11-positive cells and an unmutated IGHV), and an indolent clinical presentation (10% of patients), which generally presents as nonnodal leukemic phase (nnMCL) (SOX-11-negative, mutations of CCND1 and TLR2, and somatic hypermutation of IGHV) (2,3). MCL is typically an aggressive and incurable B-cell malignancy, but some patients may follow an indolent clinical course. MCL is characterized by the t(11;14)(q13;q32) translocation, leading to the overexpression of Cyclin D1 (CCND1), which is detected in nearly 95% of cases. Although the detection of CCND1 helps support an MCL diagnosis in unclear mature B-cell neoplasms, FISH is the current gold standard assay used to identify recurrent cytogenetic alterations, although this methodology may not detect complex or cryptic rearrangements [62, 63]. The few cases without this characteristic CCDN1 rearrangement are characterized by CCND2 or CCND3 translocations [1]. Some studies have identified significantly mutated genes such as ATM, and the tumor suppressor TP53, but also found NOTCH2 mutations in aggressive tumors with a worse prognosis [64]. MIPI (MCL International Prognostic Index) is based on a weighted sum of performance status, age, lactate dehydrogenase (LDH) levels and white blood cell count. Additional modifications, such as “MIPI genetic” (MIPIg), are being explored to refine this score. MIPIg is associated with an increased risk of progression and death when mutations of KMT2D and deletion or mutation of TP53 are present [65]. At diagnosis, the frequency of TP53 mutations is about 11–25% but increases to 45% at relapse. TP53 deletion (determined by FISH) and TP53 mutations were associated with the worst survival [66] (Table1 and Fig.1). Ibrutinib-refractory MCL patients exhibit poor survival and lack an optimal management strategy. Some studies have investigated the relationship between mutations in BIRC3, TRAF2, and CARD11 genes, MCL progression, and ibrutinib resistance [67]. Recently, a study explored the mutational profile in a subset of patients who developed disease progression or disease transformation on ibrutinib treatment. Using targeted NGS, they detected TP53 alterations in 75% of patients after progression on ibrutinib. They found mutations in chromatin-modifier genes, such as NSD2 in 75% of patients with transformed MCL on ibrutinib therapy. They concluded that NSD2 mutations are involved in altered Clinical and Translational Oncology 1 3 methylation and chromatin dysfunction, leading to aberrant gene expression with pathological significance in MCL progression and ibrutinib resistance [68]. Diffuse large B‑cell lymphoma DLBCL is the most common subtype of NHL (30–35% of cases), characterized by large mature B-cell morphology and phenotype [1, 2]. DLBCL is heterogeneous in its clinical behavior and pathological and molecular diagnosis. The most common type of DLBCL (80%) is DLBCLNOS, which has no specific clinical presentation or pathology. Three molecular subtypes have been recognized by the WHO classification based on the cell of origin (COO): germinal center (GCB), activated B-cell (ABC) or non-GCB, and unclassifiable DLBCL [1, 69]. This classification has a prognostic value, with ABC-DLBCL associated with poorer outcomes [70]. However, the COO does not imply different treatments, R-CHOP (rituximab, cyclophosphamide, adriamycin, vincristine and prednisone) being the backbone of therapy for all subtypes [71]. Up to 40% of DLBCLs will be refractory to first-line treatment or will recur [72]. Several researchers have recently proposed new genetic groups with broad concordance, suggesting that mutational analysis could be a promising alternative to classify DLCBL with prognostic and theragnostic values [1, 2, 73–76]. Each genetic cluster harbors a distinct mutational profile. Schmitz etal. defined the following subtypes: MCD (co-occurrence of MYD88L265P and CD79B mutations), BN2 (with BCL6 fusions and NOTCH2 mutations), N1 (NOTCH1 mutations), EZB (EZH2 mutations and BCL2 translocations), A53 (TP53 mutations and deletions) and ST2 (SGK1 and TET2 mutations) [73, 74]. In parallel, another approach distinguished five subsets of DLBCL, including two ABC-DLBCL groups, one with low risk and a possible marginal zone origin (C1), and the other a high-risk group (C5) enriched in cases with mutations in MYD88, CD79B, and PIM1; two subsets of GC-DLBCLs with favorable (C4) and poor (C3) outcomes, and an ABC/GC-independent group (C2) with biallelic inactivation of TP53, CDKN2A loss, and associated genomic instability [75]. To unify both classifiers, Lacy etal. established the subtypes NOTCH2, MYD88, BCL2, TET2/SGK1, and SOCS1/SGK1, according to the mutated genes that are most highly enriched in each one[76]. However, all these studies are mainly based on whole-genome sequencing and are not applicable in routine clinical practice. Hence, some efforts have been made to propose easy and feasible classifiers built with a combination of mutational and translocation data of a selected set of genes representing each genetic subtype [77, 78]. A consensus may soon be reached to develop an NGS panel for assigning genetic groups (Tables1 and 2, and Fig.1).). To move towards personalized medicine, it should include at least the analysis of the MYC, BCL2, and BCL6 rearrangements, COO determination at diagnosis, and the chosen NGS panel. Although there is no agreement about the classification of the genetic subtypes, an adequate preliminary NGS panel could be designed, including a set of common genes from the genetic classifiers: MYD88, CD79B, PIM1, PIM2, PRDM1, BTG1, CD58, ETV6, and TBL1XR1 for the MCD subtype; NOTCH2, TNFAIP3, BCL10, UBE2A, CD70, CCND3, and DTX1 for the BN2 subtype; EZH2, CREBBP, TNFRSF14, KMT2D, BCL2, IRF8, and EP300 for the EZB subtype; SGK1, SOCS1, TET2, NFKBIA, and STAT3 for the ST2 subtype, and NOTCH1 for the N1 subtype [77, 78]. Extranodal DLBCL cases arising in immune-privileged sites, such as primary DLBCL of the central nervous system (PCNSL), primary DLBCL of the testis, primary cutaneous DLBCL, leg type, and other related entities, such as breast DLBCL [79], have similar molecular features and there are some recent controversies about their classification [1, 2]. Most of the lymphomas in these locations are non-GCB/ ABC type and seem to share common molecular features Table 2 DLBCL genetic subtypes Integration of the genetic subtypes described by Wright [74], Chapuy [75], and Lacy [76] and their relation to the cell-or-origin and patient clinical outcome COO cell-of-origin; ABC activated B-cell; GCB germinal center B-cell; DH double hit; rear. rearrangement Genetic types Subtypes Main alterations COO Clinical outcome [73–77] MCD/C5/MYD88 MYD88L265P, CD79B, PIM1, PRMD1, BTG1. CD58 ABC Bad prognosis BN2/C1/NOTCH2 BCL6 rear., NOTCH2, BCL10, TNFAIP3, CD70, SPEN, CCND3, UBE2A, DTX1 ABC / GCB Intermediate prognosis EZB/C3/BCL2 EZB BCL2 rear., BCL2, EZH2, CREBBP, IRF8, KMT2D, TNFSR14, EP300. MYC rear GCB Good prognosis EZB-MYC DH Bad prognosis N1/NEC NOTCH1 Mostly ABC Bad prognosis A53/C2/NEC TP53, aneuploidy Mostly ABC Intermediate prognosis ST2/C4 SOCS1, TET2 & SGK1, STAT3, NFKBIE, BRAF, CD83 Mostly GCB Good prognosis Clinical and Translational Oncology 1 3 such as the high prevalence of MYD88L265P and CD79B mutations that characterize the DLBCL-MCD/C5/MYD88 genetic subtype. DLBCL associated with viral agents (EBV-associated, HHV-8-associated) are rare and, in most instances, their diagnosis is based on the clinical presentation and pathological features; a set of mutated genes possibly specific for this disease has been described in EBV-positive DLBCL, including CCR6, CCR7, DAPK1, TNFRSF21, CSNK2B and YY1 [80], as well as common PD-L1 genetic aberrations [81] Large B-cell lymphoma (LBCL) with the IRF4 rearrangement occurs most commonly in younger patients [1, 2]. It prefers the lymphoid tissue of Waldeyer’s ring and head and neck lymph nodes [82]. In a study with pediatric LBCL, the subtype with IRF4 rearrangement had a GCB phenotype with frequent mutations in IRF4 and NF-κB pathway genes (CARD11, MYD88, CD79B) [69]. LBCL with 11q aberration [1] (named “HGBCL with 11q aberrations” in the 5th WHO classification) [2] was classified as Burkitt-like lymphoma with 11q aberration in the previous WHO classification. The mutational pattern is more like that of GCB-DLBCL than Burkitt-like, lacks MYC rearrangements, and shows frequent mutations in GNA13. Genomic alterations affecting the ID3-TCF3 complex are quite exceptional in LBCL-11q [83]. High‑grade B‑cell lymphoma The recently revised 5th edition of the WHO Classification of Hematolymphoid Tumors and the ICC now recognize the following groups: high-grade B-cell lymphoma (HGBCL) with MYC and BCL2 rearrangements (with or without BCL6 rearrangement, HGBCL-DH-BCL2) [1, 2], a provisional entity with MYC and BCL6 rearrangements (HGBCL-DH- BCL6) [1] and HGBCL-NOS. The mutational findings in the HGBCL-DH-BCL2 lymphoma subtype are relatively homogeneous and similar to those of FL, harboring frequent molecular abnormalities in BCL2, KMT2D, CREBBP, TNFRS14, and EZH2. Several recent studies described DLBCL cases with a gene expression signature (GEP) similar to that of HGBCL (DH-like GEP signature) [84–86] and have frequent mutations in MYC, BCL2, DDX3X, TP53, and KMT2D [85] (Table1 and Fig.1). Lymphoid neoplasms with dual MYC and BCL6 rearrangements are now considered a subtype of DLBCLNOS, or HGBCL, and their gene expression profiles are highly heterogeneous and unrelated to those of DLBCL/HGB-cell lymphomas with MYC and BCL2 rearrangements. HGBCL-NOS is recognized as another subtype and covers cases that cannot be included in the other entities. From a molecular perspective, it is a heterogeneous category that includes activated B-cell lymphomas with mutations of MYD88, CD79B, or TBL1XR1. The most frequent mutations are found in TP53 and KMT2D. Gene-expression profiling showed that approximately half the cases of HGBCL-NOS harbor the previously described DH-like GEP signature [85–87]. Burkitt’s lymphoma Burkitt’s lymphoma (BL) is a highly aggressive mature B-cell NHL characterized by rapid proliferation [1, 2, 88]. It accounts for 1–2% of adult lymphomas, whereas it is a common pediatric neoplasm [89]. Historically, three BL clinical variants have been described and are currently recognized by the WHO classification: endemic, non-endemic or sporadic, and immunodeficiency associated. The three subtypes present identical morphological and immunophenotypical features but are clinically and epidemiologically different [1, 2, 90]. All clinical variants share pathological features. A defining feature of BL is the constitutive overexpression of MYC due to a translocation of this oncogene along with one of the three immunoglobulin genes located on chromosomes 14, 2 and 22, accounting for nearly 80%, 15%, and 5% of cases, respectively. Other typical lymphoma translocations, such as BCL2 and BCL6, do not occur in this entity [2, 88]. However, MYC deregulation is not sufficient for lymphomagenesis. Therefore, other genetic alterations are commonly detected by next-generation techniques [91, 92]. Distinguishing BL from other HGBCLs is an important challenge in clinical practice that must be addressed. Gene expression profile studies have revealed a distinct BL signature, making it an independent entity [93–95]. Examining the BL genetic landscape, several studies have demonstrated that ID3/TCF3-dependent centroblast gene expression program, tonic PI3K-AKT-mTOR signaling, and cell cycle deregulation and apoptosis are essential mechanisms for BL lymphomagenesis. Inactivating mutations in tumorsuppressor genes, such as TP53, CDKN2A, and DDX3X, are recurrent in BL [92, 96, 97]. Moreover, TP53 inactivation has been reported as a potential prognostic biomarker because these mutations were enriched in refractory patients [96]. 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